DOCTEUR DE L'UNIVERSITÉ DE BORDEAUX

THÈSE PRÉSENTÉE

POUR OBTENIR LE GRADE DE

DOCTEUR DE

L’UNIVERSITÉ DE BORDEAUX

ÉCOLE DOCTORALE

SPÉCIALITÉ :CHIMIE ORGANIQUE

Mme. Na LI

TITRE :NANOPARTICULES D’OR FONCTIONNELLES POUR LES APPLICATIONS BIOMEDICALES ET CATALYTIQUES

Sous la direction de : M. Didier ASTRUC

Soutenue le 26 Septembre 2014 Membres du jury : Mme Angela MARINETTI Directeur de recherche au CNRS Rapporteur M. Noël LUGAN Directeur de recherche CNRS Rapporteur Mme Marie-Hélène DELVILLE Directeur de recherche CNRS Examinateur M. Jacques ROBERT Professeur à l’Université de Bordeaux Examinateur M. Lionel SALMON Chargé de Recherche CNRS Examinateur M. Jaime RUIZ Ingénieur contractuel à l’ Université de Bordeaux Membre invité M. Didier ASTRUC Professeur à l’ Université de Bordeaux Directeur de thèse

Acknowledgement

First and foremost I would like to thank my supervisor Prof. Dr. Didier Astruc. It has been a great honor to be his Ph.D. student. He has taught me, both consciously and

un-consciously, how a good chemist is done. I appreciate all his contributions of time and ideas, making my Ph.D. experience productive and stimulating. The motivation,

enthusiasm and immense knowledge he has was contagious and motivational for my study. I also appreciate for the excellent example he has provided as a successful chemist and professor.

I would like to warmly thank Dr. Azzedine Bousseksou, a prestigious scientist, for his

precious administrative and scientific help that have greatly facilitated this thesis.

I would especially like to thank my reading committee members: Angela Marinetti and Noël Lugnan and the other three external members of my PhD defense committee,

Marie-Hélène Delville, Jacques Robert and Lionel Salmon, for their time, advice and insightful questions.

I am grateful for collaborations with María Echeverría, Dr. Pengxiang Zhao, Dr. Lionel Salmon and Dr. Roberto Ciganda, all of you have been there to efficiently and

kindly support me when I collected data for my Ph.D. thesis.

I am grateful to our group's engineer Jaime Ruiz who kept us organized and was always ready to help. The members of the Astruc group, Amalia, Yanlan, Christophe,

Changlong, Haibin, Dong, and Sylvain have contributed immensely to my personal and professional time at University of Bordeaux. You are going to be the best memories of my Ph.D. experience.

I gratefully acknowledge the funding support from the China Scholarship Council for

my 3 years of Ph.D. The University of Bordeaux, the CNRS and L’Oréal are gratefully acknowledged.

Table of Content

Introduction………………………………………………………...…………………………1

Chapter 1: Review of the state of the Art in the synthesis of AuNPs………………...……3

Chapter 2: Carborane-functionalized AuNPs for potential boron neutron capter therapy

applications………………………………………………………………….……………….33

Chapter 3: Triazole-stabilized AuNPs and their Applications………….……………..…45

Part A: How a simple „„clicked‟‟ PEGylated 1,2,3-triazole ligand stabilizes gold

nanoparticles for multiple usage……………………………………………………47

Part B: “Click” Chemistry Mildly Stabilizes Bifunctional Gold Nanoparticles for Sensing

and Catalysis …………………………….……………………………….…………50

Part C: Stabilization of AuNPs by Monofunctional Triazole Linked to Ferrocene,

Ferricenium or Coumarin and Applications to Synthesis, Sensing and

Catalysis.......................................................................................................................57

Chapter 4: Dendrimer-stabilized AuNPs and their catalytic application for p-

nitrophenol reduction ………………………………………………………………………77

Part A: “Click” Synthesis of Nona-PEG-branched Triazole Dendrimers and Stabilization of

Gold Nanoparticles That Efficiently Catalyze p‑Nitrophenol Reduction………...…79

Part B: Gold nanoparticles as electron reservoir redox catalysts for the 4-nitrophenol

reduction: strong stereoelectronic ligand influence. ……………..…………….……87

Chapter 5: A bibliographical review of anisotropic AuNPs and their applications ….…91

Conclusion and Perspectives………………………………………………………………127

ANNEX: Synthesis and in vitro Studies of AuNPs Loaded with Docetaxel……………129

Publication list………………………………………...……………………………………140

Introduction

Gold nanoparticles (AuNPs) have emerged as a key field in nanoscience and nanotechnology

because of their potential applications in catalysis, [1] materials science, optical biosensors, [2]

as well as nanomedical diagnostics and therapeutics [3] due to their quantum-related and

supramolecular properties. [4] The Huisgen-type Cu(I)-catalyzed azide-alkyne cycloaddition

(CuAAC) reaction (“click” reaction) is the most efficient strategy to assemble 1,2,3-triazole

ring linking two molecular fragments together because of its atom economy, regioselectivity,

wide substrate scope and mild reaction conditions.[5] Moreover, the triazole group is

completely bio-compatible. The “Click” modification of AuNPs has been favorable in the

past few years.[6]

This thesis includes the design and synthesis of ligands based upon “click” reactions, the

preparation, stabilization and modification of gold nanoparticles (AuNPs), as well as the

characterizations and applications of functional AuNPs in view of these applications. AuNPs

were stabilized by either linear or dendritic thiolate ligand, triazolyl neutral ligands or

triazolyl dendrimers. Various useful functional groups such as carborane, ferrocene,

coumarin, cyclodextrin, and (or) polyethylene glycol (PEG) and many others were involved

and were anticipated to potentially undergo various applications based upon their diagnostics,

electrochemical, optical, supramolecular, encapsulating and catalytic properties. PEG species

were appreciated as one of the triazole substituents owing to not only its excellent

biocompatibility and enhanced permeability and retention (EPR) effect,[7] but also it

facilitatation of the solubilization of AuNPs in water. A series of water-soluble AuNPs were

prepared with narrow dispersity and long-term stability. The size and optical properties of

AuNPs were controlled to provide catalytic, optical (sensing) and potentially biomedical

applications (the latter ones in collaboration).

The first chapter of this thesis provides a review of the literature on the state of the art in

AuNP synthesis which systematically illustrates the preparation and stabilization of AuNPs

via different approaches, and the recent development of AuNPs.

The second chapter describes the functionalization of AuNPs by PEG and carborane via

“click” reactions. The water-soluble AuNPs that were obtained may have potential

applications in boron neutron capture therapy (BNCT) thanks to the exis tence of high boron

content materials, carborane, on the AuNP surface in wide-scale.

1

The third chapter displays the stabilization of AuNPs with “clicked” triazole neutral ligands in

aqueous solution or in organic solution. These AuNPs provide various applications in

catalysis, sensing and ligand-substitution according to the specific properties of AuNPs and

the functional groups. This chapter is further divided into three subsections.

The forth chapter includes two parts. The first part concerns the stabilization of AuNPs by

PEGylated nona-branched dendrimers in aqueous solution. The size of AuNPs appears to be

tunable. The dendritic structure influences both the morphology and the catalytic performance

of AuNPs. In the second part, the catalytic activities of various AuNPs are compared via

kinetic studies of 4-nitrophenol reduction.

The fifth chapter is a bibliographical review of the synthesis, applications and toxicity of

anisotropic gold nanoparticles including nanorods, nanowires, nanopolyhedros, nanoplates,

nanostars and nanoshells. The specific optical properties of these AuNPs are also detailed.

Anisotropic AuNPs have significant importance in theranostics (therapeutic + diagnostic) and

optical devices. They are at variance with spherical AuNPs studied in the previous chapters

and open the route to further possibilities concerning biomedical and sensing applications.

The last section of this thesis is the “conclusion and perspectives” summarizing the research

works in this thesis and the potential applications of functional AuNPs.

In the ANNEX of this thesis, a paper on the construction of a targeted anticancer drug

delivery system involving biocompatible AuNPs was presented.

References

(1) a) A. Corma, P. Serna, Science 2006, 313, 332. b) Haruta, M. Catalysis: gold rush. Nature

2005, 437, 1098-1099.

(2) C. M. Cobley, J. Chen, E. C. Cho, L. V. Wang, Y. Xia, Chem. Soc. Rev. 2011, 40, 44-56.

(3) a) S. Rana, A. Bajaj, R. Mout, V. M. Rotello, Adv. Drug Deliv. Rev. 2012, 64, 200-216. b)

S. E. Lohse, C. J. Murphy, J. Am. Chem. Soc. 2012, 134, 15607-15620.

(4) N. Li, P. Zhao, D. Astruc, Angew. Chem., Int. Ed. 2014, 53, 1756-1789.

(5) a) Meldal, M.; Tornoe, C. W.; Chem. Rev. 2008, 108, 2952-3015. b) Hein, J. E.; Fokin, V.

V. Chem. Soc. Rev. 2010, 39, 1302-1315.

(6) Boisselier, E.; Diallo, A. K.; Salmon, L.; Ornelas, C.; Ruiz, J.; Astruc, J. J. Am. Chem.

Soc. 2010, 132, 2729-2742.

(7) J. Fang, H. Nakamura, H. Maeda, Adv. Drug. Deliv. Rev. 2011, 63, 136-151.

2

Chapter 1

Review of the State of the Art in the Synthesis of AuNPs

3

1.1 Introduction

This introduction consists in a review paper containing over 420 references disclosing the

recent developments in the synthesis of gold nanoparticle. The synthesis of AuNPs is

introduced by different methods based on various ligands and AuNP structures. Publications

on AuNPs are abundant. Review papers on AuNPs that were published in recent years mainly

focused on the construction and applications of AuNPs, since AuNPs became a popular

material in nanomedicine and material science. Very few review papers summarized the

synthesis of AuNPs in the last decades. However, strategies on the preparations of AuNPs

developed fast, and thus it was necessary to disclose the state of the art of the preparation of

AuNPs. This review was organized in collaboration with Dr. Pengxiang Zhao, a former group

member who defended his PhD thesis in the University of Bordeaux in 2012.

4

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Coordination Chemistry Reviews 257 (2013) 638– 665

Contents lists available at SciVerse ScienceDirect

Coordination Chemistry Reviews

jo u r n al hom ep age: www.elsev ier .com/ locate /ccr

eview

tate of the art in gold nanoparticle synthesis

engxiang Zhao, Na Li, Didier Astruc ∗

SM, Univ. Bordeaux, 351 Cours de la Libération, 33405 Talence Cedex, France

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6392. In situ synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639

2.1. AuNPs stabilized by simple molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6392.1.1. Turkevich method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6392.1.2. Brust-Schiffrin method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6402.1.3. Schmid’s Au55 cluster and the phosphorus ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6442.1.4. Other ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646

2.2. Macromolecule-stabilized AuNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6463. Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6464. Dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646

4.1. Surfactants and reverse micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6484.1.1. Surfactant-stabilized AuNPs without reverse micelle formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6484.1.2. Surfactant-stabilized AuNPs with reverse micelle formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6494.1.3. Reverse micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6494.1.4. Liposomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651

4.2. Biosynthesis and “green chemistry” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6514.2.1. Natural-source extracts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6514.2.2. Chitosan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6514.2.3. Microbes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651

5. Seed-growth method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6515.1. Principle of the seed-growth method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6515.2. Spherical or quasi-spherical AuNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6535.3. Gold nanorods (AuNRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6535.4. Other shapes of AuNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656

6. Other AuNP synthetic methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6566.1. Pulse radiolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6566.2. Top-down methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6566.3. Supported AuNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657

6.3.1. Oxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6576.3.2. Carbon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6576.3.3. Mesoporous materials and MOFs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657

7. Bimetallic AuNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6587.1. Core@shell NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6587.2. Bimetallic alloy NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660

8. Conclusion and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661

r t i c l e i n f o a b s t r a c t

rticle history:eceived 10 July 2012ccepted 4 September 2012vailable online 20 September 2012

General principles and recent developments in the synthesis of gold nanoparticles (AuNPs) are reviewed.The “in situ” Turkevich-Frens and Brust-Schiffrin methods are still major synthetic routes, with citrateand thiolate ligands, respectively, that have been improved and extended to macromolecules includingbiomacromolecules with a large biomedical potential of optical and theranostic applications. Along this

∗ Corresponding author.E-mail address: [email protected] (D. Astruc).

010-8545/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ccr.2012.09.002

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dx.doi.org/10.1016/j.ccr.2012.09.002

P. Zhao et al. / Coordination Chemistry Reviews 257 (2013) 638– 665 639

Keywords:GoldNanoparticleClusterSeed-growthCore@shellThiolOxideDendrimerP

line, however, recently developed seed-growth methods have allowed a precise control of AuNP sizesin a broad range and multiple shapes. AuNPs and core@shell bimetallic MAuNPs loosely stabilized bynitrogen and oxygen atoms of embedding polymers and dendrimers and composite solid-state materialscontaining AuNPs with supports including oxides, carbons, mesoporous materials and molecular organicframeworks (MOFs) have attracted much interest because of their catalytic applications.

© 2012 Elsevier B.V. All rights reserved.

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olymer

. Introduction

Metal nanoparticles (NPs) have long been considered to exhibitnique physical and chemical properties different from those ofhe bulk state or atoms, due to the quantum size effect resultingn specific electronic structures [1–7]. Gold nanoparticles (AuNPs)re probably the most remarkable members of the metal NP groups8–11] and have attracted considerable interest and driven a vari-ty of potential applications in catalysis [12–21], biology [22–26],nd optics [27–29]. Indeed, more than 70,000 publications haveppeared on AuNPs to date. Here we are specifically focusing onhe principles and most recent improvements disclosed in the lit-rature on the synthesis of AuNPs of various types.

After the seminal report by Faraday in 1857 [8] of the reductionf a tetrachloroaurate solution by phosphorus in carbon disulfide (aiphasic reaction), the preparation of AuNPs with controlled sizesnd shapes has raised increased attention during the second half ofhe XXth century. The breakthroughs have been those by Turkevichn 1951 with the citrate method improved by Frens in 1973, thenn 1981 with Schmid’s report of a Au55-phosphine cluster and theotion of quantum dot, then by Mulvaney and Giersing in 1993ith the first synthesis and stabilization of AuNPs by thiolates,

nd finally by the Schiffrin group in 1994 with the report of thellustrious and most convenient Brust-Schiffrin biphasic methodf thiolate-stabilized AuNPs [9]. Sophistications of these methodsuring the last decade, especially the seed-growth synthesis, haveow led to promising applications.

AuNPs can be prepared by both “top down” and “bottom up”pproaches. For “top down” procedures, a bulk state Au is system-tically broken down to generate AuNPs of desired dimensions. Inhis case, particle assembly and formation is controlled by a pattern
r matrix. However, the “top down “method is limited concern-ng the control of the size and shape of particles as well as furtherunctionalization [30]. In contrast, in the “bottom up” strategy, the
Abbreviations: 9-BBN, 9-borabicyclo[3.3.1] nonane; AFM, atomic forceicroscopy; ATO, sodium bis(2-ethylhexyl) sulfosuccinate; AuNP, gold nanopar-

icle; AuNR, gold nanorod; CNT, carbon nanotube; CPA, cyclic phenylazomethine;TAB, cetyltrimethylammonium bromide; DENs, dendrimer-encapsulated nanopar-icless; DLS, dynamic light scattering; DSNs, dendrimer-stabilized nanoparticle;MAP, 4-(N,N-dimethylamino) pyridine; EDX, energy-dispersive X-ray; GMA,lycidyl methacrylate; GUVs, giant unilamellar vesicles; HADDF-STEM, high-ngle annular dark-field scanning transmission electron microscopy; HEPES,-2-hydroxyethylpiperazine-N-2-ethanesulphonic acid; HR-TEM, high-resolution

ransmission electron microscopy; LDI, laser desorption ionization; MALDI, matrix-ssistedlaser desorption ionization; MOCVD, metal organic vapor deposition; MOF,olecular organic framework; MRI, magnetic resonance imaging; NICISS, neutral

mpact collision ion scattering spectroscopy; NIPM, poly(N-isopropylacrylamide);IR, near infrared; NP, nanoparticle; PAAPHA, poly(acryloylaminophenylarsoniccid); PAMAM, poly(aminoamide) dendrimer; PCL, poly(caprolactone); PEG,oly(ethylene glycol); PEI, poly(ethylenimene); PEO, poly(ethylene oxide); PPO,oly(propylene oxide); PS, polystyrene; PVCL, poly(N-vinyl caprolactam); PVP,oly(vinyl pyridine); SDBS, benzenesulfonate; TAOB, tetra(octylammonium) bro-ide; TEM, transmission electron microscopy; TEG, tetra(ethylene glycol); THPC,

etrakis(hydroxymethyl) phosphonium chloride; TGA, thermogravimetric analysis;RD, X-ray diffraction.

6

formation of AuNPs originates from individual molecules, becauseit involves a chemical or biological reduction [31]. This chemicalreduction method involves two steps: nucleation and successivegrowth. When the nucleation and successive growth are completedin the same process, it is called in situ synthesis; otherwise it iscalled seed-growth method. For the in situ synthesis method, wewill focus on the preparation of spherical or quasi-spherical AuNPs.For the seed-growth method, we will concentrate on the prepa-ration of AuNPs having various sizes and shapes. In addition, wewill discuss methods of AuNP functionalization. This review is notcomprehensive, but it is limited to the essential and most usefulpreparation methods of AuNPs and their improvements, in partic-ular the most recent development.

2. In situ synthesis

In general, the preparation of AuNPs by chemical reductioncontains two major parts: (i) reduction using agents such as borohy-drides, aminoboranes, hydrazine, formaldehyde, hydroxylamine,saturated and unsaturated alcohols, citric and oxalic acids, polyols,sugars, hydrogen peroxide, sulfites, carbon monoxide, hydro-gen, acetylene, and monoelectronic reducing agents includingelectron-rich transition-metal sandwich complexes; (ii) stabiliza-tion by agents such as trisodium citrate dihydrate, sulfur ligands(in particular thiolates), phosphorus ligands, nitrogen-based lig-ands (including heterocycles), oxygen-based ligands, dendrimers,polymers and surfactant (in particicular cetyltrimethylammoniumbromide abbreviated CTAB). The in situ synthesized AuNPs are alsoused for the seedgrowth or further functionalization. In this section,we will review the various in situ methods and their improvements.

2.1. AuNPs stabilized by simple molecules

2.1.1. Turkevich method2.1.1.1. Citrate as both stabilizing and reducing agent. Among allthe in situ syntheses of AuNPs by reduction of HAuCl4, citrate-stabilized AuNPs has been regarded as the most popular ones for along time, since their introduction by Turkevich in 1951 [32]. TheHAuCl4 solution is boiled, and the trisodium citrate dihydrate isthen quickly added under vigorous stirring. After a few minutes,the wine-red colloidal suspension is obtained, and the AuNP size isabout 20 nm. In 1973, Frens [33] published an improvement, i.e.a broad size range of AuNPs (from 15 to 150 nm) was obtainedby controlling the trisodium citrate to Au ratio. However, parti-cles larger than 20 nm were always polydispersed. The histogramof size distribution could be readily determined by transmissionelectron microscopy (TEM).

Recently, several research groups have improved the Turkevich-Frens method in order to promote the convenient use of
citrate-stabilized AuNPs. In particular, the mechanism of AuNPsformation using this synthetic route has been examined in details[34–38]. Kimling et al. indicated that a high concentration ofcitrate more rapidly stabilizes AuNPs of smaller sizes, whereas a

6 mistry

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40 P. Zhao et al. / Coordination Che

ow concentration of citrate leads to large-size AuNPs and even tohe aggregation of AuNPs [34].

Remarkable research on the mechanism of the Turkevich-Frensethod in multiple-step process was published by Kumar’s group

37]. The initial step of this multiple-step process, with reactionsccurring in series and parallel, is the oxidation of citrate that yieldsicarboxy acetone. Then, the auric salt is reduced to aurous salt andu0, and the aurous salt is assembled on the Au0 atoms to form

he AuNP (Fig. 1). Thus, in theTurkevich-Frens method, the actualuNP stabilizer is dicarboxy acetone resulting from the oxidationf citrate, rather than citrate itself.

In addition, the presence of a citrate salt modifies the pH of theystem and influences the size and size distribution of the AuNPs38]. On this basis, nearly monodispersed AuNPs with sizes ran-ing from 20 to 40 nm have been synthesized upon variation of theolution pH [39–42]. Other improvements of the Turkevich methodnvolved the control of the reaction temperature [43], the introduc-ion of fluorescent light irradiation [44], and the use of high-powerltrasound [45,46]. Citrate-stabilized AuNPs are always larger than0 nm, due to the very modest reducing ability of trisodium citrateihydrate. An intriguing result from Puntes’s group [47] concerningitrate-stabilized AuNPs that appeared in 2010 is the use of D2O ashe solvent instead of H2O during the synthesis of AuNPs. As shownn Fig. 2, the size of the AuNPs was tailored to 5 nm. It was concludedhat D2O increased the reducing strength of citrate.

.1.1.2. Citrate as a stabilizing agent only. In general, citrate plays aole as a stabilizing agent with preparations of AuNPs requiring rel-tively high temperatures due to its weak reducing strength. Slotiscovered a new way to prepare AuNPs using a mixture of tan-ic acid/citrate solution whereby tannic acid plays the role of aeducing agent instead of citrate, and the AuNPs are obtained at0 ◦C [48]. Then Natan’s group introduced a method using citrates a stabilized agent only and NaBH4 as a reducing agent [49]. TheuNPs were obtained upon adding the NaBH4/citrate mixture into

he HAuCl4 solution at room temperature. With this method, theize of AuNPs is tailored to 6 nm, which compares with sizes beyond0 nm using the traditional Turkevich method.

.1.1.3. Reversed addition method. Very recently, another remark-ble modification of the Turkevich method involved the reversedrder of addition that was conducted by adding HAuCl4 to theitrate solution, producing monodispersed AuNPs with relativelymall size (less than 10 nm) [50,51].

In summary, the size of the citrate-stabilized AuNPs producedy in situ synthesis is between 5 nm and 150 nm. When theize is decreased, relatively monodispersed AuNPs are obtained,hereas when the size is increased (especially > 20 nm) polydis-ersed AuNPs are obtained. Citrate-stabilized AuNPs were also useds intermediates in further preparations or functionalizations suchs ligand substitution reaction and seed-growth-mediated synthe-es.

.1.2. Brust-Schiffrin method

.1.2.1. Synthetic procedure. Thiolate-stabilized AuNPs were firsteported by Mulvaney and Giersig [52]. These authors showed theossibility of using alkylthiols of various chain lengths to stabi-

ize AuNPs. The two-phase Brust-Schiffrin method, published in994, was the first method able to prepare the thiolate-stabilizeduNPs via in situ synthesis, and it has therefore met great suc-ess [53]. Its high impact is due to (i) facile synthesis in ambientondition; (ii) relative high thermal and air stability of the AuNPs
repared in this way; (iii) repeated isolation and re-dissolutionithout aggregation or decomposition; (iv) control of the small size
less than 5 nm) with narrow dispersity; (v) relatively easily func-ionalization and modification by ligand substitution. The AuNPs

7

Reviews 257 (2013) 638– 665

are stabilized by relatively strong Au-Sbonds, their diameters arein the 2–5 nm range, and their shapes are cuboctahedral and icosa-hedral. Due to the nucleation-growth-passivation kinetics modelby which the sulfur-containing agents inhibit the growth process[54,55], larger S/Au mole ratios give smaller average core sizes. FastNaBH4 addition and cooled solutions also produce smaller, moremonodispersed AuNPs. During the reaction of the thiol with grow-ing Au0NPs, the H atom of the thiol is lost, presumably by oxidativeaddition of the S H bond onto two contiguous Au0 atoms of theAuNP surface. The fluxional properties of the Au H bonds on theAuNP surface can provide the fast walking path of the H atomson the surface until two Au H bonds become contiguous for H2reductive elimination. Very recently, the formation surface Au Sbonds was shown using Raman spectroscopy by Li et al. who actu-ally demonstrated the overall mechanism including all the stepsof the Brust-Schiffrin AuNP synthesis. In particular, they disclosedthat, interestingly, these Au S bonds are formed only after addingNaBH4 as indicated in Fig. 3. This work brings about a key under-standing of the mechanism of this synthesis [56], while a previouswidely accepted assumption had been that the thiol reduced Au(III)to Au(I) and formed [Au(I)SR]n [57].

Given the above advantages, the Brust-Schiffrin method is nowmuch in use for the preparation and application on thiolate-liganded AuNPs [58–62]. Precise Au clusters have been synthesizedusing this method and purified (see Section 2.1.2.2). From thenomenclature point of view, it is best to call “clusters” such small“NPs” (smaller than 1 nm) that are precisely defined without poly-dispersity (single molecules) and to reserve the “NP” nomenclatureto the cases for which there is some dispersity (mixture of severalclusters), even if it is low [63].

The Brust-Schiffrin method was extended in 1995 to animproved procedure upon which the p-mercaptophenol-stabilizedAuNPs were synthesized in methanol solution without the phase-transfer agent TAOB [64]. In this way, the introduction of TAOBimpurities was avoided. Indeed, methanol is an excellent solvent fora single-phase system, because both HAuCl4 and p-mercaptophenolare soluble. Any thiol that is soluble in the same solvent as HAuCl4such as methanol, ethanol or water allows the use of a single-phase system for AuNP synthesis. In the following years, a varietyof publications concentrated on functional thiol ligand-stabilizedAuNPs using the single-phase procedure [54,55]. Brust’s groupprepared biocompatible and water-soluble AuNPs capped by (1-mercaptoundec-11-yl) tetraethylene glycol [65] with less than10 nm. Due inter alia to the hydrophobic alkanethiol interior andtetra (ethylene glycol) (TEG) hydrophilic shell, AuNPs are of greatbiomedical interest [66–68], in particular in the form of AuNPscapped with thiolated polyethylene glycols (PEGs) [69,70].

Very recently, a series of thiolate-stabilized AuNPs wereprepared by a modified single-phase method. Sardar andShumaker-Parry introduced 9-borabicyclo [3.3.1] nonane (9-BBN)as a mild reducing agent for the synthesis of a series of �-functionalized alkylthiolate-stabilized AuNPs [71]. Other thiolateligands such as bifunctional alkanethiolate [72–74], arenethiolate[75–79] and other functional thiolate-stabilized have been used tosynthesize functional AuNPs [80] from the corresponding thiols.

Quantum mechanical calculations have suggested that, ifheavier chalcogens (i.e. Se or Te) were used as the anchors,they would increase the conductance between the metal and theanchored ligand [81]. Thus, during the last decade, the synthesisof AuNPs with Se [82] or Te [83] ligand has been conducted withmodified Brust-Schiffrin procedures.

The strength of the reducing agent used in Brust-Schiffrin
method is much larger than that of citrate used in the Turkevichmethod, and according to Marcus theory the reaction rate in AuNPssynthesis using NaBH4 is much larger than that of the TurkevichAuNP synthesis using citrate reduction. A direct consequence is


using

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Fig. 1. AuNP synthesis

hat the size of the AuNPs synthesized using the NaBH4 reductants much smaller than that of Turkevich method using the citrateeductant.

.1.2.2. Purification of precise Au clusters from AuNPs. Variousethods of purification and isolation of precise Au clusters orono-dispersed AuNPs from crude AuNPs that are more or less

olydispersed mixtures of such clusters have been experimented.uNPs with precise number of Au atoms and ligands such asu140(SC6)53 (SC6 = hexanethiol) [84] and Au144(SCH2CH2Ph)60

85] have been synthesized using the Brust-Schiffrin method.urray’s group [63,86,87] has prepared Au25(SCH2CH2Ph)18 by aodified version of the Brust-Schiffrin procedure. In this synthesis,uCl4− was phase-transferred from water to toluene, reacted withSCH2CH2Ph, and then reduced by adding aqueous NaBH4. Therude product Aum(SCH2CH2Ph)n (between 1 and 2 nm) was puri-ed by precipitation. For instance, the clusters Au25(SCH2CH2Ph)18nd Au140(SCH2CH2Ph)53 were isolated from the crude producty precipitation in acetonitrile, Au25(SCH2CH2Ph)18 being sol-ble in acetonitrile unlike Au140(SCH2CH2Ph)53. The formationf [oct4N+][Au25(SCH2CH2Ph)18

−] was confirmed by 1H NMR,V–vis., and mass spectrometry, and the X-ray crystal structure

s illustrated in Fig. 4. Further, the yield was improved up to 50% byuning the temperature and duration of the various steps, and theormation of oxidized neutral Au25L18 was avoided.

The purification and separation of water-soluble thiolated 3-nmuNPs is possible according to Sweeney et al. [88]. In this procedure,

he solution of AuNPs is removed using a peristatic pump through diafiltration membrane. Small molecule impurities or small NPsre eluted in the permeate, while the large NPs are retained. Thexpanded view is that of a hollow-fiber-type diafiltration mem-rane depicting the elution of small impurities and NPs and theetention of larger particles.

Kornberg’s group [89,90] introduced the precipitation method
n order to obtain Au102(P-MBA)44 (MBA: p-mercaptobenzoic acid).he prepared P-MBA-protected AuNPs were precipitated by addi-ion of ammonium acetate or NaCl and methanol and then collectedn a microfuge by several centrifugation steps to yield purified
8

the Turkevich method.

Au102(P-MBA)44. This final Au cluster was characterized by SEM,MALDI-TOF MS, TGA and XPS.

2.1.2.3. Determination of the number of thiolate ligands. For thiolateligand-stabilized AuNPs, the surface ligand coverage is determinedusing theoretical and experimental methods. The most commonlyemployed theoretical method for spherical AuNPs is that of Leff andco-workers [91]. In their assumption, the thiolate ligands are close-packed on the AuNP spherical surface. It is also assumed that eachgold atom has a constant volume, vg = 17 A3, and each thiol occupiesan area of Ssulfur = 21.4 A2 on the surface, so that both the numberof Au atoms (nAu = 4�(R − ı)3/3vg, R − ı ≈ D/2) and the number ofthiolate ligands (nthiol = 4�(R − ı)2/Ssulfur) are obtained through asimple measurement of the AuNP diameter by TEM followed bystatistical calculations. For example, the average core diameter of2.7 nm AuNP results in 577 Au atoms and 103 thiol ligands at theperiphery [92].

Murray’s spherical AuNP-core model introduces a functionalrelationship between the thiolate ligand coverage (ratio of alka-nethiolates to surface Au atoms, �) and the mass fraction ofalkanethiolate (�organic) in the cluster with a given Au core radius(Eq. (1)) [93]. The surface ligand coverage is calculated using themeasurement of �organic by elemental and TGA analyses, and Rcore

by TEM or SAXS. It was pointed out that the calculated result ofspherical core was not very different [93] from those predictedfor the face-centered cubic cuboctahedral model that was deter-mined by Brust et al. [53] through the HRTEM measurement. As anexample, an AuNP with a core radius Rcore = 1.19 nm and coverage� = 0.66 contains 409 Au atoms and 126 alkanethiolate ligands ineach AuNP.

�↓organic = (4�(R↓core − R↓Au)↑)2(�↓HCP)((MW↓)thiol)�)/

(4�(R↓core − R↓Au)↑2(�↓HCP)/(MW)↓thiol − �

+ 4/(3)�R↓core↑3(�↓Au)(AW) (1)

In Eq. (1), �organic is the mass fraction of alkanethiolate in theAuNP, RAu is the crystallographic radius of a gold atom (0.145 nm),�HCP is the density of surface gold atoms (13.89 atoms/nm2,

642 P. Zhao et al. / Coordination Chemistry Reviews 257 (2013) 638– 665

Fig. 2. Optical (UV–vis. spectroscopy) and morphological (TEM) characterization of AuNPs synthesized using various solvents: 100% D2O (top), 50% D2O/H2O (middle), and100% H2O (bottom). Inset graphs in TEM images show the size distribution measurements of AuNPs. Inset images in UV–vis. spectra show the colors of the AuNPs solutions.T

R emic

amabm

atorFtbr

hese figures are representative of three separated experiments.

eprinted with permission from [47] (Puntes’s group). Copyright 2010 American Ch

ssuming hexagonal close packing), MWthiol is the alkanethiolateolecular weight in mass/molecule, � is the coverage (ratio of

lkanethiolates to surface Au atoms), �Au is the atom density ofulk gold (58.01 atoms/nm3), and AWAu is the Au atomic weight inass/atom.In previous work of our group [94], the thiolate ligand number

nd total gold atom number could be experimentally determinedhrough measurement of the AuNP core radius by TEM and therganic fraction determined by element analysis. The result was inelatively good agreement with the reports by Murray and Brust.
rom these various determination methods, it results that Leff’sheoretical method leads to an underestimation of the actual num-er of thiolate ligands. If the thiolated AuNPs are well washed toemove excess free thiol (a key condition), i.e. if the Au/S ratio
9

al Society.

is correctly provided by elemental analysis or thermogravimetricanalysis, the AuNP size determination by TEM leads to the correctnumber of AuNP ligands. The AuNP surface coverage by thiolateligands depends on the geometry and size and varies between onethiolate ligand per two surface Au atoms to 2 thiolate ligands per 3Au surface atoms.

2.1.2.4. Other sulfur ligands. Other sulfur ligands such as disulfides[95–100], xanthates [101], thioacetates [102], dithiocarbamates[103], trithiolates [104], benzenesulfonate (SDBS) [105], and thioc-
tic acid [106] have also been used in the synthesis of AuNPs via theBrust-Schiffrin two-phase method or ligand-substitution method.Some of these ligands bind less readily than thiolates to the AuNPcores of AuNPs [107–109]. However, an opposite view recently


metaR mical

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Fig. 3. Mechanism for chalcogenate-protectedeprinted with permission from [56] (Tong’s group). Copyright 2011 American Che

ndicated that alkanethioacetates stabilized-AuNPs were as sta-le as alkanethiol-stabilized AuNPs [102]. It is expected that thelkanethioacetate ligands stabilize AuNPs with loss of the S-acetyloiety and covalent attachment of the sulfur atoms as thiolates

o the Au surface. Due to the abundance of sulfur ligand in DNAr other proteins, the sulfur ligands stabilized AuNPs as the bio-robe have a broad used in DNA or protein detection and otherio-applications [95].

.1.2.5. Methods of functionalization.2.1.2.5.1. Reactions of AuNP-citrate with thiols. Due to the

eakness of the Au-citrate bonds, the citrate-stabilized AuNPs areasily functionalized upon substitution of the citrate ligands bytronger thiolate ligands; this substitution is experimentally veryimple and involves reaction of the precursor citrate-AuNPs withhe corresponding functional thiols under ambient conditions.ompared with the Brust-Schiffrin method of direct synthesis,he AuNPs prepared from AuNP-citrate are larger, which allowsotential applications of the latter in nanomedicine; therefore, thelasmon band [110], observed only for AuNPs larger than 2 nm, isey to the diagnostic. Mulvaney and Giersig initiated this methodo synthesize thiolate-stabilized AuNPs by substituting the citrateigands by thiolate ligands using the corresponding thiols [52].his research area is already largely developed, and Mirkin’s group
as used this strategy to load AuNPs with thiolated DNA [111]. Inddition, citrate-stabilized AuNPs have been functionalized withhiolated PEG, and the PEGylated AuNPs formed in this way haveeen used as contrast agent for in vivo X-ray computed tomography
ig. 4. (left) X-ray crystal structure of [oct4N+][Au25(SCH2CH2Ph)18−].16 The icosa-

edral Au13 core is surrounded by six Au2(SR)3 semi-rings that are slightly puckeredn the reduced AuNPs as shown for the semi-ring with more pronounced yellow andink colors (right). The icosahedral Au13 core (minus the center Au) is slightly dis-orted; the blue Au Au bonds lying directly below the center of each semi-ring aren average 0.12 A shorter than the yellow Au Au bonds (average 2.96 A). Overallu–Au average 2.93 A. Au13 core diameter 9.8 A; overall AuNP diameter 23.9 A.

eprinted with permission from [63] (Murray’s group). Copyright 2010Americanhemical Society.

10

l NP synthesis by the Brust-Schiffrin method.Society.

imaging [112]. Very recently, Daniel’s group [113] synthesizedrobust AuNP-cored nitrile- and amine-terminated dendrimers byreaction between 19.5-nm AuNP-citrate and poly(propyleneimine)dendronic thiols as efficient platforms for drug delivery (Fig. 5).

2.1.2.5.2. Brust-Schiffrin method with functional thiols. Sincethe seminal report by Brust et al. [64], it is known that some func-tional thiols can be used in the Brust-Schiffrin AuNP synthesis(Section 2.1.2.1) if the functional group of the thiol is compati-ble with the reactions conditions, in particular the reductant. Thisstrategy has thus been largely exploited. Recently, 16-mercapto-n-hexadecanoic acid-capped AuNPs were used for immobilizationonto silica [114]. Thiol-functionalized polymers or dendrimers arealso used to stabilize AuNPs via Brust-Schiffrin synthesis (see Sec-tions 2.2.1 and 2.2.2). The direct synthesis of AuNPs with functionalthiols sometimes avoids the aggregation that may result from thepost-functionalization method (Section 2.1.2.5.4).

2.1.2.5.3. Thiolate-thiol ligand substitution reaction: function-alization. The ligand-substitution reaction (occasionally called“place exchange” reaction) was first initiated by Murray’s groupwho substituted alkylthiolate ligands by functional alkyl thiolateligands using the corresponding functional thiols for the syn-thesis of functional AuNPs [115]. Then these authors developedprecise Au cluster ligand-exchange reactions using toluene-3,4-dithiol CH3C6H3(SH)2, for the substitution of the HSC2Ph ligand in[Au25(SC2H4C6H5)18]− [116]. The reaction at the AuNP or Au clus-ter core surface involves transfer of the SH hydrogen atom of theincoming functional thiol to the AuNP surface-bonded S atom ofthe coordinated thiolate to form the leaving thiol (Eq. (2)).

Au-SR + R′SH → Au-S(R)· · ·H· · ·SR′ → HSR + Au-SR′ (2)

The thiolate ligand substitution is conducted by introducingexcess thiol ligands. This method has been widely utilized [117],because it avoids using the reducing conditions of the direct Brust-Schiffrin synthesis with functional thiols. Usually, the excess offunctional thiol and the exchanged non-functional alkylthiol areseparated by dissolution in methanol or ethanol in which the AuNPsare not soluble. Examples include amidoferrocenyl functionalizedalkanethiol groups that were introduced into AuNPs for the redoxrecognition of oxoanions [118], azide- or bromo-functionalizedthiols for further “click” functionalization of AuNPs [119–124],carboxylic acid-functionalized thiols for controlled preparation ofcarboxylated AuNPs [125], and small thiolate molecules for theidentification of antibiotics [126].

Some more labile ligand-stabilized AuNPs were also submittedto ligand substitution by thiol ligands. For instance, the so-called“thiol-for-DMAP exchange” was conducted [127–129] using thiolligands to substitute the DMAP-caps in AuNPs for the synthesis


thiol-dR ty of C

oA

tltict

tssatAfcA[tc

Fig. 5. Synthetic route for

eprinted with permission from [113] (Daniel’s group). Copyright 2011 Royal Socie

f liquid crystal (LC)-capped AuNPs [127], and polymer-cappeduNPs [128].

However, the ligand-substitution reaction has some drawbackshat are (i) risk of irreversible aggregation of AuNPs, (ii) incompleteigand substitution, (iii) in some cases experimental difficulty inhe determination of the amount of exchanged ligands, (iv) possiblencompatibilities between the initial medium of the AuNPs and newapping molecules, such as tolerance of the new potential ligandsowards solvent [119]. Nevertheless, it remains useful.

2.1.2.5.4. Functionalization of pre-formed AuNPs. Various func-ionalizations of pre-formed AuNPs by direct synthesis or ligandubstitution have been conducted such as halide nucleophilic sub-titution reactions [117], nucleophilic addition reactions [130],midic coupling reactions using amino termini [131], polymeriza-ions [132], and “click” functionalization [133,134]. For example,uNPs stabilized by 4-aminothiophenol were functionalized with

olic acid by condensation reaction, with potential application inancer therapy [135,136]. In our group, “click” functionalization of
uNPs has been applied for usage in drug delivery systems (Fig. 6)
124,136]. This functionalization of pre-functionalized AuNPs hashe inconvenient, however, that aggregation often occurs in theourse of reactions, in particular if a catalyst is used. Nevertheless,

11

endron-stabilized AuNPs.hemistry.

it remains very useful, because the aggregated AuNPs are easilyseparated by precipitation.

In summary, due to the strong Au S bond (47 kcal/mol) [137],sulfur ligand-stabilized AuNPs have gained considerable interestfor functionalization with thousands of publications since their dis-covery. These four functionalization methods are all currently usedand complementary.

2.1.3. Schmid’s Au55 cluster and the phosphorus ligandsThe phosphorus ligand-stabilized AuNPs have possible future

applications in catalysis, imaging, sensing, and new therapeu-tic approaches [138–151]. They are also excellent precursorsfor ligand-substitution reactions towards the functionalization ofAuNPs and for building bimetallic cores of AuNPs [152,153]. In theearly 1980s, Schmid published the illustrious phosphine-stabilizedAu55 cluster that is well known as Schmid’s cluster with narrowdispersity (1.4 ± 0.4 nm) [11]. Schmid Au cluster was defined as[Au55(PPh3)12Cl6], was well characterized by X-ray crystal struc-
ture and showed the properties of a quantum-dot particle for thefirst time [154]. Weare and Hutchison [153] improved the Schmidmethod in 2000 using HAuCl4 and N(C8H15)4Br in a water–toluenemixture to which PPh3 and NaBH4 (instead of diborane in Schmid’s


Fig. 6. Encapsulation of docetaxel in PEGylated AuNPs considerably increases its solubility in water (Astruc’s group).Reprinted with permission from [124]. Copyright 2011 Wiley-VCH.

Fig. 7. Synthesis pathway for TPP-stabilized AuNPs.Reprinted with permission from [138] (Shumaker-Parry’s group). Copyright 2009 American Chemical Society.

12

6 mistry

m[tgNAAmus1

pssp(as[a2

2

acbbr[spp

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2

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ethod) were added. The cluster [Au101(PPh3)21Cl5] formed withAu(PPh3)Cl] as an impurity. Later, Moores et al. [151] usedhe precursor complex [AuCl(SMe2)] instead of HAuCl4 as theold source and sodium naphthalenide (C10H8Na) instead ofaBH4 as the reducing agent to synthesize phosphinine-stabilizeduNPs. Phosphinines are well adapted to the coordination tou0 and are suitable for AuNPs formation. Very recently, theild reducing agent 9-borabicyclo-[3.3.1]nonane (9-BBN) was

sed in a new simple and versatile method for the synthe-is of triphenylphosphine-stabilized AuNPs with diameters of.2–2.8 nm and narrow size distribution (Fig. 7) [138].

Other recent examples of the synthesis of AuNPs stabilized byhosphines or phosphine derivatives are (i) triphenylphosphine-tabilized small Au clusters where triphenylphosphine is con-idered as a proactive etching agent [155], (ii) calixarenehosphine-stabilized AuNPs that were used for catalysis [156,157],iii) 1,1′-binaphthyl-2,2′-dithiol-stabilized AuNPs for optics [158],nd (iv) tetrakis-(hydroxymethyl)phosphonium chloride (THPC)-tabilized AuNPs for further preparation of bimetallic nanoshells159]. In addition, proteins and lipids contain many phosphorustoms that also stabilize AuNPs with these bioligands (see Section.2.1).

.1.4. Other ligandsOther possible AuNP ligands are oxygen- and nitrogen-based lig-

nds containing electronegative groups such as amine (or amino),arboxyl, carbonyl and phenol groups. In particular, amines haveeen popular AuNP ligands for a long time due to their presence iniological and environmental systems [160–166]. A seminal andemarkable example is Crooks’s octadecyl amine-capped AuNPs161]. A series of aminoalcohol-stabilized AuNPs [162], amine-tabilized AuNPs used as bioprobes [163,164,] (Fig. 8), and cyclichenylazomethine (CPA)-stabilized AuNPs used as electrochemicalrobes for metal ion sensing are known [165].

Among them, 4-(N,N-dimethylamino) pyridine (DMAP) is a fre-uent AuNP ligand, and DMAP-stabilized AuNPs have found broadse in AuNP ligand-substitution reactions [167] and heteroge-eous catalysis [168]. DMAP-liganded AuNPs were first publishedy Caruso’s group [168,169] and recently gained increased atten-ion [170–173]. These AuNPs are obtained by adding an aqueousMAP solution into the TOAB-stabilized AuNPs via phase transfer.wo other key nitrogen ligands, TOAB and CTAB will be discussedn Section 2.3.1.

Among oxygen ligands, carboxyl derivatives and phenol arenown as AuNP stabilizer. For instance, folic acid binds AuNPsia a carboxyl group, which is useful for nanomedicinal applica-ions [174]. Other carbonyl stabilizers include N-vinylpyrrolidone175] and N-2-hydroxyethylpiperazine-N-2-ethanesulphonic acidHEPES); the latter stabilizes flower-like AuNPs with its carbonylnd phenolate groups [176].

.2. Macromolecule-stabilized AuNPs

Macromolecules stabilize AuNPs by both steric embeddingffect and ligand interactions of their heteroatoms (N, O, P and Sonors) with the AuNP surface [177].

. Polymers

As reviewed by Shan and Tenhu, the use of polymers stabilizersor the synthesis of AuNPs has various advantages: (i) enhancementf long-term AuNP stability, (ii) adjustment of their solubility, (iii)
ncreased amphiphilicity, (iv) high and tunable surface density ofhell/brush, (v) tailored properties of AuNPs, and (vi) compatibil-ty and processibility [178]. Polymer-stabilized AuNPs date fromelcher’s treatise in 1718 [179] that indicated starch-stabilized
13

Reviews 257 (2013) 638– 665

water-soluble Au particles. With the rapid development of nano-technology, polymer-stabilized AuNPs are becoming actively andwidely used in catalysis [180], optics [181] and biology [182]. Thetwo major synthetic routes to polymer-stabilized AuNPs are the“grafting to” and “grafting from” techniques [183–190]. With thelatter method, polymerization occurs at the Au surface in the pres-ence of initiators; thus it can be viewed as a method of AuNPfunctionalization. Otherwise, the “grafting to” method involvesdirect AuNP synthesis by attachment of polymers onto the Au sur-face. There are two strategies for the “grafting to” method. Thefirst one uses functionalized polymers with sulfur, nitrogen orother ligands at the end or in the middle of polymers to stabilizethe AuNPs. This synthetic route is relevant to the Brust-Schiffrinmethod or the ligand substitution reaction. For the Brust-Schiffrinroute that is often used with polymers, the HAuCl4 solution ismixed with the functionalized polymers, and the reducing agentis added to form the AuNPs (both in one phase or two phases). Forinstance, the polymeric AuNP ligands used in this way include thio-late end-capped polystyrene (PS) [191–193], thiolate poly(ethyleneglycol) (PEG) [194], five-arm PEG-b-PCL star block copolymers[195], thiolate poly(N-isopropylacrylamide) (PNIPAM) [196], thio-late poly(vinyl pyridine) (PVP) [197], polypeptide with disulfidetermini [198], poly(acryloylaminophenylarsonic acid) (PAAPHA)with amine and arsenic acid group [199], poly(ethylenimine) (PEI)with amine groups [31], thioether-functionalized polymer ligands(DDT–PVAc and PTMP–PVAc) [200], ionic polymers [201], and O-ethyl-S-(1-methoxycarbonyl)ethyl dithiocarbonate functionalizedpoly(N-vinyl caprolactam) (PVCL) (Fig. 9) [202].

The AuNP size is controlled by the polymer/Au ratio that isdetected by the change of intensity of the plasmon absorption in theUV–vis spectra [203]. Some polymers such as PS and PAAPHA act asboth reducing agents and stabilizers. Thus, they form AuNPs with-out additional reducing agents, but the AuNPs formed with suchweak reducing agents are much larger than those formed usingNaBH4.

The functionalized co-polymers are also used as templates inAuNP synthesis. For instance, Suzuki developed thermosensitivehybrid core-shell AuNPs via in situ synthesis. Fig. 10 shows theroute used in this study. Thiol- and amino-functionalized poly(N-isopropylacrylamide) (NIPAM)-b-(glycidyl methacrylate) (GMA)(poly NIPAM-b-GMA) have been used as templates to stabilizeAuNPs inside the polymer shells [204].

The ligand-substitution reaction for the synthesis of polymer-stabilized AuNPs has a significant advantage in that thepre-prepared AuNPs therefore lead to relatively monodispersedAuNPs by the Turkevich or Brust method. Thus, after the ligand-substitution reaction by polymers, the polymer-stabilized AuNPsare also relatively monodispersed, because the AuNP core doesnot undergo size change (Ostwald ripening) during the ligand-substitution process. A typical ligand-substitution reaction wasconducted by Azzam et al.: PEO-b-PS-b-P4VP was added into theTOAB-stabilized AuNP solution in toluene and stirred for 24 h, andthe PEO-b-PS-b-P4VP-stabilized AuNPs were obtained [205]; somesuch recent examples are known [206–208]. The other “grafting-to”strategy uses the polymer as a template to stabilize the AuNPs ascore-shell NPs. This method is also defined as polymer-surfactant-or reverse micelle-stabilization of AuNPs, and is discussed in Sec-tion 2.2.4.

4. Dendrimers

Dendrimers are highly branched, cauliflower-shaped monodis-persed, synthetic macromolecules with well defined composition,dimension and structures [209,210]. Dendrimer- or dendron-stabilized AuNPs are classified in three parts: (i) AuNPs that are


Fig. 8. Synthesis and bioapplication of amine ligand stabilized AuNPs.Reprinted with permission from [164] (Suri’s group). Copyright 2008 Elsevier.

Fig. 9. Synthesis of PVCL and coating of AuNPs.Reprinted with permission from [202] (Marty’s group). Copyright 2011 Royal Chemical Society.

R
Fig. 10. Schematic representation of the synthesis of thermo
eprinted with permission from [204] (Kawaguchi’s group). Copyright 2005 American Ch

14

sensitive hybrid core-shell particles containing AuNPs.emical Society.


Fig. 11. Newkome-type dendron-stabilized AuNPs.R Chem

egTDApAigvg[

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eprinted with permission from [244] (Hackley’s group). Copyright 2011 American

ntrapped into the dendrimers or dendrons by the functionalroups (containing S, N, P and O) and the steric embedding effects.hese AuNPs are also called dendrimer-encapsulated AuNPs (AuENs), and are sometimes used in electrocatalysis [211–219]; (ii)uNPs that are surrounded by several small dendrimers at theireriphery are called dendrimer-stabilized AuNPs (Au DSNs); (iii)uNPs prepared as dendrimer cores and stabilized by coordinat-

ng ligands located at the focal points of dendrons. With functionalroups located at the dendron periphery, the AuNP assembly pro-ides AuNP-cored dendrimers containing peripheral functionalroups such as redox groups that are broadly used as redox sensors220–225].

Au DENs were first published by Crooks’s and Tomalia’s groupssing the polyamidoamine (PAMAM) dendrimers as stabilizers226–228], followed by a number of reports dealing with thereparation of dendrimer-stabilized AuNPs of various kinds. Theize distribution of dendrimer-stabilized AuNPs depends on thenitial dendrimer-to-Au ratio [229–231] and dendrimer genera-ion [232,233]. Other sulfur groups, hydroxyl groups [245,246],enzyl ethers [247], and amine groups [248], allow the synthe-
is of dendrimer-stabilized AuNPs [234–244] (Fig. 11). In “click”EG dendrimer-stabilized AuNPs from our group, stabilization isrovided by 1,2,3-triazole coordination, and the AuNPs are encap-ulated in the dendrimers when the latter are large enough or
15

ical Society.

surrounded by several dendrimers when the latter are too small(zeroth generation) [249,250].

Phosphorylcholine-functionalized dendrimers provide anotherexample of AuNP stabilizer. Their stability and controllable sur-face properties indicated potential use in biosensing (Fig. 12) [251].AFM and TEM were used to demonstrate the morphology and sizedistribution of the AuNPs formed. Recently, Voelcker’s use of theNICISS technique proved useful to understand the inner structureof dendrimer-stabilized AuNPs [233].

4.1. Surfactants and reverse micelles

4.1.1. Surfactant-stabilized AuNPs without reverse micelleformation

Surfactants stabilize the AuNPs by electrostatic bondingbetween the Au surface and the surfactant heads. The surfactantTOAB is normally used in the Brust-Schiffrin two-phase method asa phase-transfer agent, and it also acts as AuNP stabilizer. The TOAB-capped AuNPs is obtained by the Brust-Schiffrin two-phase methodwithout adding the additional stabilizer and utilized in further
functionalization or self-assembly [252–255]. Another example isNikoobakht et al.’ s synthesis of cetyltrimethylammonium bromide(CTAB)-stabilized AuNPs [256–259]. The AuNPs are obtained byquickly adding an ice-cold NaBH4 solution into the mixture of CTAB


ation

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poly(vinylpyridine) (PS-b-PVP) [274–279] and poly(ethyleneoxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) [280–287] are the most widely used polymer micelles

Fig. 12. Schematic representeprinted with permission from [251] (Ji’s group). Copyright 2011 Springer.

nd HAuCl4 solution, yielding AuNPs of average size up to 4 nm with net positive interfacial charge. It is frequently used as a seed for thereparation of monodispersed gold nanorods (AuNRs) [256,257]nd size- and shape-controlled AuNPs [260,261].

.1.2. Surfactant-stabilized AuNPs with reverse micelle formationBesides the electrostatic bonding, surfactants are also used

o form reverse micelles for AuNPs synthesis. Reverse micelleolutions are transparent, isotropic, thermodynamically stableater-in-oil microemulsions that are dispersed in a continuous oilhase and stabilized by surfactant molecules at the water/oil inter-ace [262–264]. Water is readily solubilized in the polar core ofeverse micelles, forming so-called water pools that play the rolef templates for AuNP formation and also prevent the aggregationf AuNPs [265]. The sizes of the AuNPs are defined by the micelleolume. Both low-molecular-weight surfactants and copolymerurfactants form reverse micelles for the synthesis of AuNPs.

Sodium bis(2-ethylhexyl) sulfosuccinate (AOT) is a widely usedow-molecular-weight surfactant in AuNPs synthesis. The reverse

icelle is thus prepared by adding water/AOT/n-heptane [266]r water/ATO/isooctane [267,268] into an appropriate amount ofAuCl4 or a gold salt. Then, the reducing agent hydrazine is added

nto the mixture to form the AuNPs. Recently, catanionic surfac-ants (mixture of octanoic acid and octylamine) such as lecithin269,270], and trichromophoric dye-reverse micelles were alsohown to stabilize AuNPs as shown in Fig. 13 [271].

However, the use of water/oil microemulsions for the synthe-is of AuNPs has a major drawback. Large amounts of surfactantre required to stabilize the AuNPs, which introduces impurities.n order to solve this problem, Hollamby et al. purified reverse

icelle-stabilized AuNPs in a single step. Thus, the AuNPs aretabilized by the microemulsion that forms in water/octane withutanol as co-additive. After adding excess water, the AuNPs areoncentrated into the upper octane-rich phase, and the impuritiesemain in the water-rich lower phase [272].

.1.3. Reverse micellesCompared with classical surfactant-formed micelles, the

opolymer surfactant-formed micelles have several advantages.irst, the critical micelle concentration (cmc) of copolymers is

16

of the synthesis of Au DSNs.

much smaller, and their kinetic stability is larger than that oflow-molecular-weight surfactants. Second, the size and shape ofcopolymer micelles is easily tuned by varying the compositionof the copolymer, the length of the constituent blocks, and thearchitecture of the copolymer. Third, the stability of the AuNPsis enhanced upon increasing the length of the coronal blocks[195,273].

A large number of studies are available in polymer micelle-stabilized AuNPs, therefore only a few representative orrecent examples are mentioned here. Poly(styrene)-block-

Fig. 13. Formation of dye-functionalized AuNPs (GPN = AuNP).Reprinted with permission from [27] (Yoda’s group). Copyright 2011 Elsevier.


Fig. 14. (a) Molecular structure of the PS-b-P4VP copolymer and schematic illustration of the micellation process with in situ synthesis of AuNPs in PS-b-P4VP. (b) Topographyimage of the surface (from AFM) of a spin-coated PS-b-P4VP film along with a schematic illustration of a self-assembled PS-b-P4VP (with AuNPs) micellar film on a substrate.(c) TEM image of PS-b-P4VP. The copolymer film is made up of a continuous bright PS matrix and dark spherical P4VP cores. (d) TEM image of PS-b-P4VP with AuNPs;P

R

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S-b-(P4VP/Au). The molar ratio of HAuCl4:P4VP is 0.1.

eprinted with permission from [278] (Leong’s group). Copyright 2008 Wiley-VCH.

or AuNPs synthesis, and these AuNPs are applied in catalysis275–277] and biosensing [287]. PS-b-PVP micelle-stabilizeduNPs are typically synthesized as described by Möller’s group

279]. A solution of the block copolymer in dry toluene is mixedith HAuCl4 in appropriate amount. The mixture is stirred for at

east 24 h in order to allow complete dissolution of the gold saltn the core of the block copolymer micelle. The reducing agentydrazine is added under vigorous stirring to form the AuNPsFig. 14) [274,278].

Various reducing agents introduced into PS-b-PVP micelle sys-ems may result in the formation of AuNPs of various sizes [279].he morphology, size and size distribution of the AuNPs formedere determined by AFM, DLS, and TEM.

17

In addition, microcalorimetry was used to investigate AuNPformation in the copolymer micelles. For instance, PEO-PPO-PEO-stabilized AuNPs were prepared in an efficient one-potaqueous-phase synthesis from the reduction of Au salts by usingPEO-PPO-PEO both as reducing agent and stabilizer [283]. The for-mation of AuNPs from Au salts comprises three steps: (i) initialreduction of Au ions in crown ether-like domains formed by blockcopolymer in solution, (ii) absorption of block copolymer on AuNPsand further reduction of Au ions on the surface of these AuNPs,
and (iii) growth of particles stabilized by block copolymers [284].Increasing the PEO chain length favors the reduction of Au saltsand formation of AuNPs [284]. In addition, the temperature [285],micelle environment [286], and shapes and sizes of micelles [286]


Fig. 15. A PEO-PPO-PEO micelle with the core occupied by PPO units and the coronaconstituted by PEO units.

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Table 1AuNPs stabilized by natural-source extracts.

Natural source Groups for stabilizing AuNPs Publicationyear

Arabic gum [294] Phenol 1999Lemon grass [295] Hydroxyl and carbonyl 2004Emblica officinalis [296] Carbonyl and phenol 2005Alove vera plant [297] Carbonyl and phenol 2006Cinnamomumcamphora [298] Carbonyl 2007Gellan gum [299] Carboxy, carbonyl and

phenol2008

Castor oil [300] Carboxyl 2008Volvariella volvacea [301] Phenol 2009Hibiscus [302] Phenol 2010Bayberry tannin (BT) [303] Phenol and carbonyl 2010

eprinted with permission from [286] (Bakshi’s group). Copyright 2011 Americanhemical Society.

re also considered to be the main contribution factors in the over-ll growth kinetics leading to a specific morphology of AuNPs [286].or example, the smaller micelle size with few surface cavities pro-uced small AuNPs (Fig. 15) [286].

Other polymer reverse micelle-stabilized AuNPs were alsoecently prepared using similar approaches. For example,oly(ethylene oxide)-b- poly(�-caprolactone) (PEO-b-PCL)-tabilized AuNPs with 5–7 nm core size have potential for thexploration of drug-delivery systems with biodegradable PCLnits and biocompatible PEO units [288]. Polyethylenimine-g-ydrocaffeic acid (PEI-C)-AuNPs are also the subject of biomedicalpplications [289].

.1.4. LiposomesLiposomes, supramolecular assemblies of amphiphilic lipids,

an be used as reverse micelles to prepare AuNPs. Early syntheses ofiposome-stabilized AuNPs have been conducted by adding NaBH4o mixtures of HAuCl4 and liposomes [290]. This method easily pro-ides size-controlled AuNPs, but NaBH4 is toxic and can modify theiological function [291]. Recently, a “green” and efficient method-logy yielding liposome-stabilized AuNPs involved a simple, rapid,nd controlled reaction. The AuNPs were obtained by adding ascor-ic acid as reducing agent into the mixture of liposome-based giantnilamellar vesicles (similar to micelles) and HAuCl4 [291]. Sim-

larly, O’Sullivan’s group used the biocompatible reducing agentlycerol for the synthesis of stabilized AuNPs (Fig. 16) [292,293].

.2. Biosynthesis and “green chemistry”

Biosyntheses and “green” syntheses of AuNPs are furtheremarkable areas in AuNP preparation via in situ synthesis. In theseyntheses, the biomolecule directly acts both as a stabilizer andeducing agent to form the AuNPs. The sources for bio- and greenreparations of AuNPs are natural source extracts, chitosan, andicrobes.

.2.1. Natural-source extractsDue to the abundance of carboxyl, carbonyl, hydroxyl and phe-

ol groups, the natural-source extracts reduce AuIII and stabilizehe AuNPs with these groups. Since Goia and Marijevic synthe-ized AuNPs stabilized by Arabic gum (originated from a naturallant) [294], many environmentally friendly AuNPs have beenynthesized, in particular by Sastry’s group [295–297]. Non-toxichemicals from natural source extracts were used in the syntheses
n order to avoid adverse effects in medical and biology applica-ions (Table 1). These AuNP syntheses using natural-source extractsre simple, just mixing the extracts with aqueous HAuCl4 until theolor changes to red or purple [295]. Besides this green-chemistry
18

Tannic acid [304] Phenol and carboxyl 2010Zingiber officinale [305] Carbonyl and phenol 2011

aspect, AuNPs stabilized by natural-source extracts are also used inother fields involving AuNPs assembly [306].

4.2.2. ChitosanChitosan, the second-most abundant natural polymer in the

world, is known as the deacetylated chitin and has a good water sol-ubility and biocompatibility [307,308]. Chitosan stabilizes AuNPswith the amine groups and the steric effect of its own structure.Chitosan-stabilization of AuNPs by adding NaBH4 as a reducingagent was first published in 2003 [308], then Huang’s group [309]used chitosan both as a stabilizing agent and reducing agent andobtained AuNPs upon heating a HAuCl4-chitosan mixture for twohours at 70 ◦C, a fully “green” synthesis. From then on, chitosan-stabilized AuNPs have been widely investigated in catalysis [310],biomedicine [311], and sensing [162]. In addition, carboxymethylchitosan has later also been used to synthesize AuNPs, due to itshigher sorption of metal ions than that of chitosan [312].

4.2.3. MicrobesThe stabilization by microbes provides a remarkable mode of

AuNP biosynthesis that has been studied for more than threedecades. Beveridge and Murray showed that Bacillus subtilisreduces AuIII to AuNPs with a size range of 5–25 nm sizes insidethe cell wall [313]. Up to now, four major microbes have been usedfor AuNPs synthesis: bacteria, fungi, actinomycete and yeast. Theabundance of carboxyl groups in microbes is considered to play amajor role in the reduction of AuIII [313]. Moreover, the abundantelectronegative groups in microbes (amine, carboxyl, thiol, disulfur,etc.) contribute to the microbe stabilization of AuNPs. The synthe-sis of AuNPs with microbes follows two procedures: extracellularproduction and intracellular production. For the extracellular pro-duction, AuIII is reduced by the cell wall reducing enzymes orsoluble secreted enzymes. For the intracellular production, reduc-tion occurs inside the cell. The extracellular production of AuNPshas wider applications than intracellular accumulation in optoelec-tronics, electronics, bioimaging and sensor technology [314].

In Table 2, some identified data from [314] are recollectedtogether with some newer data showing recent microbe-stabilizedAuNPs.

5. Seed-growth method

5.1. Principle of the seed-growth method

The seed growth method is another popular technique for AuNPsynthesis that has been used for more than a century. Compared
with the in situ synthesis, the seed-growth method enlarges theparticles step by step, and it is easier to control the sizes and shapesof formed AuNPs. Thus, this procedure is widely used in the mostrecent size- and shape-controlled AuNPs syntheses.


Fig. 16. (a) Designed liposomal nanoreactor. (b) Formation stages of AuNPs inside the glycerol-incorporated (15%, v/v) liposomes: liposomes before reaction (top left), lipo-somes during the reaction (middle) (scale bars = 10 nm), and purified AuNPs synthesized in the nanoreactor (bottom right, scale bar 20 nm). Photon correlation spectroscopygraph of the liposome size distribution before the reaction, PI = 0.232 (bottom left corner) and graph of the calculated AuNP size distribution using TEM (top right corner).

Reprinted with permission from [293] (O’Sullivan’s group). Copyright 2011 American Chemical Society.

Table 2Microbe-stabilized AuNPs.

Microbe type Microbe Localization Size Reference

Bacteria Sulfate-reducing bacteria Intracellular <10 nm [315]Shewanella algae Intracellular 10–20 nm [316]Plectonema Intracellular 10 nm [317]Rhodopseudomonus capsulata Extracellular 50–400 nm [318]

Fungi Verticillium sp. Intracellular 20 ± 8 nm [319]Fusarium oxysporum Extracellular 20–40 nm [320]

Actinomycete streptomyces viridogens strain HM10 Intracellular 18–20 nm [321]Thermomonospora sp. Extracellular 8 nm [322]

Yeast Extremophilic Yeasts Intracellular 30–100 nm [323]Yarrowia lipolyrica NCIM 3580 Intracellular 15 nm [324]

19

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The seed growth usually involves two steps. In the first step,mall-size AuNP seeds are prepared. In the second step, the seedsre added to a “growth” solution containing HAuCl4 and the sta-ilizing and reducing agents, then the newly reduced Au0 growsn the seed surface to form large-size AuNPs. The reducing agentssed in the second step are always mild ones that reduce AuIII tou0 only in the presence of Au seeds as catalysts, thus the newlyeduced Au0 can only assemble on the surface of the Au seeds, ando new particle nucleation occurs in solution. Moreover, due to these of a mild reducing agent, the second step is much slower thanhe first one, and it can be repeated to continue the growth process.

In the course of the seed-growth synthesis of AuNPs, the for-ation of seeds takes a significant place correlated to the size,

hape and surface properties that are controlled by the amountnd nature of reducing agent and stabilizer, and their ratio to theu precursor. The earliest gold nano seeds were proposed by Natan

325] using citrate reductant and capped spherical Au seeds withiameter 12 nm for the overgrowth of spherical AuNPs. Murphy’sroup [326,345] reported the synthesis of 3.5 nm citrate-cappedold seeds by dropping an ice-cold aqueous solution of NaBH4nto a solution of a mixture of HAuCl4 and citrate. These seeds

ere originally used for the formation of AuNRs. This procedure ofu seed formation was modified by El-Sayed [327] using hexade-yltrimethylammonium bromide (CTAB) as the stabilizer insteadf citrate. These Au seeds with a diameter smaller than 4 nm weresed to promote the narrow dispersity of AuNRs. Subsequently,his seed formation was regarded as the most primary nucleationrocess in the synthesis of AuNPs. Other monodispersed, large-ized, spherical or quasi-spherical AuNPs, AuNRs, and other shapeduNPs have been synthesized using the seed-growth method, as

ollows.

.2. Spherical or quasi-spherical AuNPs

The traditional in situ synthesis provides spherical or quasi-pherical AuNPs. The disadvantage is, however, that when the sizencreases it becomes out of control, and the shape is not con-rolled either. Therefore, the seed-growth strategy has emerged as

very efficient method to synthesize monodispersed AuNPs witharge sizes (up to 300 nm) precisely and with well-defined shapes327–331].

Natan and co-workers [325,332,333] pioneered the seed-rowth method in a European patent [334]. In this procedure,uNPs between 20 nm and 100 nm were prepared by addingitrate-capped, NaBH4-reduced seeds into a “growth” solutionontaining a mild reducing agent such as citrate [332,333] orydroxylamine [329]. These results provided an improvementf physical properties compared with the Turkevich and Frensethod. However, this synthetic route also generated a small pop-

lation of rod-shaped AuNPs as impurities. Later, Murphy’s group335] improved the method by using ascorbic acid as a reducinggent as mild as citrate in growth solution and using CTAB as a sta-ilizer to synthesize monodispersed spherical AuNPs up to 40 nmthe citrate-stabilized AuNPs with a relative standard deviation thatas lower than 10% were considered as monodisperse [335,336]).

his method was later used by Han’s group for the synthesis ofcosahedral AuNPs having controlled size (from 10 nm to 90 nm)Fig. 17) [337].

In 2006, Liz-Marzan’s group first reported the synthesisf gold nanoparticles via the seeded growth method up to00 nm, also showing optical properties with quadrupolar modes329]. Recently, highly monodispersed, spherical, citrate-stabilized
uNPs were synthesized up to 300 nm by using hydroquinone [330]r ascorbic acid (Fig. 18) [338] as reducing agent in the seed-rowth process. Reaction conditions such as temperature [331], pH331], Au precursors to seed particle concentration [331] and citrate
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Reviews 257 (2013) 638– 665 653

concentration [336] were considered to affect the size distributionand shape of the AuNPs.

5.3. Gold nanorods (AuNRs)

The AuNRs show two plasmon bands: a strong longitudinal bandin the near-infrared region and a weak transverse band, similar tothat of gold nanospheres, in the visible region. The band in the near-infrared region, where tissue absorption is minimal, is very usefulfor potential in vivo applications. Consequently, due to their spe-cific structure and shape, the AuNRs exhibit wide potential use innanomedicine [339–341]. During the last few decades, AuNRs hadbeen prepared using electrochemical and photochemical reductionmethods in aqueous surfactant media and nanoporous templates[342–344]. However, the seed-growth method developed in par-ticular by the Murphy group [326] then by the El Sayed group [327]now clearly appears as the most favorable one for synthesizingAuNRs, because it can easily generate high yields of well-definedand monodispersed AuNRs.

The current seed-growth method has indeed been first pub-lished by Murphy’s group [326]. Briefly, 3–4 nm citrate cappedAuNPs are used as seeds, then the seeds are added into the growthsolution containing appropriate HAuCl4, CTAB and freshly preparedascorbic acid, without further stirring or agitation. After 5–10 min,AuNRs with 4.6 ± 1 aspect ratio are generated in the solution. AuNRswith a high aspect ratio (up to approximate 20) are obtained bythree-step growth: the first-step forms AuNRs that are used asseeds for the second growth, and the second-step-formed AuNRsare used as seeds for the third growth (Fig. 19) [326,344,346].

The AuNRs together with other shapeswere also obtained andpurified by centrifugation. Indeed, this method has the disadvan-tage that large amounts of sphericalAuNPs and AuNPs with othershapes are formed as by-products, which greatly reduces the AuNRyield. The Mulvaney and Li-Marzan group then showed that whenthe temperature and CTAB concentration were reduced, nanorodswith small aspect ratio of 1–6 could be obtained with up to 50%yields [328]. The situation is much improved in the presence of sil-ver nitrate, as initially reported in Murthy’seminal articles whereup to 50% bipyramidal AuNRs were obtained [326]. Nikoobakht andEI-Sayed very efficiently overcame the drawbacks by using silvernitrate in the presence of CTAB. The single-crystalline CTAB-cappedseeds were used instead of citrate-capped seeds, and silver nitratewas used in the seed-growth process to control the aspect ratioof AuNRs. This optimized protocol resulted in high yield of AuNRs(99%) with ratios from 1.5 up to 5 and generated only traces ofspherical AuNPs (Fig. 20) [327].

The yield, monodispersity and size of AuNRs were affected bymany parameters. The addition of nitric acid into the growth solu-tion leads to a high yield of AuNRs [347,348]. The presence ofiodide at ppm concentrations in CTAB prevents the formation ofAuNRs in the growth media [349,350]. Moreover, the purifica-tion of AuNRs from other shapes of AuNPs is also important forAuNRs synthesis. An efficient and relatively simple method forisolation of single-size rods from a mixture of different-sizerods,spheres and plates was reported by Jana [351]. Briefly, in a con-centrated dispersion of a mixture of various-size rods, spheres andplatelets formed when a surfactant (CTAB) was added, nanorodsand platelets precipitate from the mixture leaving the spheres insolution. Under similar experimental conditions, the long rods pre-cipitate more easily than the short rods, followed by platelets.Recently, it was disclosed that the micelle nature of CTAB wasa key factor in NR purification from other shapes due to deple-
tion attraction forces of surfactant micelles [352], and the bromideanions of the CTAB surfactant played a greater role than the CTA+
cations for the process of AuNRs formation [353]. In addition,it was figured out that bromide anions played a crucial role in


.3 ± 2R mical

tcidbg

Fig. 17. TEM images of AuNPs in solution (a) 11.0 ± 0.8 nm, (b) 13eprinted with permission from [337] (Han’s group). Copyright 2007 American Che

he formation of rod-like AuNPs in the sense that there was aritical [Br−]/[AuIII] ratio (around 200) to form AuNRs with a max-
mum aspect ratio; beyond this value, the aspect ratio of AuNRsecreased [354]. Details of the mechanism of AuNR formation haveeen carefully reviewed by the EI-Sayed’s [339] and Murphy’sroups [340].
21

.0 nm, (c) 32.2 ± 1.8 nm, (d) 69.0 ± 3.7 nm and (e) 87.3 ± 12.1 nm. Society.

The post functionalization of AuNRs has been exploited forthe synthesis of various hybrid nanomaterials. For instance, silver
coating was achieved upon silver nitrate reduction in the pres-ence of various stabilizers, silicon passivation was conducted bymixing with 3-mercaptopropyl trimethoxysilane (MPTMS) or 3-mercaptopropyl triethoxysilane (MPTES), and iron oxide coating


Fig. 18. TEM images of AuNPs in solutions (a) 15 ± 2 nm, (b) 31 ± 3 nm, (c) 69 ± 3 nm, (d) 121 ± 10 nm, (e) 151 ± 8 nm and (e) 294 ± 17 nm. Scale bars are 200 nm for parts a–cand 500 nm for parts d–f.

Reprinted with permission from [338] (Eychmüller’s group). Copyright 2011 American Chemical Society.

Fig. 19. General methodology for the generation of AuNRs.Reprinted with permission from [346] (Murphy’s group). Copyright 2004 American Chemical Society.

F

R

ig. 20. TEM images of gold NRs synthesized in high yield with plasmon band energies at

eprinted with permission from [327] (EI-Sayed’s group). Copyright 2003 American Chem

22

(a) 700, (b) 760, (c) 790, (d) 880, (e) 1130, and (f) 1250 nm. The scale bar is 50 nm.

ical Society.

6 mistry

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as achieved by coprecipitation of iron saltsor adsorption of ironxide NPs. AuNRs have been integrated with polymer beads forrug delivery, and microgel beads are widely used due to theirnique thermal-responsive properties. Supramolecular assembliesf AuNRs have also been designed end-to-end or side-by side [339].

.4. Other shapes of AuNPs

Besides spherical or quasi-spherical AuNPs, anisotropic AuNPsave also recently been synthesized and widely used iniomedicine [355] and nanotherapy [356]. Among the shape-ontrolled strategies [357], seed growth is an efficient method forhe synthesis of anisotropic AuNPs. It allows rational design ofanocrystal shape, size distribution and monodispersity throughhe adaption of nucleation and growth conditions. In par-icular, anisotropic AuNPs include AuNRs [57], Au nanocubes358], Au nanohexapods [359], Au nanoribbons [360], Au hollowanocages [361], Au nanobranches [362–364], and Au nanopoly-edra [365–367].

Herein we are focusing on the main examples of anisotropicuNPs syntheses and their improvements. A seminal report of

solution-based “chemical” route to multiple shaped-controlleduNPs in 2004 is that of Murphy [358] and co-workers. In a

ypical procedure, a HAuCl4 solution is added to a CTAB solu-ion followed by addition to the growth solution of an aqueousolution containing AgNO3, ascorbic acid, and HAuCl4. In givenonditions, nanorods, and other particles with triangular andquare outlines were formed and, by increasing the ascorbiccid concentration, hexagonal nanocrystal appeared. Then, uponurther increase in ascorbic acid, cube-shaped particles wereormed in high yield (90%). A variation of branched AuNPsere also synthesized by controlling the various combinations

f [seed]/[AuIII] ratio or the concentrations of CTAB and ascorbiccid.

Huang’s [368] group organized a systematic shape evolutionrocess from CTAC-capped truncated cubic Au seeds to trioctahe-ral and rhombic dodecahedral AuNPs via a two-step seed growthrocess. Systematic shape evolutions from truncated cube to cubic,risoctahedral, and rhombic dodecahedral structures have beenontrolled upon addition of various amounts of ascorbic acid.

Xia [359] and coworkers designed a facile method for the forma-ion of thermodynamically unfavorable Au nano-hexapods by using, N-dimethylformamide (DMF) to reduce HAuCl4 in the presencef single crystal of octahedral Au as the seed. The shapes of theexapods were controlled by variation of the amount of HAuCl4 inhe growth solution or changing the reaction temperature. Polyhe-ron is another shape of AuNPs that has recently been obtained bydding the CTAC-capped Au seeds into the growth solution contain-ng HAuCl4, CTAC, and various salts, followed by reduction usingscorbic acid. The shapes of the AuNPs formed are controlled by theature of various salts in the growth solution. For example, NaBr issed for rhombic dodecahedra, and KI is used for octahedral [367].ery recently, Mirkin’s group [361] synthesized octahedral AuNPsith hollow features. In the growth process, Au concave nanocubes

re prepared as seeds [363], and the reaction is initiated by the addi-ion of the seeds to the growth solution containing the appropriateatio of HCl, HAuCl4, AgNO3, ascorbic acid, and cetyltrimethylam-onium chloride (CTAC). The yield is higher than 90%, and the

tructure of the Au hollow is well characterized (Fig. 21 shows somexamples of anisotropic AuNPs).

It was found that the temperature, pH, Au precur-ors/surfactants ratio and salts used in the growth solution
nfluenced the growth of Au seeds on each facet, and finallyffected the size and shapes of the AuNPs [369–372]. Usually,nisotropic AuNPs are formed when the Au ionsand a reductantre added, together with some shape-templating surfactant,
23

Reviews 257 (2013) 638– 665

and the seeds are grown into larger particles of particular mor-phologies. However, the mechanism of anisotropic nanocrystalformation is presently not well understood, although a detaileddiscussion has been proposed [369].

6. Other AuNP synthetic methods

Other methods involve both “top down” and “bottom up” strate-gies and are discussed here. They also include supported AuNPs andbimetallic AuNPs.

6.1. Pulse radiolysis

Pulse-radiolysis is another “bottom-up” method that involvesgamma-ray irradiation for the reduction of AuIII instead of the tra-ditional addition of a chemical reductant [373]. As a suggestedmechanism, radiolysis generates radicals by ionization and excita-tion of the solvent (usually water). A radical scavenger is introducedin order to trap the primary radical formed (OH•) to give a newradical that is unable to oxidize the gold ions but exhibits strongreducing power, such as the radicals of secondary alcohols (2-propanol is the most-commonly used one). This is followed bythe disproportionation of AuII species giving AuI and AuIII species.Meanwhile, the mild reducing agent reduces AuIII to AuII, andAuI to Au0. During this stepwise process, AuIII is progressivelyreduced to Au0, and the formation of AuNPs proceeds in thepresence of a stabilizer that is required in order to avoid the over-growth and aggregation of the AuNPs [374]. The stabilizer mustbe unable to reduce the gold salt directly before the irradiation.For instance, poly(vinyl alcohol) (PVA), octadecylamine(OA), andolyvinyl pyrrolidone (PVP) were used as stabilizers.

In a recent example, Abidiet al. [375] published a one-pot radi-olytic synthesis of AuNRs of well-controlled aspect ratios in a CTABmicelle. The synthetic procedure involved addition of HAuCl4 andTOAB to a stirred aqueous CTAB solution; after further stirring for1 h at 50 ◦C, acetone, cyclohexane, and AgNO3 were successivelyadded into the previous solution, and then flushed with nitrogenand irradiated by a 60Co panoramic gamma source. A series ofAuNRs with various aspect ratios were obtained by variation of theAgI concentration.

The radiolysis strategy yielded spherical AuNPs with diameters6 nm and 13 nm [376] bimetallic Au-Pd [377] and Au-AgNPs [378],but altogether rather few publications have appeared.

6.2. Top-down methods

The top-down strategies start with a bulk gold substrate(generally film or pellet), followed by a nanoscale patterning pro-cedure during which the major part of the gold film is removed,yielding AuNPs with predetermined scale and shape [339]. Oneof the most commonly utilized top-down techniques is theelectron-beam lithographic method that results in the formationof multiple-shaped nanostructures with dimensional control ontens of nanometer length scale [379]. Another most popular top-down technique is the laser-based ablation [380], first introducedby Cotton et al. [381]. As a recent example, Meunier’s group devel-oped a two-step femtosecond laser-assisted technique producingsize-controlled, low dispersed (20%), and functionalized sphericalAu NPs in aqueous solution in the size range of 2–80 nm. In the
first step, seeds were obtained by ablating a gold pellet substrateimmersed in aqueous dextran (as stabilizer ligand) solutions. Theseed-growth proceeds under femtosecond laser irradiation for 1 h[382].


Fig. 21. (a) Cubic AuNPs. Reprinted with permission from [358] (Murphy’s group). Copyright 2004 American Chemical Society.(b) Trisoctahedra AuNPs. Reprinted with permission from [368] (Huang’s group). Copyright 2010 American Chemical Society.( 2011( ction w

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c) Start-like AuNPs. Reprinted with permission from [359] (Xia’s group). Copyrightd) SEM images of (A) the concave cube seeds and the products of the octahedra rea

eprinted with permission from [362] (Mirkin’s group). Copyright 2011 American C

.3. Supported AuNPs

As in the synthesis of ligand-stabilized AuNPs, the primary rolef the support is to avoid the aggregation of AuNPs. Moreover, theupport also plays a direct or indirect role at the AuNP-supportnterface in gold-catalyzed reactions. AuNPs supported by meso-orous oxides including TiO2, CeO2, SiO2, Fe3O4, Al2O3, ZrO2, theorms of carbon, and metal-organic framework (MOFs) have broadpplications in homogeneous and heterogeneous catalysis [383].

.3.1. OxidesThe most widely used procedure for the preparation of

uNPs supported on these insoluble oxides solids is therecipitation–deposition method. Starting from an aqueous solu-ion of HAuCl4, addition of a base leads to precipitation of a mixturef Au(OH)4 or Au(OH)x

−Cl4−x−. Related gold oxy/hydroxides that

dsorb into the solid are then reduced to metallic Au by boiling thedsorbed species in methanol or any other alcohol. After adsorp-ion on the solid surface, AuNP formation occurs by nucleationnd growth. The pH of the precipitation and the other experi-ental conditions (nature of the alcohol, temperature and time

f the reduction, calcination procedure, etc.) provides a certainontrol of the particle size of the resulting NPs [384]. The idealolid oxide support should have a high density of hydroxyl groupsnd a large surface area according to the deposition-precipitation
echanism in order to achieve the formation of AuNPs with nar-
ow size distribution [383,385–393]. Characterization techniquesor the oxide-supported AuNPs include TEM, SEM, XRD, Ramannd UV–vis spectroscopies. Since Haruta’ seminal discovery [384]

24

Wiley-VCH.ith (B) 50, (C) 100, and (D) 150 �L of a 10 mM HAuCl4 solution. Scale bars: 100 nm.

cal Society.

in the 1980s of CO oxidation by O2 to CO2 at low temperatureusing TiO2-supported AuNPs that are smaller than 5 nm, theseoxide-stabilized AuNPs are widely studied in catalysis for aero-bic oxidations of various substrates including alcohol oxidation, COoxidation, and hydrolytic dehydrogenation and for hydrogenationreactions [385–393].

6.3.2. CarbonIn the family of activated carbons, carbon blacks, graphites and

carbon nanotubes (CNTs) are known to support AuNPs for catalyticapplications [394] and sensing [395]. The precipitation–depositionmethod that is very useful with oxide supports results instead inaggregation with carbon supports [383]. Thus, in order to depositAuNPs on carbons, two steps are required. This first step is the syn-thesis of the AuNPs by either the Turkevich method or the Brustmethod using a stabilizer such as citrate, thiol, polymer. The sec-ond step is the immobilization of preformed AuNPs on the surfaceof active carbons (also carbon blacks and graphite) or into thematrixes of CNTs. Concerning the immobilization step, as shownby the group of Prati and Rossi [15,396], the carbon support isadded into a sol of preformed AuNPs with vigorous stirring, andthe AuNPs are immobilized on the support with a certain amountof AuNP loading. A high stabilizer/Au ratio maintains the originalsizes of the AuNPs during the immobilization step [396]. Sol-carboninteractions are critical to control the resulting AuNP size [396,397].

6.3.3. Mesoporous materials and MOFs6.3.3.1. Mesoporous materials. Mesoporous material-supportedAuNPs are widely used as catalysts. The production of these types


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f catalysts leads to high surface-area systems, in which the shape-elective behavior of mesoporous materials can be combined withhe catalytic action of metal particles. This shape selectivity can-ot be achieved with amorphous oxide-supported metal catalysts398,399]. Among all the mesoporous materials, the mesoporousilicas have gained great attention due to the properties of MCM-1 (MCM: Mobil Composition of Matters) and related materials,

ncluding highly ordered mesopores, controlled pore size, specificurface areas and pore volumes [383,400,401]. Mulvaney’ groupublished an early synthesis of silica-coated AuNPs in 1996. Theilane coupling agent (3-aminopropyl)-trimethoxysilane was usedo render the gold surface vitreophilic. After the formation of a thinilica layer in aqueous solution, the particles were transferred intothanol for further growth using the Stober method. Varying the sil-ca shell thickness and the refractive index of the solvent allowedontrol over the optical properties of the dispersions [110].

The use of task-specific ligands with calcining as post-treatmentrovides AuNPs that are encapsulated into the mesoporous chan-els or loaded on the surface of silica spheres [383,402]. Forxample, Corma’s group [403] showed that task-specific ligandsontaining a cetylammonium moiety act as structure-directinggent with AuNPs containing a trialkoxysilyl group. The latter co-ondenses with tetraethoxysilane (TEOS) to form mesoporous silicaFig. 22). In another recent example [403], NH2 and –NH function-lized mesoporous carbon nitride (MCN) was shown to stabilizeuNPs. The synthesis involved the reduction of AuCl4 by NaBH4 inater suspension in the presence of MCN.

Besides task-specific ligands, the AuNPs are also coated witholymers and then encapsulated by mesoporous materials asore-shell AuNPs. For instance, according to Jan et al. [404], areparation of AuNP/mesoporous silica tubular nanostructures.oly(L-lysine) (PLL) and poly(L-glutamic acid) (PLGA) multilayer-oated membranes could be immersed in a HAuCl4 solution toorm AuNP/PLL/PLGA multilayers. Subsequently the membranesere taken out from the solution and inserted in a freshly pre-ared orthosilicic acid solution for 6–12 h, to allow precipitation
f silica in this multilayer. After thoroughly rinsing with waternd drying at room temperature, the as-prepared AuNP/meso-iO2/PLL/PLGAmultilayer was obtained and purified by calcinationFig. 23).
25

ulated in mesoporous silica.ociety.

6.3.3.2. MOFs. MOFs are another form of mesoporous materialsthat are thermally robust and in many cases highly porous. It isexpected that the crystalline porous structures of MOFs limit themigration and aggregation of AuNPs. Thus, MOF-supported AuNPshave gained progressive attention since the first report by Fisherand co-workers in 2005 [405]. In Fisher’s method, the precursorAuNPs are mixed with MOF-5 and loaded into MOF-5 both by ther-mal metal organic chemical vapor deposition (MOCVD) and photoMOCVD. In addition, the MOF-5-encapsulated AuNPs were also pre-pared by solid grinding without organic solvent (Fig. 24) [406].

Very recently, Xu’ group [407,408] published thesynthesis of ZIF-8-encapsulated AuNPs (Zn(MeIM)2 MeIM = 2-methylimidazole). The pretreated ZIF-8 is dispersed in aHAuCl4/MeOH solution, and the mixture is pumped for 1–2 hto be mushy, then suitable amounts of MeOH are added into theslurry, and NaBH4 in MeOH is added under vigorous stirring for thecomplete reduction of AuCl4−. The solid is recovered by filtrationand thoroughly washed with MeOH. Very weak diffractions weredetected from powder XRD patterns, indicating the formation ofsmall AuNPs that was confirmed by TEM and HADDF-STEM.

7. Bimetallic AuNPs

Au bimetallic NPs are classified in two types of mixing patterns:core@shell NPs and alloy bimetallic NPs. The core@shell NPs consistof a metal shell surrounding a gold core, or gold shell surroundinganother metal core. These NPs could be considered as heteroge-neous. The alloy bimetallic NPs consists of a homogeneous mixtureof gold and another metal in the NP. Many Au bimetallic NPs areknown with Ag, Pd, Pt, Zn, Cu, ZrO2, CdS, Fe2O3, Eu, Ni, and Rh [9].

7.1. Core@shell NPs

Core@shell heterobimetallic NPs have appeared in the 1970s[409,410], and Toshima [411,412] has synthesized PVP-stabilizedAu@Pd and Pd@Au NP catalysts, characterized them by X-ray
absorption fine structures and shown that Au@PdNPs weremore active than PdNPs for catalytic hydrogenation reactions,due to synergistic electronic effects [413–415]. The Au-Fe3O4bimetallic NPs are attractive materials for biological and medical


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Fig. 23. Procedure used for preparing meprinted with permission from [404] (Jan’s group). Copyright 2011 American Chem

reas, due to their theranostic (therapy + diagnostic) propertiesnvolving magnetic resonance imaging (MRI) and hyperthermia416,417].

The Au-core@other metal-shell NPs are generally synthe-ized by sequential reduction of appropriate precursors [418].or example, Crooks’s group indicated various ways of formingu-Pd bimetallic NPs in dendrimers. The reduction of metallicrecursors is initiated either by the polyol method or by additionf NaBH4. The co-complexation of dendritic PAMAM interiorigands followed by reduction results in a core@shell structure.or instance, the polyol reduction often results in the formation ofu-core@Pd-shell NPs, because of the difference in the reduction

III
otentials of Au and Pd. The Au precursor is easier to reducehan various transition metal cations including PdII and provides aeed for PdII to be reduced on for the synthesis of Au@Pd NPs. Theizes of the core and shell are controlled by the Au/Pd ratio used
Fig. 24. Synthetic procedure of MOF-5-encapsulatedeprinted with permission from [406] (Haruta’s group). Copyright 2008 Wiley-VCH.

26

rous silica and AuNP/meso-silica tubes.ociety.

during the synthetic procedure. Alternatively, an elegant methodused by Crooks is galvanic displacement that involves the redoxreaction between a DEN and metal ions of another metal [418].Another typical example of core@shell NPs from Xie’s group istheAu@Pt@Au nano raspberries that are used for catalysis [419].As shown in Fig. 25, the first step is the formation of an Ag shellaround the Au core. The conversion from Au@Ag to Au@Pt particlesis achieved via the galvanic displacement of Ag by Pt through theaddition of hexa-chloroplatinic(IV) acid. Silver is deposited onthe Pt surface in a second coating step, again using AgNO3 andsodium citrate as reducing agent. In the last step of the synthesis,raspberry-like Au@Pt@Au NPs are formed via the concerted action
of both reagent reduction and galvanic replacement (vide infra).As shown in the SEM image in Fig. 25b, this approach leads to thegrowth of the desired Au protuberances instead of the formationof a complete and smooth Au shell.
AuNPs. (PCP: porous coordination polymer.)


Fig. 25. (a) Reaction scheme showing morphological and structuralchanges involved in the fabrication of Au/Pt/Au core/shell nanoraspberries and (b) SEM image of thep

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Au25−nAgn(SC12H25)18 by reducing various ratios of HAuCl4/AgNO3mixtures and purified them by precipitation in acetonitrile. Thestructures were confirmed by MALDI and LDI mass spectra [426].Later, this method was developed in order to obtain the alloy

roduct Au@Pt@Au.

eprinted with permission from [419] (Schlücker’s group). Copyright 2011 America

The other metal-core@Au-shell NPs are usually synthesized byorming the Au shell on the other metal core, i.e. sequential loadingnd reduction of the metals leads to the choice of core and shell,ecause the metal that is first introduced forms the core [418]. Aariation involves core surface modification with functional groupserving as templates for the nucleation of Au [409,420]. For exam-le, small Fe3O4 NPs (5–15 nm) were first synthesized by reductionf Fe(acac)3 by 1,6-hexadecanediol in the presence of the cappinggents oleic acid (OA) and oleylamine. Then, the Fe3O4 NPs serveds seeds for the coating of the Au shell. Oleylamine is a crucialurfactant, providing an amine functional group that coordinateso the Au atoms, which is followed by reduction of Au(CH3COO)3y 1,6-hexadecanediol in the presence of oleylamine. As a result,he HR-TEM confirmed the formation of monodispersed FexOy@AuPs with a 5–15 nm core and 0.5–2 nm Au shell thickness [421].ore@shell AuNPs are also known with AuNPs coated with silicahells (Section 4.3.3.1). Murphy et al. disclosed silica nanospheresith a nanoscale overcoat of gold (“nanoshells”) that have tunable

bsorption in the visible and NIR regions, which leads to remarkableotential use of these AuNPs in cellular imaging [422].

.2. Bimetallic alloy NPs

The bimetallic Au alloy NPs are generally synthesized byimultaneous reduction of appropriate precursors [423,424].or instance, theAu-Cu nanocube could be formed by simul-aneous reduction of copper(II) acetylacetonate and HAuCl4y 1,2-hexadecanediol in diphenyl ether in the presence
f 1-adamantanecarboxylic acid, 1-hexadecylamine, and 1-odecanethiol. The TEM image showed that the as-preparedarticles were perfectly cubic in shape and uniform in size, averag-
ng 23 nm, and the EDX spectroscopy line scanning analysis showed

27

mical Society.

a homogeneous distribution of copper and gold across the entirenanocube [425].

Recently, Negishi et al. synthesized the precise alloy clusters

Fig. 26. UV–vis. spectra of Au92Ag52(SR)60 clusters for Au/Ag precursor ratio of1:0.66 with phenylethane thiol (dotted), hexane thiol(dashed), and dodedane thiol(solid).

Reprinted with permission from [427] (Dass’s group). Copyright 2011 Royal Chem-ical Society.

mistry

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lusters Au144−nAgn(SR)60(SR = SCH2CH2Ph, SC6H13 or SC12H25) bytching of the pre-formed Au/Ag clusters with excess thiol [426].he optical absorption spectra of the nanoalloy clusters in theV–-vis. region exhibit three distinct features: a “plasmonic” peakround 430 nm (2.9 eV) and two shoulders around 310 (4.0 eV) and60 nm (2.2 eV). The higher is the n value, the clearer is the appear-nce of these features (Fig. 26) [427,428].

. Conclusion and outlook

The preparation of AuNPs that has been known for a very longime has met a considerable amount of variations involving multi-le materials from biology to functional molecules and finally theolid state. The engineering of AuNPs has become finely tuned withize and shape control towards targeted applications. The intrin-ic lack of toxicity of the AuNP cores and their topological, optical,ensing, catalytic and biomedical properties will obviously lead to auge expansion of their applications in nanotechnology [429–431].

In summary, AuNPs with size below 10 nm are easily pre-ared by the Brust-Schiffrin method, the mechanism havingecently been disclosed [56], or by high-temperature reductionith oxide and other solid supports for catalytic applicationsith supported AuNPs smaller than 5 nm. In molecular chem-

stry, thiolate ligands provide robust AuNPs of 1–10 nm size, andirect syntheses, ligand substitution reactions with functional thi-ls and post functionalizations using for instance olefin metathesis,lick reaction and amide bond formation provide rich means ofultiple functionalizations for potential biomedical applications

432].AuNPs larger than 2–3 nm present the plasmon band resulting

rom the interaction of light with the collective conducting sur-ace electrons of the AuNPs that is not observed for AuNPs smallerhan 2 nm due to the localization of electron in molecular Au clus-er bonds. The plasmon band of relatively large AuNPs is thus mostseful for various imaging and other optical techniques. Thereforehe improved Turkevich method using citrate AuIII reduction is still

uch in use for the synthesis of such AuNPs in the 10–50 nm-sizeange that are functionalized with biomolecules, drugs, receptorsnd imaging agents for diagnostic and therapy applications. Heregain, recent mechanistic investigations have successfully delin-ated the two roles, reductant and stabilizer of citrate [37]. Theeed-growth method with spectacular recent progress, in partic-lar by both Murphy’s and El sayed’s groups, however, is nowonsidered as more precise than the Turkevich method, becauset provides narrower size distributions. For the synthesis of AuNPsarger than 100 nm, the seed-growth method is also specifically effi-ient. AuNPs with various shapes (rods, cubes, triangles, hexapods,ibbons, hollow cages, branches, polyhedra) are synthesized usinghis method by careful controlling of the synthesis conditions. Thushe formation of AuNPs of a specific shape is possible, but its ratio-alization is awaiting more progress because the mechanisms areot yet well understood.

The technology of solid state-supported AuNPs that started withlass decoration (e.g. the IVth-century Lycurgus cup) continueso fascinate scientists with the remarkable catalytic properties ofnter alia oxide-supported AuNPs. The latter, pioneered by Haruta5 years ago, is still expanding using a variety of solids includingesoporous materials, MOFs, nano- and supracrystals [432] and

eterobimetallic NPs towards promising “green-chemistry” appli-ations.

cknowledgments

Financial support from the China Scholarship Council (CSC) ofhe People’s Republic of China (Ph.D. grants to Na Li and Pengx-ang Zhao), the Université Bordeaux 1, the Centre National de la

28

Reviews 257 (2013) 638– 665 661

Recherche Scientifique (CNRS) and the Agence Nationale pour laRecherche (ANR) is gratefully acknowledged.

References

[1] V. Rotello (Ed.), Nanoparticles. Building Block for Nanotechnology, KluwerAcademic Publishers, New York, 2004.

[2] G. Schmid (Ed.), Nanoparticles: From Theory to Application, Wiley-VCH,Weinheim, 2006.

[3] F. Caruso, Colloids and Colloid Assemblies, Wiley-VCH, Weinheim, 2004.[4] L.M. Liz-Marzan, P.V. Kamat, Nanoscale Materials, Kluwer Academic Publish-

ers, New York, 2003.[5] C. Burda, X. Chen, R. Narayanan, M.A. El-Sayed, Chem. Rev. 105 (2005) 1025.[6] X. Chen, S.S. Mao, Chem. Rev. 107 (2007) 2891.[7] Y. Xia, Y. Xiong, B. Lim, S.E. Skrabalak, Angew. Chem. Int. Ed. 48 (2009) 60.[8] M. Faraday, Philos. Trans. 147 (1857) 145.[9] M.-C. Daniel, D. Astruc, Chem. Rev. 104 (2004) 293.

[10] H. Häkkinen, Nat. Chem. 4 (2012) 443.[11] C. Louis, O. Pluchery (Eds.), Gold Nanoparticles for Physics, Chemistry, Biology,

Imperial College Press, 2012.[12] M. Haruta, M. Date, Appl. Catal. A 222 (2001) 427.[13] A. Corma, P. Serna, Science 313 (2006) 332.[14] A.S.K. Hashmi, G.J. Hutchings, Angew. Chem. Int. Ed. 45 (2006) 7896.[15] F. Porta, L. Prati, M. Rossi, G. Scari, J. Catal. 210 (2002) 464.[16] C.G. Bond, D.T. Thompson, Gold Bull. 33 (2000) 41.[17] C.K. Costello, J.H. Yang, H.Y. Law, Y. Wang, J.N. Lin, L.D. Marks, M.D. Kung, H.H.

Kung, Appl. Catal. A 243 (2003) 15.[18] M.S. Chen, D.W. Goodman, Acc. Chem. Res. 39 (2006) 739.[19] G.C. Bond, C. Louis, D. Thompson, Catalysis by Gold, Imperial College Press,

London, 2006.[20] B.K. Min, C.M. Friend, Chem. Rev. 107 (2007) 2709.[21] N. Dimitratos, J.A. Lopez-Sanchez, G.J. Hutchings, Chem. Sci. 3 (2012) 20.[22] P.K. Jain, I.H. El-Sayed, M.A. El-Sayed, Nano Today 2 (2007) 18.[23] R.A. Sperling, P. Rivera-Gil, F. Zhang, M. Zanella, W.J. Parak, Chem. Soc. Rev.

37 (2008) 1896.[24] M.A. El-Sayed, Acc. Chem. Res. 37 (2004) 326.[25] A. Schroeder, D.A. Heller, M.M. Winslow, J.E. Dahlman, G.W. Pratt, R. Langer,

T. Jacks, D.G. Anderson, Nat. Rev. Cancer 12 (2012) 39.[26] K. Saha, S.S. Agasti, C. Kim, X. Li, V.M. Rotello, Chem. Rev. 112 (2012) 2739.[27] R. Bardhan, S. Lal, A. Joshi, N.J. Halas, Acc. Chem. Res. 44 (2011) 936.[28] G.C. Schatz, Proc. Natl. Acad. Sci. U.S.A. 104 (2007) 6885.[29] R. Elghanian, J.J. Storhoff, R.C. Mucic, R.L. Letsinger, C.A. Mirkin, Science 277

(1997) 1078.[30] D.T. Nguyen, D.J. Kim, K.S. Kim, Micron 42 (2011) 207.[31] H. Parab, C. Jung, M.A. Woo, H.G. Park, J. Nanopart. Res. 13 (2011) 2173.[32] J. Turkevich, P.C. Stevenson, J. Hillier, Discuss. Faraday Soc. 11 (1951) 55.[33] G. Frens, Nature: Phys. Sci. 241 (1973) 20.[34] J. Kimling, M. Maier, B. Okenve, V. Kotaidis, H. Ballot, A. Plech, J. Phys. Chem.

B 110 (2006) 15700.[35] B.K. Pong, H.I. Elim, J.X. Chong, W. Ji, B.L. Trout, J.Y. Lee, J. Phys. Chem. C 111

(2007) 6281.[36] J. Polte, T.T. Ahner, F. Delissen, S. Sokolov, F. Emmerling, A.F. Thunemann, R.

Kraehnert, J. Am. Chem. Soc. 132 (2010) 1296.[37] S. Kumar, K.S. Gandhi, R. Kumar, Ind. Eng. Chem. Res. 46 (2007) 3128.[38] X. Ji, X. Song, J. Li, Y. Bai, W. Yang, X. Peng, J. Am. Chem. Soc. 129 (2007) 13939.[39] C. Li, D. Li, G. Wan, J. Xu, W. Hou, Nanoscale Res. Lett. 6 (2011) 440.[40] M.R. Rahman, F.S. Saleh, T. Okajima, T. Ohsaka, Langmuir 27 (2011) 5126.[41] H. Xia, S. Bai, J. Hartmann, D. Wang, Langmuir 26 (2010) 3585.[42] W. Patungwasa, J.H. Hodak, Mater. Chem. Phys. 108 (2008) 45.[43] A. Rohiman, I. Anshori, A. Surawijaya, I. Idris, AIP Conf. Proc. 1415 (2011) 39.[44] J.H. Kim, B.W. Lavin, R.D. Burnett, B.W. Boote, Nanotechnology 22 (2011)

285602.[45] L.M.C. Aguilera, M.F. Romano, M.L.A. Gil, I.N. Rodrigurez, J.L. Hidalgo-Hidalgo

de Cisneros, J.M.P. Santander, Untrason. Sonochem. 18 (2011) 789.[46] C.H. Su, P.L. Wu, C.S. Yeh, J. Phys. Chem. B 107 (2003) 14240.[47] I. Ojea-Jimenez, F.M. Romero, N.G. Bastus, V. Puntes, J. Phys. Chem. C 114

(2010) 1800.[48] J.W. Slot, H.J. Geuze, Eur. J. Cell Biol. 38 (1985) 87.[49] K.R. Brown, A.P. Fox, M.J. Natan, J. Am. Chem. Soc. 118 (1996) 1154.[50] S.K. Sivaraman, S. Kumar, V. Santhanam, J. Colloid Interface Sci. 361 (2011)

543.[51] D. Philip, Spectrochim. Acta A: Mol. Biomol. Spectrosc. 71 (2008) 80.[52] M. Giersig, P. Mulvaney, Langmuir 9 (1993) 3408.[53] M. Brust, M. Walker, D. Bethell, D.J. Schiffrin, R.J. Whyman, J. Chem. Soc., Chem.

Commun. (1994) 801.[54] M.J. Hostetler, S.J. Green, J.J. Stockes, R.W. Murray, J. Am. Chem. Soc. 118 (1996)

4212.[55] A.C. Templeton, W.P. Wuelfing, R.W. Murray, Acc. Chem. Res. 33 (2000) 27.[56] Y. Li, O. Zaluzhna, B. Xu, Y. Gao, J.M. Modest, Y.J. Tong, J. Am. Chem. Soc. 133

(2011) 2092.
[57] R. Jin, Nanoscale 2 (2010) 343.[58] O. Zaluzhna, Y. Li, C. Zangmeister, T.C. Alison, Y.J. Tong, Chem. Commun. 48
(2012) 362.[59] F. Vitale, I. Fratoddi, C. Battocchio, E. Piscopiello, L. Tapfer, M.V. Russo, G.

Polzonetti, C. Giannini, Nanoscale Res. Lett. 6 (2011) 103.

6 mistry
[60] J. Akola, M. Walter, R.L. Whetten, H. Häkkinen, H. Grönbeck, J. Am. Chem. Soc.130 (2008) 3756.

[61] O. Toikkanen, V. Ruiz, G. Ronnholm, N. Kalkkinen, P. Liljeroth, B.M. Quinn, J.Am. Chem. Soc. 132 (2008) 11049.

[62] P.J.G. Goulet, R.B. Lennox, J. Am. Chem. Soc. 132 (2010) 9582.[63] J.F. Parker, C.A. Fields-Zinna, R.W. Murray, Acc. Chem. Res. 43 (2010) 1289.[64] M. Brust, J. Fink, D. Bethell, D.J. Schiffrin, C.J. Kiely, J. Chem. Soc., Chem. Com-

mun. (1995) 1655.[65] A.G. Kanaras, F.S. Kamounah, K. Schaumburg, C.J. Kiely, M. Brust, Chem. Com-

mun. (2002) 2294.[66] B. Duncan, C. Kim, V.M. Rotello, J. Control. Release 148 (2010) 122.[67] E. Glogowski, R. Tangirala, H. Jinbo, T.P. Russell, T. Emrick, Nano Lett. 7 (2007)

389.[68] C. Miesch, I. Kosif, E. Lee, J.K. Kim, T.P. Russell, R.C. Hayward, T. Emrick, Angew.

Chem. Int. Ed. 51 (2012) 145.[69] M. Zheng, Z. Li, X. Huang, Langmuir 20 (2004) 4226.[70] Y. Hao, X. Yang, S. Song, M. Huang, C. He, M. Cui, J. Chen, Nanotechnology 23

(2012) 045103.[71] R. Sardar, J.S. Shumaker-Parry, Chem. Mater. 21 (2009) 1167.[72] G. Chen, M. Takezawa, N. Kawazoe, T. Tateishi, Open Biotechnol. J. 2 (2008)

152.[73] A.J. Di-Pasqua, R.E. Mishler, Y.L. Ship, J.C. Davrowiak, T. Asefa, Mater. Lett. 63

(2009) 1876.[74] A.F.G. Leontowich, C.F. Calver, M. Dasog, R.W.J. Scott, Langmuir 26 (2010)

1285.[75] M. Busby, C. Chiorboli, F. Scandola, J. Phys. Chem. B 110 (2006) 6020.[76] R.K. Gupta, M.P. Srinivasan, R. Dharmarajan, Colloid Surf. A 390 (2011) 149.[77] E.R. Zubarev, J. Xu, A. Sayyad, J.D. Gibson, J. Am. Chem. Soc. 128 (2006) 4958.[78] R.M. Pattabi, M. Pattabi, Spectrochim. Acta A 74 (2009) 195.[79] C.J. Ackerson, P.D. Jadzinsky, J.Z. Sexton, D.A. Bushnell, R.D. Kornberg, Biocon-

jugate Chem. 21 (2010) 214.[80] C.I. Müller, C. Lambert, Langmuir 27 (2011) 5029.[81] Y. Li, O. Zaluzhna, C. Zangmeister, T.C. Allison, Y.J. Tong, J. Am. Chem. Soc. 134

(2012) 1990.[82] B.S. Zelakiewicz, T. Yonezawa, Y.Y. Tong, J. Am. Chem. Soc. 126 (2004) 8112.[83] Y. Li, L.C. Silverton, R. Haasch, Y.J. Tong, Langmuir 24 (2008) 7048.[84] D.T. Miles, R.W. Murray, Anal. Chem. 75 (2003) 1251.[85] B.M. Quinn, P. Liljeroth, V. Ruiz, T. Laaksonen, K. Kontturi, J. Am. Chem. Soc.

125 (2003) 6644.[86] R.L. Donkers, D. Lee, R.W. Murray, Langmuir 20 (2004) 1945.[87] J.B. Tracy, G. Kalyuzhny, M.C. Crowe, R. Balasubramanian, J.P. Choi, R.W. Mur-

ray, J. Am. Chem. Soc. 129 (2007) 6706.[88] S.F. Sweeney, G.H. Woehrle, J.E. Hutchison, J. Am. Chem. Soc. 128 (2006) 3190.[89] Y.L. Kalisman, P.D. Jadzinsky, N. Kalisman, H. Tsunoyama, T. Tsukuda, D.A.

Bushnell, R.D. Kornberg, J. Am. Chem. Soc. 133 (2011) 2976.[90] P.D. Jadzinsky, G. Calero, C.J. Ackerson, D.A. Bushnell, R.D. Kornberg, Science

318 (2007) 430.[91] D.V. Leff, P.C. Ohara, J.R. Heath, W.M. Gelbart, J. Phys. Chem. 99 (1995) 7036.[92] P. Zhao, M. Grillaud, L. Salmon, J. Ruiz, D. Astruc, Adv. Synth. Catal. 354 (2012)

1001.[93] R.H. Terrill, T.A. Postlethwaite, C.H. Chen, C.D. Poon, A. Terzis, A. Chen, J.E.

Hutchison, M.R. Clark, G. Wignall, J.D. Londono, R. Superfine, M. Falvo, C.S.Johnson Jr., E.T. Samulski, R.W. Murray, J. Am. Chem. Soc. 117 (1995) 12537.

[94] A. Labande, J. Ruiz, D. Astruc, J. Am. Chem. Soc. 124 (2002) 1782.[95] D. Zhang, O. Neumann, H. Wang, V.M. Yuwono, A. Barhoumin, M. Perham, J.D.

Hartaerink, P. Wittung-Stafshede, N.J. Halas, Nano Lett. 9 (2009) 666.[96] J.R.G. Navarro, M. Plugge, M. Loumaigne, A. Sanchez-Gonzalez, B. Mennucci,

A. Debarre, A.M. Brouwer, M.H.V. Werts, Photochem. Photobiol. Sci. 9 (2010)1042.

[97] E. Oh, K. Susumu, R. Goswami, H. Mattoussi, Langmuir 26 (2010) 7604.[98] A. Manna, P. Chen, H. Akiyama, T. Wei, K. Tamada, W. Knoll, Chem. Mater. 15

(2003) 20.[99] Y. Li, O. Zaluzhna, Y.J. Tong, Chem. Commun. 47 (2011) 6033.

[100] Z. Tang, B. Xu, B. Wu, M.W. Germann, G. Wang, J. Am. Chem. Soc. 132 (2010)3367.

[101] S. Sistach, M. Beija, V. Rahal, A. Brulet, J. Marty, M. Destarac, C. Mingotaud,Chem. Mater. 22 (2010) 3712.

[102] S. Zhang, G. Leem, T.R. Lee, Langmuir 25 (2009) 13855.[103] M.S. Vickers, J. Cookson, P.D. Beer, P.T. Bishop, B. Thiebaut, J. Mater. Chem. 16

(2006) 209.[104] K. Wojczykowski, D. Meißner, P. Jutzi, I. Ennen, A. Hütten, M. Fricke, D. Volk-

mer, Chem. Commun. (2006) 3693.[105] S. Wang, K. Qian, X. Bi, W. Huang, J. Phys. Chem. C 113 (2009) 6505.[106] A.A. Volkert, V. Subramaniam, M.R. Ivanov, A.M. Goodman, A.J. Haes, ACS Nano

5 (2011) 4570.[107] Y. Kang, D.J. Won, S.R. Kim, K. Seo, H.S. Choi, G. Lee, Z. Noh, T.S. Lee, C. Lee,

Mater. Sci. Eng. C 24 (2004) 43.[108] M.I. Bethencourt, L. Srisombat, P. Chinwangso, T.R. Lee, Langmuir 25 (2009)

1265.[109] S.C. Biradar, D.B. Shinde, V.K. Pillai, M.G. Kulkarni, J. Mater. Chem. 22 (2012)

10000.
[110] M. Liz-Marzan, M. Giersig, P. Mulvaney, Langmuir 12 (1996) 4329.[111] D.A. Giljohann, D.S. Seferos, W.L. Daniel, M.D. Massich, P.C. Patel, C.A. Mirkin,
Angew. Chem. Int. Ed. 49 (2010) 3280.[112] D.K. Kim, S.J. Park, J.H. Lee, Y.Y. Jeong, S.Y. Jon, J. Am. Chem. Soc. 129 (2007)

7661.

29

Reviews 257 (2013) 638– 665

[113] M.C. Daniel, M.E. Grow, H. Pan, M. Bednarek, W.E. Ghann, K. Zabetakis, J.Cornish, New J. Chem. 35 (2011) 2366.

[114] R.K. Gupta, M.P. Srinivasan, R. Dharmarajan, Mater. Lett. 67 (2012) 315.[115] A.C. Templeton, M.J. Hostetler, C.T. Kraft, R.W. Murray, J. Am. Chem. Soc. 120

(1998) 1906.[116] C.A. Fields-Zinna, J.F. Parker, R.W. Murray, J. Am. Chem. Soc. 132 (2010) 17193.[117] Y.S. Shon, H. Choo, C. R. Chimie 6 (2003) 1009.[118] A. Labande, D. Astruc, Chem. Commun. (2000) 1007.[119] D. Baranov, E.N. Kadnikova, J. Mater. Chem. 21 (2011) 6152.[120] Y. Zhou, S. Wang, K. Zhang, X. Jiang, Angew. Chem., Int. Ed. 47 (2008) 1.[121] J.L. Brennan, N.S. Hatzakis, T.R. Tshikhudo, N. Dirvianskyte, V. Razumas, S.

Patkar, J. Vind, A. Svendsen, R.J.M. Nolte, A.E. Rowan, M. Brust, Bioconj. Chem.17 (2006) 1373.

[122] E. Boisselier, L. Salmon, J. Ruiz, D. Astruc, Chem. Commun. 578 (2008) 8.[123] D.A. Fleming, C.J. Thode, M.E. Williams, Chem. Mater. 18 (2006) 2327.[124] A. Franc ois, A. Laroche, N. Pinaud, L. Salmon, J. Ruiz, J. Robert, D. Astruc,

ChemMedChem 6 (2011) 2003.[125] A.W. Shaffer, J.G. Worden, Q. Huo, Langmuir 20 (2004) 8343.[126] J. Bresee, K.E. Maier, C. Melander, D.L. Feldheim, Chem. Commun. 46 (2010)

7516.[127] J. Milette, V. Toader, L. Reven, R.B. Lennox, J. Mater. Chem. 21 (2011) 9043.[128] S. Rucareanu, M. MacCarini, L.J. Shepherd, R.B. Lennox, J. Mater. Chem. 18

(2008) 5830.[129] S. Rucareanu, V.J. Gandubert, R.B. Lennox, Chem. Mater. 18 (2006) 4674.[130] S.A. Jadhav, J. Mater. Chem. 22 (2012) 5894.[131] M. Geng, Y. Zhang, Q. Huang, B. Zhang, Q. Li, W. Li, J. Li, Carbon 48 (2010) 3570.[132] M. Alloisio, A. Demartini, C. Cuniberti, G. Dellepiane, S.A. Jadhav, G. Petrillo, E.

Giorgetti, C. Gellini, M. Muniz-Miranda, J. Phys. Chem. C 113 (2009) 19475.[133] L. Liang, D. Astruc, Coord. Chem. Rev. 255 (2011) 2933.[134] D. Astruc, E. Boisselier, C. Ornelas, Chem. Rev. 110 (2010) 1857.[135] A. Shakeri-Zadeh, M. Ghasemifard, G.A. Mansoori, Phys. E: Low-dim. Sys.

Nanostr. 42 (2010) 1272.[136] P. Zhao, D. Astruc, ChemMedChem 7 (2012) 952.[137] R.D. Felice, A.J. Selloni, J. Chem. Phys. 120 (2004) 4906.[138] P.M. Shem, R. Sardar, J.S. Shumaker-Parry, Langmuir 25 (2009) 13279.[139] R.W. Burgess, V.J. Keast, J. Phys. Chem. C 115 (2011) 21016.[140] J. Ramirez, M. Sanau, E. Fernandez, Angew. Chem. Int. Ed. 47 (2008) 5194.[141] A. Fürstner, L. Morency, Angew. Chem. Int. Ed. 47 (2008) 5030.[142] M. Walter, J. Akola, O. Lopez-Acevedo, P.D. Jadzinsky, G. Calero, C.J. Ackerson,

R.L. Whetten, H. Gronbeck, H. Häkkinen, PNAS 105 (2008) 9157.[143] J.F. Hainfield, Science 236 (1987) 450.[144] J.M. Pettibone, J.W. Hudgens, Small 128 (2012) 715.[145] A.D. Jewell, E.C.H. Sykes, G. Kyriakou, ACS Nano. 6 (2012) 3545.[146] P.D. Jadzinsky, G. Calero, C.J. Ackerson, D.A. Bushnell, R.D. Kornberg,.Science

318 (2007) 430.[147] M.H. Heaven, A. Dass, P.S. White, K.M. Holt, R.W. Murray, J. Am. Chem. Soc.

130 (2008) 3754.[148] P. Gruene, D.M. Rayner, B. Redlich, A.F.G. Van der Meer, J.T. Lyon, G. Meijer, A.

Fielicke, Science 321 (2008) 674.[149] M. Zhu, C.M. Aikens, F.J. Hollander, G.C. Schatz, R. Jin, J. Am. Chem. Soc. 130

(2008) 5883.[150] S.W. Chen, R.S. Ingram, M.J. Hostetler, J.J. Pietron, R.W. Murray, T.G. Schaaff,

J.T. Khoury, M.M. Alvarez, R.L. Whetten, Science 280 (1998) 2098.[151] A. Moores, F. Goettmann, C. Sanchez, P. Le Floch, Chem. Commun. (2004) 2842.[152] N. Zheng, J. Fan, G.D. Stucky, J. Am. Chem. Soc. 128 (2006) 6550.[153] W.W. Weare, S.M. Reed, M.G. Warner, J.E. Hutchison, J. Am. Chem. Soc. 122

(2000) 12890.[154] G. Schmid, R. Pfeil, R. Boese, F. Bandermann, S. Meyer, G.H.M. Calis, J.W.A. van

der Velden, Chem. Ber. 114 (1981) 3634.[155] J.M. Pettibone, J.W. Hudgens, ACS Nano 5 (2011) 2989.[156] N. De-Silva, J.M. Ha, A. Solovyov, M.M. Nigra, I. Ogino, S.W. Yeh, K.A. Durkin,

A. Katz, Nat. Chem. 2 (2010) 1062.[157] J.M. Ha, A. Solovyov, A. Katz, Langmuir 25 (2009) 10548.[158] C. Gautier, R. Taras, S. Gladiali, T. Burgi, Chirality 20 (2008) 486.[159] A. Villa, D. Wang, D. Su, G.M. Veith, L. Prati, Phys. Chem. Chem. Phys. 12 (2010)

2183.[160] C. Xu, L. Sun, L.J. Kepley, R.M. Crooks, Anal. Chem. 65 (1993) 2102.[161] A. Kumar, S. Mandal, P.R. Selvakannan, R. Paricha, A.B. Mandale, M. Sastry,

Langmuir 19 (2003) 6277.[162] F. Porta, Z. Krpetic, L. Prati, A. Gaiassi, G. Scari, Langmuir 24 (2008) 7061.[163] N. Wangoo, K.K. Bhasin, R. Boro, C.R. Suri, Anal. Chim. Acta 610 (2008) 142.[164] N. Wangoo, K.K. Bhasin, S.K. Mehta, C.R. Suri, J. Colloid Interf. Sci. 323 (2008)

247.[165] R. Shomura, K.J. Chung, H. Iwai, M. Higuchi, Langmuir 27 (2011) 7972.[166] N. Wangoo, K.J. Kaushal, K. Bhasin, S.K. Mehta, C.R. Suri, Chem. Commun.

(2006) 5755.[167] F. Griffin, D. Fitzmaurice, Langmuir 23 (2007) 10262.[168] D.I. Gittins, F. Caruso, Angew. Chem. Int. Ed. 40 (2001) 3001.[169] A. Yu, Z. Liang, J. Cho, F. Caruso, Nano Lett. 3 (2003) 1203.[170] V.J. Gandubert, R.B. Lennox, Langmuir 21 (2005) 6532.[171] B.C. Barlow, I.J. Burgess, Langmuir 23 (2007) 1555.
[172] H. Lange, J. Maultzsch, W. Meng, D. Mollenhauer, B. Paulus, N. Peica, S.
Schlecht, C. Thomsen, Langmuir 27 (2011) 7258.[173] M.A. Raj, S.B. Revin, S.A. John, Colloid Surf. B 87 (2011) 353.[174] G. Li, D. Li, L. Zhang, J. Zhai, E. Wang, Chem. Eur. J. 15 (2009) 9868.[175] M.S. Yavuz, W. Li, Y. Xia, Chem. Eur. J. 15 (2009) 13181.

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176] B. Kumar-Jean, C.R. Raj, Langmuir 23 (2007) 4064.177] N.T.K. Thanh, L.A.W. Green, Nano Today 5 (2010) 213.178] J. Shan, H. Tenhu, Chem. Commun. (2007) 4580.179] H.H. Helcher, Aurum Postabile oder Gold Tinstur, J. Herbord Klossen, Breslau,

Leipzig, 1718.180] Z. Tuzar, P. Kratochvil, Surface and Colloid Science, Plenum Press, New York,

1993, p. 1.181] R. Shenhar, T.B. Norsten, V.M. Rotello, Adv. Mater. 17 (2005) 657.182] T. Sun, G. Qing, Adv. Mater. 23 (2011) H57.183] R. Jordan, Adv. Polym. Sci. (2006) 198.184] R. Contreras-Caceres, A. Sanchez-Iglesias, M. Karg, I. Pastoriza-Santos, J. Perez-

Juste, J. Pacifico, T. Hellweg, A. Fernandez-Barbero, L.M. Liz-Marzan, Adv.Mater. 20 (2008) 1666.

185] K. Gries, M.E.I Helou, G. Witte, S. Agarwal, A. Greiner, Polymer 53 (2012) 1632.186] D.J. Kim, S.M. Kang, B. Kong, W.J. Kim, H.J. Paik, H. Choi, I.S. Choi, Macromol.

Chem. Phys. 206 (2005) 1941.187] D. Li, Q. He, Y. Cui, K. Wang, X. Zhang, J. Li, Chem. Eur. J. 13 (2007) 2224.188] D. Li, Q. He, Y. Cui, J. Li, Chem. Mater. 19 (2007) 412.189] C. Kruger, S. Agarwal, A. Greiner, J. Am. Chem. Soc. 130 (2008) 2710.190] A.M. Alkilany, P.K. Nagaria, M.D. Wyatt, C.J. Murphy, Langmuir 26 (2010) 9328.191] M.K. Corbierre, N.S. Cameron, R.B. Lennox, Langmuir 20 (2004) 2867.192] S.K. Bae, S.Y. Lee, S.C. Hong, React. Funct. Polym. 71 (2011) 187.193] A. Buonerba, C. Cuomo, S.O. Sanchez, P. Canton, A. Grassi, Chem. Eur. J. 18

(2012) 709.194] C. Gentilini, F. Evangelista, P. Rudolf, P. Franchi, M. Lucarini, L. Pasquato, J. Am.

Chem. Soc. 130 (2008) 15678.195] C.A. Fustin, C. Colard, M. Filali, P. Guillet, A.S. Duwez, M.A.R. Meier, U.S. Schu-

bert, J.F. Gohy, Langmuir 22 (2006) 6690.196] J. Shan, M. Nupponen, H. Jiang, T. Viitala, E. Kauppinen, K. Kontturi, H. Tenhu,

Macromolecules 38 (2005) 2918.197] J.J. Chiu, B.J. Kim, E.J. Kramer, D.J. Pine, J. Am. Chem. Soc. 127 (2005) 5036.198] N. Higashi, J. Kawahara, M. Niwa, J. Colloid Interf. Sci. 288 (2005) 83.199] J.G. Serrano, U. Pal, A.M. Herrera, P. Salas, C.A. Chavez, Chem. Mater. 20 (2008)

5146.200] X. Huang, B. Li, H. Zhang, I. Hussain, L. Liang, B. Tan, Nanoscale 3 (2011) 1600.201] I. Biondi, G. Laurencay, P.J. Dyson, Inorg. Chem. 50 (2011) 8038.202] M. Beija, J.D. Marty, M. Destarac, Chem. Commun. 47 (2011) 2826.203] I. Hussain, S. Graham, Z. Wang, B. Tan, D.C. Sherrington, S.P. Rannard, A.I.

Cooper, M. Brust, J. Am. Chem. Soc. 127 (2005) 16398.204] D. Suzuki, H. Kawaguchi, Langmuir 21 (2005) 8175.205] T. Azzam, L. Bronstein, A. Eisenberg, Langmuir 24 (2008) 6521.206] C.D. Gasselin, M. Capelot, N. Sanson, N. Lequeux, Langmuir 26 (2010) 12321.207] D. Miyamoto, M. Oishi, K. Kojima, K. Yoshimoto, Y. Nagasaki, Langmuir 24

(2008) 5010.208] N.S. Ieong, K. Brebis, L.E. Daniel, R.K. O’Reilly, M.I. Gibson, Chem. Commun. 47

(2011) 11627.209] G.R. Newkome, C. Shreiner, Chem. Rev. 110 (2010) 6338.210] A.M. Caminade, C.O. Turin, R. Laurent, A. Ouali, B. Delavaux-Nicot, Dendrimers

Towards Catalytic, Material and Biomedical Uses, Wiley, Chichester, 2011.211] K. Esumi, K. Miyamoto, T. Yoshimura, J. Colloid Interf. Sci. 254 (2002) 402.212] K. Esumi, H. Houdatsu, T. Yoshimura, Langmuir 20 (2004) 2536.213] D. Astruc, F. Lu, J. Ruiz, Angew. Chem. Int. Ed. 44 (2005) 7852.214] T. Endo, T. Yoshimura, K. Esumi, J. Colloid. Interf. Sci. 286 (2005) 602.215] T.H. Kim, H.S. Choi, R.B. Go, J. Kim, Electrochem. Commun. 12 (2010) 788.216] H. Liu, K. Sun, J. Zhao, R. Guo, M. Shen, X. Cao, G. Zhang, X. Shi, Colloid. Surf. A

(2012) ASAP, http://dx.doi.org/10.1016/j.colsurfa.2012.04.028217] J. Won, K.J. Ihn, Y.S. Kang, Langmuir 18 (2002) 8246.218] D.F. Yancey, E.V. Carino, R.M. Crooks, J. Am. Chem. Soc. 132 (2010) 10988.219] C. Ornelas, D. Méry, E. Cloutet, J. Ruiz, D. Astruc, J. Am. Chem. Soc. 130 (2008)

1495.220] D. Astruc, Nat. Chem. 4 (2012) 255.221] A. Labande, J. Ruiz, D. Astruc, J. Am. Chem. Soc. 124 (2002) 1728.222] M.C. Daniel, J. Ruiz, S. Nlate, J.C. Blais, D. Astruc, J. Am. Chem. Soc. 125 (2003)

2617.223] C. Kaewtong, G. Jiang, R. Ponnapati, B. Pulpoka, R. Advincula, Soft Matter 6

(2010) 5316.224] J. Ruiz, C. Belin, D. Astruc, Chem. Commun. (2007) 3456.225] D. Astruc, Electron Transfer and Radical Processes in Transition Metal Chem-

istry, VCH, New York, 1995, Chapter 3.226] L. Balogh, R. Valluzzi, K.S. Laverdure, S.P. Gido, G.L. Hagnauer, D.A. Tomalia, J.

Nanopart. Res. 1 (1999) 353.227] M.E. Garcia, L.A. Baker, R.M. Crooks, Anal. Chem. 71 (1999) 256.228] V. Chechik, R.M. Crooks, Langmuir 15 (1999) 6364.229] Y. Shan, T. Luo, C. Peng, R. Sehng, X. Cao, H. Cao, M. Shen, R. Guo, H. Tomas, X.

Shi, Biomaterials 33 (2012) 3025.230] C. Peng, L. Zheng, Q. Chen, M. Shen, R. Guo, H. Wang, X. Cao, G. Zhang, X. Shi,

Biomaterials 33 (2012) 1107.231] Y.G. Kim, S.K. Oh, R.M. Crooks, Chem. Mater. 16 (2004) 167.232] C.S. Love, V. Chechik, D.K. Smith, C. Brennan, J. Mater. Chem. 14 (2004) 919.233] L.W. Hoffman, G.G. Andersson, A. Sharma, S.R. Clarke, N.H. Voelcker, Langmuir

27 (2011) 6759.
234] M.C. Daniel, J. Ruiz, S. Nlate, J. Palumbo, J.C. Blais, D. Astruc, Chem. Commun.
(2001) 2000.235] T. Selvaraju, J. Das, K. Jo, K. Kwon, C.H. Huh, T.K. Kim, H. Yang, Langmuir 24

(2008) 9883.236] D. Astruc, L. Liang, A. Rapakousiou, J. Ruiz, Acc. Chem. Res. 45 (2012) 630.

30

Reviews 257 (2013) 638– 665 663

[237] R. Wang, J. Yang, Z. Zheng, M.D. Carducci, J. Jiao, S. Seraphin, Angew. Chem.Int. Ed. 40 (2001) 549.

[238] D. Thompson, J.P. Hermes, A.J. Quinn, M. Mayor, ACS Nano 6 (2012)3007.

[239] K.R. Gopidas, J.K. Whitesell, M.A. Fox, J. Am. Chem. Soc. 125 (2003) 6491.[240] A. Taubert, U.M. Wiesler, K. Müllen, J. Mater. Chem. 13 (2003) 1090.[241] M.R. Knecht, J.C.M. Garcia, R.M. Crooks, Langmuir 21 (2005) 11981.[242] S. Deng, T.M. Fulghum, G. Krueger, D. Parron, J.Y. Park, R.C. Advincula, Chem.

Eur. J. 17 (2011) 8929.[243] J.P. Hermes, F. Sander, T. Peterle, R. Urbani, T. Pfohl, D. Thompson, M. Mayor,

Chem. Eur. J. 17 (2011) 13473.[244] T.J. Cho, R.A. Zangmeister, R.I. Mac-Cuspie, A.K. Patri, V.A. Hackley, Chem.

Mater. 23 (2011) 2665.[245] M. Frasconi, C. Tortolini, F. Botre, F. Mazzei, Anal. Chem. 82 (2010) 7335.[246] H. Namazi, A.M.P. Fard, Mater. Chem. Phys. 129 (2011) 189.[247] G. Jiang, L. Wang, T. Chen, H. Yu, C. Chen, Mater. Chem. Phys. 98 (2006) 76.[248] E. Murugan, R. Rangasamy, J. Polym. Sci. A: Polym. Chem. 48 (2010) 2525.[249] E. Boisselier, A.K. Diallo, L. Salmon, J. Ruiz, D. Astruc, Chem. Commun. (2008)

4819.[250] E. Boisselier, A.K. Diallo, L. Salmon, C. Ornelas, D. Astruc, J. Am. Chem. Soc. 132

(2010) 2729.[251] L. Jia, L.P. Lv, J.P. Xu, J. Ji, J. Nanopart. Res. 13 (2011) 4075.[252] Y. Chaikin, H. Leader, R. Popovitz-Biro, A. Vaskevich, I. Rubinstein, Langmuir

27 (2011) 1298.[253] S.S. Nair, S.A. John, T. Sagara, Electrochim. Acta 54 (2009) 6837.[254] M. Wanunu, R. Popovita-Biro, H. Cohen, A. Vaskevich, I. Rubinstein, J. Am.

Chem. Soc. 127 (2005) 9207.[255] M. Brust, R. Etchenique, E.J. Calvo, G.J. Gordillo, Chem. Commun. (1996) 1949.[256] J.A. Edgar, A.M. McDonaph, M.B. Cortie, ACS Nano 6 (2012) 1116.[257] B. Nikoobakht, M.A. El-Sayed, Langmuir 17 (2001) 6368.[258] A. Swami, A. Kumar, M. Sastry, Langmuir 19 (2003) 1168.[259] K.T. Yong, M.T. Swihart, H. Ding, P.N. Prasad, Plasmonics 4 (2009) 79.[260] S. Pyrpassopoulos, D. Niarchos, G. Nounesis, N. Boukos, I. Zafiropuolou, V.

Tzitzios, Nanotechnology 18 (2007), no: 485604.[261] S.Y. Moon, T. Kusunose, T. Sekino, Mater. Lett. 63 (2009) 2038.[262] P.L. Luisi, M. Giomini, M.P. Pileni, B.H. Robinson, Biochem. Biophys. Acta 947

(1988) 209.[263] M.P. Pileni, J. Phys. Chem. 97 (1993) 6961.[264] M. Wu, D. Chen, T. Huang, Langmuir 17 (2001) 3877.[265] C.J. Murphy, T.K. Sau, A. Gole, C.J. Orendorff, MRS Bull. 30 (2005) 349.[266] F. Aliotta, V. Arcoleo, S. Buccoler, G.L. Manna, V.T. Liver, Thermochim. Acta

265 (1995) 15.[267] C.L. Chiang, J. Colloid Interf. Sci. 230 (2000) 60.[268] A.P. Herrera, O. Resto, J.G. Briano, C. Rinaldi, Nanotechnology 16 (2005) S618.[269] P. Calandra, C. Giordano, A. Longo, V.T. Liveri, Mater. Chem. Phys. 98 (2006)

494.[270] B. Abecassis, F. Testard, T. Zemb, Soft Matter 5 (2009) 974.[271] M. Takahashi, S. Ohno, N. Fujita, T. Sengoku, H. Yoda, J. Colloid Interf. Sci. 356

(2011) 536.[272] M.J. Hollamby, J. Eastoe, A. Chemelli, O. Glatter, S. Rogers, R.K. Heenan, I. Grillo,

Langmuir 26 (2010) 6989.[273] G. Riess, Prog. Polym. Sci. 28 (2003) 1107.[274] N. Ali, S.Y. Park, Langmuir 24 (2008) 9279.[275] J. Spatz, S. Mö�mer, M. Möller, M. Kocher, D. Neher, G. Wegner, Adv. Mater.

10 (1998) 473.[276] T.F. Jaramillo, S.H. Baeck, B.R. Cuenya, E.W. McFarland, J. Am. Chem. Soc. 125

(2003) 7148.[277] B.R. Cuenya, S.H. Baeck, T.F. Jaramillo, E.W. McFarland, J. Am. Chem. Soc. 125

(2003) 12928.[278] W.L. Leong, P.S. Lee, A. Lohani, Y.M. Lan, T. Chen, Adv. Mater. 20 (2008) 2325.[279] S. Papp, L. Korösi, B. Gool, T. Dederichs, P. Mela, M. Möller, I. Dékány, J. Therm.

Anal. Calorim. 101 (2010) 865.[280] T. Sakai, P. Alexandridis, Langmuir 20 (2004) 8426.[281] M.S. Bakshi, A. Kaura, P. Bhandari, G. Kaur, K. Torgoe, K. Esumi, J. Nanosci.

Nanotechnol. 6 (2006) 1405.[282] S. Chen, C. Guo, G.H. Hu, J. Wang, J.H. Ma, X.F. Liang, L. Zheng, H.Z. Liu, Langmuir

22 (2006) 9704.[283] S.G. Lopez, E. Castro, P. Taboada, V. Mosquera, Langmuir 24 (2008) 13186.[284] T. Sakai, P. Alexandridis, J. Phys. Chem. B 109 (2005) 7766.[285] P. Khullar, A. Mahal, V. Singh, T.S. Banipal, G. Kaur, M.S. Bakshi, Langmuir 26

(2010) 11363.[286] P. Khullar, V. Singh, A. Mahal, H. Kaur, V. Singh, T.S. Banipal, G. Kaur, M.S.

Bakshi, J. Phys. Chem. C 115 (2011) 10442.[287] J. Liu, J. Niu, L. Yin, F. Jiang, Analyst 136 (2011) 4802.[288] T. Azzam, A. Eisenberg, Langmuir 23 (2007) 2126.[289] Y. Lee, T.G. Park, Langmuir 27 (2011) 2965.[290] P. He, M.W. Urban, Biomacromolecules 6 (2005) 1224.[291] T.K. Sau, A.S. Urban, S.K. Dondapati, M. Fedoruk, M.R. Horton, A.L. Rogach, F.D.

Stefani, J.O. Radler, J. Feldmann, Colloid. Surf. A 342 (2009) 92.[292] R. Genc, M. Ortiz, C.K. O’Sullivan, Langmuir 25 (2009) 12604.[293] R. Genc, G. Clergeaud, M. Ortiz, C.K. O’Sullivan, Langmuir 27 (2011) 10894.
[294] D.V. Goia, E. Marijevic, Colloid Surf. A 146 (1999) 139.[295] S.S. Shankar, A. Rai, B. Ankamwar, A. Singh, A. Ahmad, M. Sastry, Nat. Mater.
3 (2004) 482.[296] B. Ankamwar, C. Damle, A. Ahmad, M. Sastry, J. Nanosci. Nanotechnol. 5 (2005)

1665.

http://dx.doi.org/10.1016/j.colsurfa.2012.04.028

6 mistry
[297] S.P. Chandran, M. Chaudhary, R. Pasricha, A. Ahmad, M. Sastry, Biotechnol.Progr. 22 (2006) 577.

[298] J. Huang, Q. Li, D. Sun, Y. Lu, Y. Su, X. Yin, H. Wang, Y. Wang, W. Shao, N. He, J.Hong, C. Chen, Nanotechnology 18 (2007) 105104.

[299] S. Dhar, E.M. Reddy, A. Shiras, V. Pokharkar, B.L.V. Prasad, Chem. Eur. J. 14(2008) 10244.

[300] E.C. da Silva, M.G.A. da Silva, S.M.P. Meneghetti, G. Machado, M.A.R.C. Alencar,J.M. Hickmann, M.R. Meneghetti, J. Nanopart. Res. 10 (2008) 201.

[301] D. Philip, Spectrochim. Acta A 73 (2009) 374.[302] D. Philip, Physica E 42 (2010) 1417.[303] S.K. Sivaraman, S. Kumar, V. Santhanam, Gold Bull. 43 (2010) 275.[304] X. Huang, H. Wu, X. Liao, B. Shi, Green Chem. 12 (2010) 395.[305] K.P. Kumar, W. Paul, C.P. Sharma, Process Biochem. 46 (2011) 2007.[306] H. Wang, N.J. Halas, Adv. Mater. 20 (2008) 820.[307] M. Mathew, A. Sureshkumar, N. Sandhyarani, Colloid. Surf. B (2012), ASAP.[308] K. Esumi, N. Takei, T. Yoshimura, Colloid. Surf. B 32 (2003) 117.[309] H. Huang, X. Yang, Biomacromolecules 5 (2004) 2340.[310] A. Primo, F. Quignard, Chem. Commun. 46 (2010) 5593.[311] L.C. Cheng, J.H. Huang, H.M. Chen, T.C. Lai, K.Y. Yang, R.S. Liu, M. Hsiao, C.H.

Chen, L.J. Her, D.P. Tsai, J. Mater. Chem. 22 (2012) 2244.[312] M.J. Laudenslager, J.D. Schirrman, G.L. Schauer, Biomacromolecules 9 (2008)

2682.[313] T.J. Beveridge, R.G.E. Murray, J. Bacteriol. 141 (1980) 876.[314] K.B. Narayanan, N. Sakthivel, Adv. Colloid Interf. Sci. 156 (2010) 1.[315] M. Lengke, G. Southam, Geochim. Cosmochim. Acta 70 (2006) 3646.[316] Y. Konishi, T. Tsukiyama, T. Tachimi, N. Saitoh, T. Nomura, S. Nagamine, Elec-

trochim. Acta 53 (2007) 186.[317] M. Lengke, M.E. Fleet, G. Southam, Langmuir 22 (2006) 2780.[318] S. He, Z. Guo, Y. Zhang, S. Zhang, J. Wang, N. Gu, Mater. Lett. 61 (2007) 3984.[319] P. Mukherjee, A. Ahamd, D. Mandal, S. Senapati, S.R. Sainkar, M.I. Khan, R.

Ramani, R. Parischa, P.V. Ajayakumar, M. Alam, M. Sastry, R. Kumar, Angew.Chem. Int. Ed. 40 (2001) 3585.

[320] A. Ahamd, S. Senapati, M.I. Khan, R. Kumar, M. Sastry, J. Biomed. Nanotechnol.1 (2005) 47.

[321] R. Balagurunathan, M. Radhakrishnan, R.B. Rajendran, D. Velmurugan, IndianJ. Biochem. Bio. 48 (2011) 331.

[322] A. Ahamd, S. Senapati, M.I. Khan, R. Kumar, M. Sastry, Langmuir 19 (2003)3550.

[323] A. Mourato, M. Gadanho, A.R. Lino, R. Tenreiro, Bioinorg. Chem. Appl. (2011),http://dx.doi.org/10.1155/2011/546074.

[324] M. Agnihotri, S. John, A.R. Kumar, S. Zinjarde, S. Kulkarini, Mat. Lett. 63 (2009)1231.

[325] K.R. Brown, M.J. Natan, Langmuir 14 (1998) 726.[326] N.R. Jana, L. Gearheart, C.J. Murphy, Adv. Mater. 13 (2001) 1389;

N.R. Jana, L. Gearheart, C.J. Murphy, J. Phys. Chem. B 105 (2001) 4065.[327] B. Nikoobakht, M.A.E.I-Sayed, Chem. Mater. 15 (2003) 1957.[328] J. Perez-Juste, L.M. Liz-Marzan, S. Carnie, D.Y.C. Chan, P. Mulvaney, Adv. Funct.

Mater. 101 (2004) 571.[329] J. Rodriguez-Fernandez, J. Perez-Juste, F.J. Garcia, L.M. Liz-Marzan, Langmuir

22 (2006) 7007.[330] S.D. Perrault, W.C.W. Chan, J. Am. Chem. Soc. 131 (2009) 17042.[331] N.G. Bastus, J. Comenge, V. Puntes, Langmuir 27 (2011) 11098.[332] K.R. Brown, D.G. Walter, M.J. Natan, Chem. Mater. 12 (2000) 306.[333] K.R. Brown, L.A. Lyon, A.P. Fox, B.D. Reiss, M.J. Natan, Chem. Mater. 12 (1999)

314.[334] E.G. Schutt, Eur. Patent Application 90317671.4, filled Sept. 25, 1990.[335] N.R. Jana, L. Gearheart, C.J. Murphy, Langmuir 17 (2001) 6782.[336] A.A. Volkert, V. Subramaninam, A.J. Haes, Chem. Commun. 47 (2011) 478.[337] K. Kwon, K.Y. Lee, Y.W. Lee, M. Kim, J. Heo, S.J. Ahn, S.W. Han, J. Phys. Chem.

C 111 (2007) 1161.[338] C. Ziegler, A. Eychmüller, J. Phys. Chem. C 115 (2011) 4502.[339] X. Huang, S. Neretina, M.A. El-Sayed, Adv. Mater. 21 (2009) 4880.[340] C.J. Murphy, L.B. Thompson, D.J. Chernak, J.A. Yang, S.T. Sivapalan, S.P. Boulos,

J. Huang, A.M. Alkilany, P.N. Sisco, Curr. Opin. Colloid Interface Sci. 16 (2011)128.

[341] J.P. Juste, I.P. Santos, L.M.L. Marzan, P. Mulvaney, Coord. Chem. Rev. 249 (2005)1870.

[342] X. Huang, X. Qi, Y. Huang, S. Li, C. Xue, C.L. Gant, F. Boey, H. Zhang, ACS Nano4 (2012) 6196.

[343] J.Y. Kim, C.S. Ah, D.J. Jang, J. Nanomater. (2011) http://dx.doi.org/10.1155/2011/405853

[344] A. Govindaraj, B.C. Satishkumar, M. Nath, C.N.R. Rao, Chem. Mater. 12 (2000)202.

[345] B.D. Busbee, S.O. Obare, C.J. Murphy, Adv. Mater. 15 (2003) 414.[346] A. Gole, C.J. Murphy, Chem. Mater. 16 (2004) 3633.[347] H.Y. Wu, H.C. Chu, T.J. Kuo, C.L. Kuo, M.H. Huang, Chem. Mater. 17 (2005) 6447.[348] H.Y. Wu, W.L. Huang, M.H. Huang, Cryst. Growth Des. 7 (2007) 831.[349] D.K. Smith, B.A. Korgel, Langmuir 24 (2008) 644.[350] D.K. Simth, N.R. Miller, B.A. Korgel, Langmuir 25 (2009) 9518.[351] N.R. Jana, Chem. Commun. (2003) 1950.[352] K. Park, H. Koerner, R.A. Vaia, Nano Lett. 10 (2010) 1433.
[353] N. Grag, C. Scholl, A. Mohanty, R. Jin, Langmuir 26 (2010) 10271.[354] S. Si, C. Leduc, M.H. Delville, B. Lounis, ChemPhysChem 13 (2012) 193.[355] S.R. Beeram, F.P. Zamborini, J. Am. Chem. Soc. 131 (2009) 11689.[356] W.T. Lu, A.K. Singh, A.A. Khan, D. Senapati, H.T. Yu, P.C. Ray, J. Am. Chem. Soc.
132 (2010) 18103.

31

Reviews 257 (2013) 638– 665

[357] J.Y. Xiao, L.M. Qi, Nanoscale 3 (2011) 1383.[358] T.K. Sau, C.J. Murphy, J. Am. Chem. Soc. 126 (2004) 8648.[359] D.Y. Kim, T. Yu, E.C. Cho, Y. Ma, O.O. Park, Y. Xia, Angew. Chem. Int. Ed. 50

(2011) 6328–6331.[360] M.S. Bakshi, F. Possmayer, N.O. Petersen, J. Phys. Chem. C 112 (2008) 8259.[361] Y. Zhang, F.G. Xu, Y.J. Sun, C.L. Guo, K. Cui, Y. Shi, Z.W. Wen, Z. Li, Chem. Eur.

J. 16 (2010) 9248.[362] M.R. Langille, M.L. Personick, J. Zhang, C.A. Mirkin, J. Am. Chem. Soc. 133 (2011)

10414.[363] J.A. Zhang, M.R. Langille, M.L. Personick, K. Zhang, S.Y. Li, C.A. Mirkin, J. Am.

Chem. Soc. 132 (2010) 14012.[364] X.S. Kou, Z.H. Sun, Z. Yang, H.J. Chen, J.F. Wang, Langmuir 25 (2009) 1692.[365] G.H. Jeong, M. Kim, Y.W. Lee, W. Choi, W.T. Oh, Q.H. Park, S.W. Han, J. Am.

Chem. Soc. 131 (2009) 1672.[366] J. Li, L.H. Wang, L. Liu, L. Guo, X.D. Han, Z. Zhang, Chem. Commun. 46 (2010)

5109.[367] H.L. Wu, H.R. Tsai, Y.T. Hung, K. Un Lao, C.W. Liao, P.J. Chung, J.S. Huang, I.C.

Chen, M.H. Huang, Inorg. Chem. 50 (2011) 8106.[368] H.L. Wu, C.H. Kuo, M.H. Huang, Langmuir 26 (2010) 12307.[369] M. Grzelczak, J. Perez-Juste, P. Mulvaney, L.M. Liz-Marzan, Chem. Soc. Rev. 37

(2008) 1783.[370] T. Ming, W. Feng, Q. Tang, F. Wang, L.D. Sun, J.F. Wang, C.H. Yan, J. Am. Chem.

Soc. 131 (2009) 16350.[371] X. Zhang, X. He, K. Wang, F. Ren, Z. Qin, Nanotechnology 22 (2011), no: 355603.[372] M.M. Mariscal, J.J.V. Salazar, M.J. Yacaman, CrystEngComm. 14 (2012) 544.[373] J. Belloni, M. Mostafavi, H. Remita, J.L. Marignier, M.O. Delcourt, New J. Chem.

22 (1998), 1239 and 1257.[374] S. Kageyama, A. Murakami, S. Ichikawa, S. Seino, T. Nakagawa, H. Daimon, Y.

Ohkubo, T.A. Yamamoto, J. Mater. Res. 27 (2012) 1037.[375] W. Abidi, P.R. Selvakannan, Y. Guillet, I. Lampre, P. Beaunier, B. Pansu, B.

Palpant, H. Remita, J. Phys. Chem. C 114 (2010) 14794.[376] N. Misra, J. Biswal, A. Gupta, J.K. Sainis, S. Sabharwal, Radiat. Phys. Chem. 81

(2012) 195.[377] K. Roy, S. Lahiri, Anal. Chem. 80 (2008) 7504.[378] M. Treguer, C. de Cointet, H. Remita, J. Khatouri, M. Mostafavi, J. Amblard, J.

Belloni, J. Phys. Chem. B 102 (1998) 4310.[379] M. Hu, F.S. Ou, W. Wu, I. Naumov, X.M. Li, A.M. Bratkovsky, R.S. Williams, Z.Y.

Li, J. Am. Chem. Soc. 132 (2010) 12820.[380] W.Y. Huang, W. Qian, M.A. El-Sayed, J. Am. Chem. Soc. 128 (2006) 13330.[381] J. Neddersen, G. Chumanov, T.M. Cotton, Appl. Spectrosc. 47 (1993) 1959.[382] S. Besner, A.V. Kabashin, F.M. Winnik, M. Meunier, J. Phys. Chem. C 113 (2009)

9526.[383] A. Corma, H. García, Chem. Soc. Rev. 37 (2008) 2096.[384] M. Haruta, N. Yamada, T. Kobayashi, S. Iijima, J. Catal. 115 (1989) 301.[385] J.M. Yan, X.B. Zhang, T. Akita, M. Haruta, M.Q. Xu, J. Am. Chem. Soc. 132 (2010)

5326.[386] T. Fujitani, I. Nakamura, T. Akita, M. Okumura, M. Haruta, Angew. Chem. Int.

Ed. 48 (2009) 9515.[387] A. Leyva-Perez, A. Corma, Angew. Chem. Int. Ed. 51 (2012) 614.[388] H. Yoshida, Y. Kuwauchi, J.R. Jinschek, K. Sun, S. Tanaka, M. Kohyama, S. Shi-

mada, M. Haruta, S. Takeda, Science 335 (2012) 317.[389] Y. Wei, J. Liu, Z. Zhao, A. Duan, G. Jiang, J. Catal. 287 (2012) 13.[390] H.Y. Kim, H.M. Lee, G. Henkelman, J. Am. Chem. Soc. 134 (2012) 1560.[391] R. Zanella, S. Giorgio, C.H. Shin, C.R. Hernry, C. Louis, J. Catal. 222 (2004) 357.[392] A. Hugon, N. El-Kolli, C. Louis, J. Catal. 274 (2010) 239.[393] Y. Borensztein, L. Delannoy, A. Djedidi, R.G. Barrera, C. Louis, J. Phys. Chem. C

114 (2010) 9008.[394] L. Alves, B. Ballesteros, M. Boronat, J.R. Cabrero-Antonino, P. Concepcion, A.

Corma, M.A. Correa-Duarte, E. Mendoza, J. Am. Chem. Soc. 133 (2011) 10251.[395] M. Ding, D.C. Sorescu, G.P. Kotchey, A. Star, J. Am. Chem. Soc. 134 (2012) 3472.[396] L. Prati, A. Villa, A.R. Lupini, G.M. Veith, Phys. Chem. Chem. Phys. 14 (2012)

2969.[397] L. Prati, F. Porta, Appl. Catal. A: Gen. 291 (2005) 199.[398] Z. Konya, V.F. Puntes, I. Kiricsi, J. Zhu, J.W. Ager, M.K. Ko, H. Frei, P. Alivisatos,

G.A. Somorjai, Chem. Mater. 15 (2003) 1242.[399] P. McMorn, G.J. Htchings, Chem. Soc. Rev. 33 (2004) 108.[400] C.T. Kresge, M.E. Leonowicz, W.J. Roth, J.C. Varuli, J.S. Beck, Nature 359 (1992)

710.[401] G.S. Mishra, A. Kumar, Appl. Catal. A: Gen. (2012) 429.[402] J.C. Hu, L.F. Chen, K. Zhu, A. Suchopar, R. Richards, Catal. Today 122 (2007)

277.[403] C. Aprile, A. Abad, H. Garcia, A. Corma, J. Mater. Chem. 15 (2005) 4408.[404] J.S. Jan, T.H. Chuang, P.J. Chen, H. Teng, Langmuir 27 (2011) 2834.[405] S. Hermes, M.K. Schroter, R. Schmid, L. Khodeir, M. Muhler, A. Tissler, R.W.

Fischer, R.A. Fischer, Angew. Chem. Int. Ed. 44 (2005) 6237.[406] T. Ishida, M. Nagaoka, T. Akita, M. Haruta, Chem. Eur. J. 14 (2008) 8456.[407] H.L. Jiang, B. Liu, T. Akita, M. Haruta, H. Sakurai, Q. Xu, J. Am. Chem. Soc. 131

(2009) 11302.[408] H.L. Jiang, T. Akita, T. Ishida, M. Haruta, Q. Xu, J. Am. Chem. Soc. 133 (2011)

1304.[409] K.C. Leung, S. Xuan, X. Zhu, D. Wang, C.P. Chak, S.F. Lee, W.K. Ho, B.C. Chung,

Chem. Soc. Rev 41 (2012) 1911.[410] Y. Sun, Y. Xia, Science 298 (2002) 2176.[411] H. Zhang, N. Toshima, Appl. Catal. A: Gen. 400 (2011) 9.[412] H. Zhang, T. Watanabe, M. Okumura, M. Haruta, N. Toshima, Nat. Mater. 11

(2012) 49.

dx.doi.org/10.1155/2011/546074

http://dx.doi.org/10.1155/2011/405853

http://dx.doi.org/10.1155/2011/405853

mistry

[[

[[

[

[

[

[

[

[429] A. Travesset, Science 334 (2011) 183.[430] Z. Qin, J.C. Bischof, Chem. Soc. Rev. 41 (2012) 1191.[431] A. Llevot, D. Astruc, Chem. Soc. Rev. 41 (2012) 242.


413] R.W.J. Scott, O.M. Wilson, R.M. Crooks, J. Phys. Chem. B 109 (2005) 692.414] O.M. Wilson, R.W.J. Scott, J.C. García-Martinez, R.M. Crooks, J. Am. Chem. Soc.

127 (2005) 1015.415] D.F. Yancey, L. Zhang, R.M. Crooks, G. Henkelman, Chem. Sci. 3 (2012) 1033.416] I. García, J. Gallo, N. Genicio, D. Padro, S. Penádes, Bioconjugate Chem. 22

(2011) 264.417] D. Kim, M.K. Yu, T.S. Lee, J.J. Park, Y.Y. Jeong, S. Jon, Nanotechnology 22 (2011),

no: 155101.418] M.R. Knecht, M.G. Weir, A.I. Frenkel, R.M. Crooks, Chem. Mater. 20 (2008)

1019.419] W. Xie, C. Herrmann, K. Kömpe, M. Haase, S. Schlücker, J. Am. Chem. Soc. 133

(2011) 19302.420] Y.D. Jin, C.X. Jia, S.W. Huang, M. O’Donnell, X.H. Gao, Nat. Commun. 1 (2010)

41.421] L.Y. Wang, H.Y. Park, S.I.I. Lim, M.J. Schadt, D. Mott, J. Luo, X. Wang, C.J. Zhong,

J. Mater. Chem. 18 (2008) 2629.

32

Reviews 257 (2013) 638– 665 665

[422] C.J. Murphy, A.M. Golet, J.W. Stone, P.N. Sisco, A.M. Alkilany, E.C. Goldsmith,S.C. Baxter, Acc. Chem. Res. 41 (2008) 1721.

[423] C. Wang, H. Yin, R. Chan, S. Peng, S. Dai, S. Sun, Chem. Mater. 21 (2009) 433.[424] S. Link, Z.L. Wang, M.A. El-Sayed, J. Phys. Chem. B 103 (1999) 3529.[425] Y. Liu, A.R.H. Walker, Angew. Chem. Int. Ed. 49 (2010) 6781.[426] Y. Negishi, T. Iwai, M. Ide, Chem. Commun. 46 (2010) 4713.[427] C. Kumara, A. Dass, Nanoscale 3 (2011) 3064.[428] S. Malola, H. Häkkinen, J. Phys. Chem. Lett. 2 (2011) 2316.

[432] N. Goubet, H. Portales, C. Yan, A. Mermet, M.P. Pileni, J. Am. Chem. Soc. 134(2012) 3714.

Chapter 2

Carborane-functionalized AuNPs for Potential Boron Neutron

Capture Therapy Applications

33

2.1 Introduction

Carboranes that have a structure of 12-vertex icosahedral C2B10H12 possess a high boron

content and stability to catabolism, which can increase the thermal and chemical stability of

complexes. Carborane is a key material for boron neutron capture therapy (BNCT) for the

treatment of cancer. AuNPs have shown extraordinary performances in the areas of

photothermal therapy, biosensing, imaging and drug delivery. Incorporation of carboranes

into AuNPs could be a viable approach for the delivery of boron to the tumor tissues a nd the

treatment of cancer through BNCT.

Since [CuItren(CH2Ph)6][Br] (Cu(I)-tren) has been synthesized and utilized as excellent

catalyst of “click” reaction in our previous reports, carborane and PEG were grafted onto the

periphery of AuNPs with a satisfying yield in this chapter. AuNPs were also prepared in one-

step through capping of a pre-functionalized thiolate dendron. Carboranes containg an ethynyl

group were provided by the group of Professor Narayan Osmane with who we collaborated

in the publications.

34

“Click” Star-Shaped and Dendritic PEGylated Gold Nanoparticle-Carborane AssembliesNa Li,† Pengxiang Zhao,†,‡ Lionel Salmon,§ Jaime Ruiz,† Mark Zabawa,∥ Narayan S. Hosmane,*,∥

and Didier Astruc*,†

†ISM, Univ. Bordeaux, 351 Cours de la Liberation, 33405 Talence Cedex, France‡Science and Technology on Surface Physics and Chemistry Laboratory, P.O. Box 718-35, Mianyang 621907, Sichuan, China§LCC, CNRS, 205 Route de Narbonne, 31077 Toulouse Cedex, France∥Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois 60115-2862, United States

*S Supporting Information

ABSTRACT: Carboranes that have a high boron content are key materials for boronneutron capture therapy (BNCT), while PEGylated gold nanoparticles (AuNPs) are alsomost useful in various aspects of nanomedicine including photothermotherapy, imagingand drug vectorization. Therefore, methods to assemble these key components have beeninvestigated for the first time. Strategies and results are delineated in this article, and thenanomaterials have been characterized using transmission electron microscopy (TEM),dynamic light scattering (DLS), UV−vis., mass and multinuclear NMR data. A series ofwell-defined water-soluble bifunctional AuNPs containing carborane and polyethyleneglycol (PEG) were synthesized through either two-step Cu(I)-catalyzed azide−alkynecycloaddition CuAAC (“click”) reactions at the periphery of azido-terminated AuNPs inthe presence of the efficient catalyst [CuItren(CH2Ph)6][Br] or simply by directstabilization of AuNPs using a tris-carborane thiol dendron or a hybrid dendron containingboth PEG and carborane.

■ INTRODUCTION

Carborane chemistry has been developed into nanomaterialsduring the past few decades because of the robustness andphysicochemical properties of the carborane frameworks.Because of the structure of 12-vertex icosahedral C2B10H12,this carborane possesses high boron content and stability tocatabolism, can increase thermal and chemical stability ofcomplexes, and provides the possibility of use as building blockand template in material science,1 nanomedicine,2 and synthesisof highly stable dendrimers, polymers, or other supramole-cules.3 It has been demonstrated that the use of carborane canenhance hydrophobic interactions between pharmaceuticalsand their receptors and increase the in vivo stability of pharma-ceuticals. Gold nanoparticles (AuNPs) have been among themost extensively studied nanomaterials over a century becauseof their remarkable optical properties related to their plasmonabsorption and are now heavily utilized in chemistry, biology,engineering, and medicine because of their unique optical,chemical, electrical, and catalytic properties.4 AuNPs haveattracted the interest of scientists especially in the areas ofphotothermal therapy, biosensing, imaging, and drug delivery.5

Therefore, incorporation of carboranes into AuNPs could be aviable approach for the delivery of boron to the tumor tissuesand cancer treatment through boron neutron capture therapy(BNCT). BNCT is a binary radiation therapy for the treatmentof cancer that is based on the capture of thermal neutrons by10B nuclei which have a large capture cross section, and these

10B nuclei can be selectively delivered to tumor cells.6 Poly-ethylene glycol (PEG) has been extensively used as modifyingagent in many biomedical products because of its nontoxicity,water-solubility, and the enhanced permeability and retention(EPR) effect. The PEGylated NPs can postpone or prevent therapid clearance by the reticular-endothelium system (RES).Therefore, drugs carried by PEGylated AuNPs can have aprolonged circulation time in blood.7 Thus, the PEGylatedAuNPs have been widely utilized in materials science,8 bio-logical and pharmaceutical applications.9 The AuNPs contain-ing both carborane and PEG could be regarded as valuablenanomaterials with useful optical properties, increased water-solubility and biocompatibility, and further suitable forbiomedical studies. The Huisgen-type Cu(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction (“click” reaction) is themost efficient strategy to assemble a 1,2,3-triazole ring linkingtwo molecular fragments together because of its atom econ-omy, regioselectivity, wide substrate scope, and mild reactionconditions.10 Moreover, the triazole group is completelybiocompatible. The “click” modification of AuNPs has been achallenging topic of research in the past few years because ofserious aggregation of AuNPs that induced low yield.11

Recently, an efficient “click” catalyst [CuI(CH2Ph)6tren][Br](abbreviated CuI-tren), has been reported, and only 7% of this

Received: May 30, 2013Published: September 10, 2013

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pubs.acs.org/IC

catalyst is needed in toluene solution for the fabrication ofsterically demanding “click” dendrimers.12 Subsequently, thisCuI-tren catalyst has also been successfully employed for the“click” functionalization of AuNPs. High yields were obtainedusing this functionalization method, and the aggregation waslargely avoided because of the dendritic effect around thecatalytically active metal center.13

With these tools in hands, it was desirable to investigate thepossibility of synthesis, stability, and physicochemical behaviorof assemblies between PEGylated AuNPs and carboranes usingthiolate Au-ligands and “click” linkages. In this work, we haveinvestigated the synthesis of bifunctional AuNPs containingboth PEG and ortho-carborane units through “click” reactionsbetween azido-terminated AuNPs and alkyne ligands in thepresence of the CuI-tren catalyst. We have also examined thedirect AuNP formation and stabilization using a tris-carboranethiol dendron or a hybrid thiol dendron containing one PEGbranch and two carborane branches. The morphologies of thecore size, hydrodynamic diameter, and polydispersity of thecarborane-functionalized AuNPs have been determined bytransmission electron microscopy (TEM) and dynamic lightscattering (DLS), while the distribution of various functionalgroups on AuNPs have been verified by 1H NMR, and thefunctional properties of AuNPs were further characterized byinfrared (IR) spectroscopy.

■ RESULTS AND DISCUSSION

Synthesis of Azido-Terminated AuNPs. Dodecanethiolate-AuNPs (AuNPs-1) were synthesized through the typicalBrust−Schiffrin “two-phases” method,14 and the prefunc-tionalization of AuNPs-1 was carried out by a classicalligand-substitution reaction. Briefly, AuNPs-1 was dissolvedin CH2Cl2 solution containing certain amount of undecanethiol,stirred under N2 at 25 °C for a few days, during which timethe ligand-replacement occurred on the surface of theAuNPs (Scheme 1). Three azido-terminated AuNPs (AuNPs-2a, AuNPs-2b, AuNPs-2c) with different dodecanethiolate:azidoundecanethiolate ligand ratio were obtained under differ-ent ligand-substitution conditions (Table 1): AuNPs-2b thatcontains 33% azido ligands on the surface was obtained with 1:1ratio of azidoundecanethiol to dodecanethiolate ligands within2 days. When the reaction time was prolonged to 5 days,AuNPs-2a containing 50% azido ligands was obtained under thesame ligand ratio. With the purpose of introducing a higher % ofazido groups, the ligand-exchange reaction was repeated 3 timeswith a ligand ratio of 2: 1, and the reaction time was 3 days for

each time. This procedure yielded AuNPs-2c with 80% azidoligands in 80% yield, which was a little bit lower than the yieldof the single substitution to obtain AuNPs-2a (90%) andAuNP-2b (>95%), because of increase of aggregation in theprocess of extended multiple-step ligand-substitution reaction.The presence of azido group in the AuNPs has been

confirmed by 1H NMR (Supporting Information, Figure S1)and IR (Supporting Information, Figure S3) spectra. Thespectra also indicated the percentage of azido-functional groupon AuNPs, obtained through ligand substitution, dependingupon both the reaction time and the feed ratio of the twodifferent ligands.

“Click” Functionalization of AuNPs with Carboraneand (or) PEG. The carborane-functionalized AuNP-3a was firstobtained through a “click” reaction in the presence of thehomogeneous [CuI(CH2Ph)6tren][Br] catalyst (10%) intoluene solution, while an excess carborane alkyne per azidogroup (2: 1) was employed. The reaction was monitored by IRspectra until the νN3 band had disappeared. The excess car-borane and catalyst were removed by washing the AuNPs withethanol and diethyl ether successively. AuNP-3a containing50% carborane groups was obtained in 40% yield after removalof a precipitate of Au black by filtration. Subsequent stepwise“click” reactions were carried out for the synthesis of bifunc-tional AuNPs containing both PEG and carborane. In thismethod, azido-terminated AuNPs were reacted with carborane-alkyne and PEG (Mw 350 or 2000)-alkyne successively inthe presence of 10% CuI-tren catalyst (Scheme 2). WhenAuNPs-2b, containing 33% azido ligands, were used as startingmaterial, AuNP-3b was obtained with 17% carborane and 17%PEG350 ligands involving 4:1:1 molar ratio of dodecanethiolateligands, carborane, and PEG350, respectively (see SupportingInformation, Figure S7). The yield of AuNP-3b was increasedup to 65% with the decrease in functional group, whencompared to that of AuNP-3a. With the purpose of obtain-ing water-soluble carborane-AuNPs, PEG2000-alkyne and

Scheme 1. Synthesis of AuNPs-1 by the Brust−Schiffrin Method, and the Ligand-Exchange Synthesis of Azido-TerminatedAuNPs

Table 1. Ligand-Substitution Reaction of Azido-TerminatedAuNPs-2a, AuNPs-2b, and AuNPs-2c

azido-AuNPs

percentage(-N3)

reaction time(day)

feed ratioa

(azido/alkane)yield(%)

AuNPs-2a 50% 5 1: 1 90AuNPs-2b 33% 2 1: 1 95AuNPs-2c 80% 3 + 3 + 3 2: 1b 80aLigand ratio of azidoundecanethiol to dodecanethiolate ligand boundto AuNPs. bThe feed ratio was 2: 1 in each time.

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36

AuNPs-2c containing a large percentage of azido groups wereemployed. Ultimately, water-soluble AuNPs-3c was ob-tained with the surface capped by 17% carborane, 66% PEGligands, and 17% dodecanethiolate ligands. The molar ratio ofdodecanethiolate-ligands: carborane: PEG350 on the surfaceof AuNPs-3c was 1: 1: 4, as confirmed by 1H NMR spectra(Supporting Information, Figure S10). In this case, the hydro-philic PEG ligand properties led to improved water solubilityand biocompatibility of AuNPs-3c. Another advantage ofintroducing a large percentage of PEG2000 was that the “click”reaction did not decrease the yield significantly, despite PEGbeing a longer chain and present in high proportion. Thisattributed to the flexibility of PEG in solution. The coating ofPEG2000 onto the Au surface isolated the AuNPs from eachother, which inhibited the AuNPs aggregation.The UV−vis spectrum of AuNPs-3c, in Figure 1, exhibits a

plasmon band at 524 nm, while its TEM image indicates theaverage core diameter of 4.75 nm. The hydrodynamic diameterof AuNPs-3c in aqueous solution, provided by DLS measure-ment, is 10.2 nm. The complete disappearance of the νN3 bandat 2090.9 cm−1 in the IR spectrum was evident after the secondset of “click” reactions, when compared to the strong νN3 peak

of AuNP-2c (Figure 2). IR spectrum of AuNPs-3c also showsclearly the σB−H stretching vibration at 2580.84 cm−1. The coresize determined using TEM images for AuNPs-3a, AuNPs-3b,and AuNPs-3c are similar to those recorded before the “click”reaction (Supporting Information), which demonstrated thatthe “click” reactions with AuNPs have no adverse effects on thepolydispersity, despite the reaction yields being decreasedbecause of aggregation. The DLS measurement showed thehydrodynamic diameters of AuNPs-3a (15.6 nm) and AuNPs-3b (15.4 nm), but the hydrodynamic diameter of AuNP-3c wasmuch smaller (10.2 nm), presumably because of the effect ofsuppressing long linear PEG2000 branches during assemblyamong individual AuNPs. The DLS size-distribution histogramsof AuNPs-3a, AuNPs-3b, and AuNPs-3c displayed narrowpolydispersity of the “clicked” AuNPs, as TEM indicated.

Direct Synthesis of Bifunctional AuNPs. The tris-carborane thioacetate dendron 3, a precursor for dendriticAuNPs, was synthesized by “click” reaction between the tris-alkyne dendron 1 and carborane-azide 2 in the presence ofcopper sulfate and sodium ascorbate (Scheme 3a). The hybridthioacetate dendron 4, containing one carborane branch andtwo PEG branches, was synthesized by “click” reaction between

Scheme 2. Schematic Illustration of the “Click” Functionalization of AuNPs



37

the dendron 1 and only 1 equiv of compound 2 and thenfurther “click” reaction with 2 equiv of PEG2000-azide(Scheme 3b). Interestingly, the direct synthesis does notundergo any aggregation, contrary to the multistep synthesis.With the direct-synthetic approach, the tris-carborane thioldendron 5 was obtained first from dendron 3, in situ, and theAuNPs-4a stabilized by bifunctional PEG550-SH mixed-ligandswere subsequently synthesized through a simple one-stepreduction procedure (Scheme 4a).The direct synthesis involved 1: 1: 1 molar ratio of tris-

carborane thiol dendron 5, PEG550 thiol ligand, and HAuCl43H2O, respectively. After purification, AuNPs-4a was shown tocontain 20% dendron 5 and 80% PEG550 thiolate ligands atthe periphery and, consequently, the ratio of carborane group

to PEG ligand was found to be 3: 4 (Supporting Information,Figure S26). An increase in the number of carborane moietieswas accomplished by utilizing the tris-carborane dendron 5(Scheme 4a). With the purpose of precisely controlling theratio of two functional groups (herein, the PEG/carboraneratio), the hybrid tris-dendron 6, obtained from dendron 4 insitu, was used for direct AuNP synthesis. The water-solubleAuNPs-4b capped with dendron 6 was synthesized in methanolsolution through a simple reduction of Au(III) by NaBH4(Scheme 4b). The ratio of carborane to PEG in AuNPs-4b wasexactly the same as with dendron 4, revealing that theinvaluable advantage of this strategy is the control of relativeamounts of two functional groups. The AuNPs that wereobtained by this reaction essentially preserve the properties of

Figure 1. (a) UV−visible spectrum, (b) DLS size-distribution histogram (measured in water solution), (c) TEM image, and (d) the core size-distribution histogram of AuNPs-3c.

Figure 2. IR spectrum of AuNPs-3c (top, blue curve) compared to that of AuNP-2c (bottom, red curve). It shows the complete disappearance ofthe νN3 band at 2090.9 cm−1 after “click” reactions, and the appearance of the σB−H stretching vibration at 2580.8 cm−1.



38

the dendron. The TEM images of AuNPs-4a and AuNPs-4bare presented in Figure 3 showing the average core diameterof 3.43 and 7.59 nm, respectively. The size-distributionhistograms showed that AuNPs-4a and AuNPs-4b are quitemonodisperse.The average core diameter of AuNPs-4b is larger (7.59 nm,

Figure 3b) than those of other AuNPs, described above, whichpresumably results from slower thiol-gold interactions due todendronic bulk inhibition around the thiol group. Thehydrodynamic diameters of AuNPs-4a and AuNPs-4b werealso measured in aqueous solution by DLS analysis. The resultsindicate that the hydrodynamic diameters of AuNPs-4a andAuNPs-4b are 19 and 14.5 nm, respectively.The FT-IR spectra of dendron 4 and AuNPs-4b are shown

in Figure 4. The characteristic band due to the strong stretchingmode of vibration of the C−O−C bond (σC−O−C) in the PEGchain at 1105 ± 10 cm−1 is the dominating feature in bothspectra. The secondary strong and broad absorption around2580 ± 10 cm−1 is due to σB−H stretching vibration,15 thatindicates the existence of the carborane cluster structure. Thecomparison of the FT-IR spectra of dendron 4 and AuNP-4bindicates a subsequent bonding of the carborane dendron tothe AuNPs with a weak σB−H vibration as a result of shielding ofthe carborane absorptions by nearby AuNPs. A similarcharacteristic σB−H signal was also observed in the FT-IRspectra of other carborane-containing molecules (SupportingInformation).According to the core size determined by TEM and the

ligand ratio estimated by 1H NMR, the amounts of carboraneunits and of PEG ligand per AuNP are calculated using Leff’s

method based on both theoretical and experimental data.16

As shown in Table 2, each AuNP carries more than 50carborane units, and particularly, AuNPs-4b with more than220 carborane units at the periphery could potentially findapplications in BNCT for cancer treatment.

■ CONCLUSIONThe present study showed two feasible approaches to syn-thesize the AuNPs-carborane assemblies. The two-step“click” modification of azido-terminated AuNPs in the pres-ence of the [CuI(CH2Ph)6tren][Br] catalyst gives bifunc-tional AuNPs in good yield, and the core size remainsunchanged during the “click” reaction. The ratio of car-borane to PEG functional ligands can be controlled bythe feed ratio. Water-soluble AuNPs were obtained whena large percentage of long chain PEG (Mw 2000) was em-ployed. With this method, bifunctional AuNPs can beobtained with a narrow polydispersity. In the direct synthesismethod, the mono- or bifunctional thiol dendron was intro-duced onto the surface of AuNPs through a simple reductionreaction. This direct synthesis method would be of greatinterest for multifunctionalization of AuNPs, because theprefunctionalization of a dendron can be efficiently achievedto avoid multistep AuNP synthesis. Remarkably, the hybriddendron-stabilized AuNPs have an invariable ratio of twofunctional groups, and this ratio is thus exactly the same asthat of the dendron. Furthermore, no aggregation of AuNPsoccurred in this method. We conclude that the direct syn-thesis method would facilitate the procedure of AuNPfunctionalization. Thus, a series of well-designed bifunctional

Scheme 3. “Click” Syntheses of Carborane-Containing Dendronsa

aCopper sulphate and sodium ascorbate were employed stoichiometrially in each case.



39

AuNPs containing carborane and PEG ligands with core sizesin the range of 3.42 to 7.59 nm were synthesized andfully characterized. The bifunctional AuNPs, in particular the

water-soluble AuNPs such as AuNPs-3c, AuNPs-4a, andAuNPs-4b could provide a biocompatible platform in thera-peutical BNCT investigation or some other applications.

Figure 3. TEM images and diameter histogram distribution of AuNPs-4a and AuNPs-4b, respectively.

Scheme 4. Schematic Illustration of Direct Synthesis of (a) AuNPs-4a and (b) AuNPs-4b



40

■ EXPERIMENAL SECTIONGeneral Information. All chemicals and solvents were used as

received. 1H NMR spectra were recorded at 25 °C with a BrukerAC200, 300, or 400 MHz spectrometer. The 13C NMR spectra wereobtained in the pulsed FT mode at 50, 75, or 100 MHz with a BrukerAC 200, 300, or 400 MHz spectrometer. All the chemical shifts arereported in parts per million (δ, ppm) with reference to Me4Si (TMS)for the 1H and 13C NMR spectra. The mass spectra were recordedusing an Applied Biosystems Voyager-DE STR-MALDI-TOF spec-trometer. The DLS measurements were made using a MalvernZeta-sizer 3000 HAS instrument at 25 °C at an angle of 90°. UV−visibleabsorption (UV−vis) spectra were measured with a Perkin-ElmerLambda 19 UV−visible spectrometer. The infrared (IR) spectra weremeasured with an ATI Mattson Genesis series FT-IR spectropho-tometer. The elemental analyses were performed by the Center ofMicroanalyses of the CNRS at Lyon Villeurbanne, France.Synthesis of Dodecanethiolate-AuNPs (AuNP-1). Dodecane-

thiolate-AuNPs (AuNP-1) were synthesized through the typicalBrust−Schiffrin method.14 Briefly, an aqueous solution of hydrogentetrachloroaurate (15 mL, 106 mg, 0.27 mmol) was mixed with thetoluene solution of tetraoctylammoniumbromide (20 mL, 600 mg,1.09 mmol). The two-phase mixture was vigorously stirred until thehydrogen tetrachloroaurate was totally transferred into the organiclayer, followed by the addition of dodecanethiol (28 mg, 0.14 mmol),then the mixture was further stirred for 20 min. A freshly preparedsolution of sodium borohydride (11 mL, 131 mg, 4.8 mmol) wasquickly added with vigorous stirring, and the mixture immediatelybecame dark. After further stirring for 2 h, the organic phase was

separated and dried over sodium sulfate, then concentrated to 5 mLunder vacuum. The crude product was precipitated in 150 mL ofethanol and then washed again with ethanol, yield: 90%. 1H NMR(CDCl3, 200 MHz): δ = 1.55 (2H, HS-CH2), 1.26 (20H, -CH2CH2-),0.87 (3H, -CH3).

Ligand-Substitution Synthesis of Azido-Terminated AuNPs-2a,AuNPs-2b, and AuNPs-2c. AuNPs-1 (80 mg) and azidoundecane-thiol (50 mg) were mixed in CH2Cl2 solution, and the solution wasstirred for 2 days under N2 at room temperature. After removal ofsolvent by rotary evaporator, the obtained AuNPs-2b were thenwashed with ethanol to remove the excess thiols (yield: 95%). 1HNMR (CDCl3, 200 MHz): δppm = 3.24 (2H, CH2-N3), 1.58 (2H,HS-CH2) 1.26 (20H, -CH2CH2-), 0.87 (3H, -CH3). Upon continuingthe reaction during 5 more days, after the same treatment, AuNPs-2awere obtained with yield 90%. 1H NMR (CDCl3, 200 MHz): δppm =3.24 (2H, CH2-N3), 1.55 (2H, HS-CH2) 1.27 (20H, -CH2CH2-), 0.88(3H, -CH3). Through a repeated ligand-substitution process (3 times)with prolonged reaction time (3 days) in each period, AuNPs-2c wereobtained in 80% yield. 1HNMR (CDCl3, 200 MHz): δppm = 3.24 (2H,CH2-N3), 1.58 (2H, HS-CH2), 1.28 (20H, -CH2CH2-), 0.88 (3H,-CH3). UV−vis: SPB at 518 nm. TEM: average diameter: 4.43 nm. IR:νN3 2090 cm−1.

“Click” Synthesis of Carborane-AuNPs, AuNP-3a. Azido-terminated AuNPs-2a (50 mg, 0.022 mmol azido-ligand) and 1-Me-9-benzyl-o-carborane containing an ethynyl substituent of the benzenering3 (carborane alkyne) (12 mg, 0.044 mmol) were dissolved in20 mL of toluene; then the solution was degassed and flushed with N2.The “click” catalyst [Cu(I)(hexabenzyl)tren)]Br (CuI-tren) (0.1 equiv,0.4 mg) was added, and the solution was allowed stir 2 days at 30 °Cunder N2. After removal of toluene under vacuum, AuNPs-3a werewashed with ethanol and diethyl ether to remove the excess carboranealkyne and the catalyst, respectively (yield: 40%). 1H NMR (CDCl3,200 MHz): δppm = 7.46 (3H, CH in Ar, and CH in triazole), 7.15 (2H,CH in Ar), 3.45 (4H, CH2-carborane and CH2-triazole), 1.59−1.25(20H, -CH2CH2-), 0.89 (3H, -CH2CH3). UV−vis: SPB at 522 nm. IR:disappearance of νN3 band at 2090 cm

−1. TEM: average core-diameter:3.42 nm. DLS analysis: average diameter = 15.6 nm.

“Click” Synthesis of Both Carborane and PEG350 Function-alized AuNP-3b. AuNPs-2b (40 mg, 0.012 mmol azido-ligand) andthe carborane alkyne (0.006 mmol, 0.5 equiv per N3 branch) weredissolved in 15 mL of toluene, then the solution was flushed with N2.CuI-tren (0.001 mmol, 0.1 equiv) was added, the solution was thenstirred at 30 °C under N2. The reaction was finished in 1 day as

Figure 4. FT-IR spectra of dendron 4 (upper, in blue curve) and AuNP-4b (bottom, red curve).

Table 2. Core Size, Ligand Ratio, and Calculated Number ofCarborane or PEG Ligands of Carborane-AuNPs

AuNPscore diameter

(nm)ligandratioa

number ofcarboraneb

number ofPEGc

AuNP-3a 3.42 1:1:0 86 0AuNPs-3b 5.18 4:1:1 65 65AuNPs-3c 4.75 1:1:4 55 222AuNPs-4a 3.43 0:3:4 74 99AuNPs-4b 7.59 0:1:2 282 565aMolar ratio of dodecanethiolate: carborane: PEG. bCalculated amountof carborane per AuNP. cCalculated amount of PEG per AuNP.



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monitored by FT-IR, which was indicated by the disappearance of thetypical σCC band at 2120 cm−1. Then the propargylated PEGmonomethyl ether (Mw = 388 g/mol, 0.006 mmol, 0.5 equiv.) wasinjected and the second “click” reaction was carried out in situ. Thesecond reaction was finished in 24 h. After removal of toluene undervacuum, AuNPs-3b was washed with methanol and diethyl ether toremove the excess carborane, PEG, and the catalyst (yield 65%). 1HNMR (CDCl3, 300 MHz), δppm = 7.36−7.24 (5H, HAr), 3.69 (28H,-CH2CH2O-), 3.61 (3H, -OCH3), 3.51 (2H, CH2-triazole), 3.41 (2H,CH2-carborane), 2.73 (2H, -CH2SH), 2.20 (3H, carborane-CH3),1.30 (22H, -CH2CH2CH2-), 0.91 (3H, -CH2CH3). UV−vis: SPB at530 nm. IR: disappearance of both the σCC band at 2121 cm−1, andthe νN3 band at 2090 cm−1. TEM: average core diameter = 5.18 nm.DLS: average diameter = 15.4 nm.“Click” Synthesis of Both Carborane and PEG2000 Function-

alized AuNP-3c. AuNPs-2c (40 mg, 0.029 mmol azido-ligand) andthe carborane alkyne (0.0058 mmol, 0.2 equiv. per N3 branch) weredissolved in 15 mL of toluene, then the solution was degassed andflushed with N2. After addition of CuI-tren (0.0029 mmol, 0.1 equiv.),the solution was stirred at 30 °C under N2. The reaction was finishedin 1 day as the typical σCC band at 2100 cm−1 disappeared. Then atoluene solution (2 mL) of propargylated PEG monomethyl ether(PEG2000) (Mw 2038 g/mol, 0.023 mmol, 0.8 equiv.) was injected,and the second “click” reaction was carried out in situ. The secondreaction was confirmed to be finished in 36 h, as monitored by IR.After removal of toluene in vacuum, AuNPs-3c were obtained afterwashing with methanol and diethyl ether to remove the excess car-borane, PEG, and catalyst (yield 60%). 1H NMR (CDCl3, 300 MHz):δppm = 7.88 (1H, CH in trizaole), 7.86 (1H, CH in triazole), 7.55−7.46(4H, CHAr), 4.67 (2H, -OCH2CH2-triazole), 3.64 (176H, -CH2CH2O-),3.51 (2H, CH2-triazole), 3.41 (2H, CH2-carborane), 3.36 (3H, -OCH3),2.62 (2H, -CH2SH), 2.16 (3H, carborane-CH3), 1.24 (22H,-CH2CH2CH2-), 0.88 (3H, -CH2CH3). UV−vis: SPB at 524 nm. IR:σB−H stretching vibration at 2580 cm−1; disappearance of both the σalkyneband at 2120 cm−1, and the νN3 band at 2090 cm

−1. TEM: average corediameter = 4.75 nm. DLS: average diameter = 10.2 nm.Synthesis of Carborane-Azide 2. Carborane alkyne (0.8 mmol,

216.8 mg) and 1,4-bis-(azidomethyl)benzene (8 mmol, 1.5 g) weredissolved in 15 mL of tetrahydrofuran (THF). CuSO4 5H2O (8 mmol,200 mg) aqueous solution was then added, followed by the dropwiseaddition of a freshly prepared aqueous solution of sodium ascorbate(16 mmol, 316 mg) to obtain a 1: 1 THF/water ratio. The solutionwas stirred overnight at room temperature under N2 atmosphere. Afterremoval of THF under vacuum, CH2Cl2 was added to dissolve theproduct, and the organic solution was washed 3 three times withwater to remove the catalyst. After drying with anhydrous Na2SO4,the solvent was removed under vacuum. Purification by silica gelchromatography (petroleum ether/CH2Cl2 1: 1) provided the pureproduct as white crystals (yield 92%). 1H NMR (CDCl3, 300 MHz):δppm = 7.81−7.80 (2H, CHAr), 7.71 (1H, CHtriazole), 7.33: (4H, CHAr),7.25−7.24 (2H, CHAr), 5.59 (2H, CH2-triazole), 4.36 (2H, CH2-N3),3.47 (2H, CH2-carborane), 2.16 (3H, carborane-CH3).

13C NMR(CDCl3, 75 MHz): δppm = 147.60, 136.21, 134.94, 134.78, 130.86,130.34, 128.91, 128.49, 125.86, 119.97, 75.04, 54.27, 53.85, 40.95,23.69. 11B NMR (CDCl3, 96 MHz): δppm = −4.19, −5.80, −10.53(typical for o-carborane). MS (ESI, M+Na+): calcd. for 484.3 m/z,found in 484.3 m/z. IR: νN3 band at 2098 cm−1, σB−H at 2583.1 cm−1.Anal. Calcd. for C20H28B10N6: C 52.18, H 6.13, N 18.25; found: C51.62, H 5.99, N 18.07.Synthesis of the Tris-Alkyne Thioactetate Dendron 1. A

dimethylformamide (DMF) solution of 5-(bromomethyl)-3,4,5-tris-(prop-2-yn-1-yloxy)benzene17 (3 mmol, 996 mg) and potassium thiol-acetate (4 mmol, 343 mg) was stirred at room temperature for 20 hunder N2 atmosphere. Then water was added to quench the reaction,and the product was extracted with CH2Cl2. The organic phase waswashed 3 times with water, and then dried over anhydrous Na2SO4.The solvent was removed by rotary evaporation (yield 95%). 1H NMR(CDCl3, 300 MHz): δppm = 6.09 (2H, CHAr), 4.74 (4H, CH2-CCH), 4.70 (2H, CH2-CCH), 4.07 (2H, CH2S-), 2.51 (2H, HCC−), 2.45 (1H, HCC−), 2.36 (3H, CH3-CO).

13C NMR (CDCl3,

75 MHz): δppm = 194.9, 151.55, 136.45, 133.80, 109.25, 79.23, 78.42,75.94, 75.26, 60.34, 57.09, 33.65, 30.34. MS (ESI, M+Na+): calcd. for351.3 m/z, found in 351.1 m/z. IR: σCC band at 2121 cm−1. Anal.Calcd. For C18H16O4S: C 65.84, H 4.91, S 9.76; found: C 65.04, H4.98, S 9.65.

Synthesis of the Tris-Carborane Thioacetate Dendron 3. Thedendron 1 (0.32 mmol, 106 mg) and carborane-azide 2 (0.96 mmol,444 mg) were dissolved in 10 mL of THF. CuSO4 5H2O (0.96 mmol,240 mg) in aqueous solution was added, followed by the dropwiseaddition of a freshly prepared aqueous solution of sodium ascorbate(1.92 mmol, 380 mg) to obtain a 1: 1 THF/water ratio. The solutionwas stirred overnight at room temperature under N2. After removal ofTHF under vacuum, CH2Cl2 and 5 mL of a concentrated (30%)aqueous ammonia solution were added. The mixture was stirredduring 30 min to remove the Cu ions trapped inside the dendron as[Cu(NH3)2(H2O)2]

2+, and the organic layer was washed with water.After drying with anhydrous Na2SO4, the solvent was removed undervacuum (yield 92%). 1H NMR (CDCl3, 300 MHz): δppm = 7.8−7.7(12H, CHtriazole and CHAr), 7.19−7.17 (12H, CHAr), 6.53 (2H, CHArin the focal point), 5.52−5.28 (12H, Ar-CH2-triazole), 5.01 (6H,-CH2-O-), 3.92 (2H, CH2-S-), 3.42 (6H, CH2-carborane), 2.28 (3H,CH3-CO), 2.12 (9H, CH3-carborane).

13C NMR (CDCl3, 75 MHz):δppm = 195.36, 152.19, 147.77, 144.32, 136.81, 135.77, 135.56, 135.50,135.42, 135.14, 134.22, 131.07, 130.43, 129.00, 128.90, 128.85, 128.78,128.70, 126.03, 123.77, 120.58, 120.37, 120.17, 108.82, 75.22, 66.38,63.24, 54.04, 54.39, 41.12, 33.72, 30.62, 23.90. 11B NMR (CDCl3, 96MHz): δppm = −6.38, −10.54 (typical for o-carborane). MS (MALDI-TOF, M+Na+): calcd. for 1733.1 m/z, found in 1732.7 m/z. IR:disappearance of νN3 band at 2098 cm−1, σB−H at 2583 cm−1. Anal.Calcd. for C78H100B30N18O4S+H2O: C 54.21, H 5.95, N 14.59, S 1.86;found: C 54.00, H 5.98, N 14.24, S 2.14.

Synthesis of the Hybrid Dendron 4. The dendron 1 (0.65mmol, 212 mg) and carborane-azide 2 (0.65 mmol, 300 mg) weredissolved in 30 mL of THF, and CuSO4 5H2O (0.65 mmol, 162 mg)in 2 mL aqueous solution was added, followed by the dropwiseaddition of a freshly prepared aqueous solution of sodium ascorbate(1.3 mmol, 257 mg) to obtain a 1:1 THF/water ratio. This solutionwas stirred overnight under N2 at room temperature. After removal ofTHF under vacuum, 20 mL of CH2Cl2 and 5 mL of a concentrated(30%) aqueous ammonia solution were added. The mixture wasstirred 30 min to remove the Cu ions trapped inside the dendron as[Cu(NH3)2(H2O)2]

2+. The organic layer was isolated and washed withwater. After drying with anhydrous Na2SO4, the solvent was removedunder vacuum. The monocarborane dendron was obtained as amixture of carborane in the m- branch (major) or in the p- branch.(yield 87%). 1H NMR (CDCl3, 300 MHz): δ = 7.8−7.7 (4H, CHtriazoleand CHAr), 7.3−7.21 (6H, CHAr), 6.72−6.65 (2H, CHAr in the focalpoint), 5.6−5.4 (4H, Ar-CH2-triazole), 5.33 (2H, -CH2-O-), 4.77−4.76 (2H, -CH2-O-CCH), 4.74−4.73 (2H, -CH2-O-CCH), 4.10 (2H,CH2-S-), 3.42 (2H, CH2-carborane), 2.55 (1H, HCC−), 2.49 (1H,HCC−), 2.38 (3H, CH3-CO), 2.20 (3H, CH3-carborane). MS (ESI,M+Na+): calcd. for 812.4 m/z, found in 812.4 m/z. IR spectroscopy:σC−O−C band at 1107 cm−1, and σCC band at 2121 cm−1. Sub-sequently, the monocarborane dendron (0.24 mmol, 190 mg) andPEG-alkyne monomethylether (0.48 mmol, 975 mg) were dissolved in10 mL of THF, an aqueous solution of CuSO4 5H2O (0.48 mmol,120 mg, 5 mL) was then added. After degassing and refilling with N2,the aqueous solution of sodium ascorbate (0.96 mmol, 190 mg, 5 mL)was dropwise added into the reaction solution. After stirring overnightunder N2 at room temporature, the solvent was evaporated with arotary evaporator, and 30 mL of CH2Cl2 and 10 mL of a concentrated(30%) aqueous ammonia solution were added. The mixture wasstirred until the organic layer became colorless to remove the Cu ionstrapped inside the dendron. The organic layer was then isolated andwashed with water. After drying with anhydrous Na2SO4, the sol-vent was removed under vacuum. 1H NMR (CDCl3, 300 MHz):δppm = 7.72−7.69 (6H, CHtriazole and CHAr), 7.27−7.16 (6H, CHAr),6.72−6.65 (2H, CHAr in the focal point), 5.54−5.48 (6H, Ar-CH2-triazole), 3.61−3.50 (176H, -CH2CH2O-), 3.42 (2H, CH2-carborane),3.34 (3H, CH3-CO), 2.12 (3H, CH3-carborane).

13C NMR



42

(CDCl3, 75 MHz): δppm = 152.23, 151.57, 147.46, 144.37, 135.54,134.93, 130.92, 130.45, 129.73, 128.89, 128.71, 125.88, 124.55, 120.56,109.28, 95.57, 87.32, 87.10, 78.95, 76.47, 75.78, 75.18, 72.69, 72.02,71.43, 70.65, 70.40, 69.45, 62.36, 61.66, 59.07, 53.77, 50.31, 42.89,40.95, 30.47, 23.78. 11B NMR (CDCl3, 96 MHz): δppm = −6.05,−10.50 ppm. IR spectroscopy: disappearance of νN3 band at 2098 cm

−1,σB−H at 2579 cm−1. MS (MALDI, M+Ag+) of dendron 4: Calcd. at4888.8 m/z, found at 4888.5 m/z. Anal. Calcd. for C216H402B10N12O92S+2H2O: C 53.87, H 8.50, N 3.49, S 0.67; found: C 53.23, H 8.45, N2.80, S 0.65.Synthesis of AuNPs-4a Stabilized by Mixed Ligands. Syn-

thesis of the Tris-Carborane Thiol Dendron 5 and Me-PEG550-SH.The dendron 3 (128 mg, 0.075 mmol) was dissolved in 2 mL ofCH2Cl2, and mixed with Me-PEG550-thioacetate (41.85 mg, 0.075mmol), and the obtained solution was refluxed in 10 mL of methanolfor 3 h under N2 in the presence of 0.5 mL of concentrated (37%)HCl solution. Then the mixture was cooled down to roomtemperature, and the obtained thiol dendron 6 and Me-PEG550-SHwere used for the next step without any purification.Synthesis of Tris-Carborane Thiolate-Dendron 5 and AuNPs-4a

Stabilized by Mixed Me-PEG550-SH Ligands. HAuCl4 3H2O (30 mg,0.075 mmol) was added to the mixture of Me-PEG550-SH (39 mg,0.075 mmol) and dendron 5 (125 mg, 0.075 mmol) in a solution of10% CH2Cl2/methanol, then an aqueous solution (5 mL) of freshlyprepared NaBH4 (0.75 mmol, 28 mg) was added dropwise withvigorous stirring. After further stirring for 2 h, the organic solvent wasremoved by evaporation under vacuum, then AuNPs-4a was dissolvedin water. The free ligands were removed by dialysis in a large volumeof distilled water (3 × 4 h). 1H NMR (CDCl3, 300 MHz): δppm =7.75−7.69 (6H, CHtriazole), 7.2−7.13 (24H, CHAr), 5.55−5.45 (12H,triazole-CH2-Ar), 5.05−4.93 (6H, -CH2O-), 3.60 (44H, -CH2CH2O-),3.35(3H, -OCH3), 2.14 (9H, CH3-carborane). UV−vis: SPB at522 nm. IR: σCC at 1645 cm−1, σC−O−C band at 1110 cm−1, σB−Hat 2580 cm−1. TEM: average diameter of the core = 3.4 nm. DLSanalysis (in aqueous solution): average hydrodynamic diameter = 19 nm.Synthesis of AuNPs-4b. Synthesis of the Hybrid Thiol Dendron

6 from Dendron 4. Dendron 4 (283 mg, 0.063 mmol) was dissolvedin 2 mL of CH2Cl2; then the solution was refluxed in 10 mL ofmethanol for 3 h under N2 in the presence of 0.3 mL of concentrated(37%) HCl solution. The solution was cooled down to roomtemperature; then the obtained solution containing the thiol dendron6 was used for the next step without any purification.Synthesis of AuNPs-4b Capped with Dendron 6. HAuCl4 3H2O

(16.5 mg, 0.042 mmol) was added into the thiol dendron 6 (0.075mmol) in solution of 20% CH2Cl2/methanol; then a freshly preparedNaBH4 (0.21 mmol, 8.3 mg) aqueous solution (3 mL) was slowlyadded with vigorous stirring. After further stirring for 1 h, the organicsolvent was removed by evaporation. AuNPs-4b was then dissolved in10 mL of water, and the free ligands was removed by dialysis in800 mL of distilled water for 4 h. The dialysis process was repeatedtwo more times. 1H NMR (CDCl3, 300 MHz): δppm = 7.79−7.76(6H, CHtriazole and CHAr), 7.059 (6H, CHAr), 6.53 (2H, CHAr in thecore arene), 5.40 (6H, Ar-CH2-triazole), 3.50 (176H, -CH2CH2O-),3.42 (2H, CH2-carborane), 3.23 (3H, CH3-CO). UV−visible spec-troscopy: plasmon band at 522.4 nm. TEM image: average corediameter = 7.6 nm. DLS analysis (in aqueous solution): averagehydrodynamic diameter = 14.5 nm. IR spectroscopy: σC−O−C band at1107 cm−1, σB−H at 2583 cm−1.

■ ASSOCIATED CONTENT

*S Supporting InformationCharacterizations and data of ligands and AuNPs. This materialis available free of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATION

Corresponding Authors*E-mail: [email protected] (N.S.H.).*E-mail: [email protected] (D.A.).

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSFinancial support from the China Scholarship Council (CSC)(Ph.D. grants to N.L. and P.Z.), the Universities Bordeaux 1and Toulouse III, and the CNRS is gratefully acknowledged.N.S.H. gratefully acknowledges the support by grant from theNational Science Foundation (CHE-0906179) and NIU for anInaugural Board of Trustees Professorship and for granting aLeave of Absence.

■ REFERENCES(1) (a) Newkome, G. R.; Moorefield, C. N.; Keith, J. M.; Baker, G.R.; Escamilla, G. S. Angew. Chem., Int. Ed. Engl. 1994, 33, 666−668.(b) Hawthorne, M. F.; Zink, J. I.; Skelton, J. M.; Bayer, M. J.; Liu, C.;Livshits, E.; Baer, R.; Neuhauser, D. Science 2004, 303, 1849−1850.(c) Faraha, O. K.; Spokoyny, A. M.; Mulfort, K. L.; Hawthorne, M. F.;Mirkin, C. A.; Hupp, J. T. J. Am. Chem. Soc. 2007, 129, 12680−12681.(d) Toppino, A.; Bova, M. E.; Crich, S. G.; Alberti, D.; Diana, E.;Barge, A.; Aime, S.; Venturello, P.; Deagostino, A. Chem.Eur. J.2013, 19, 721−728.(2) (a) Wang, S. H.; Shreiner, C. D.; Moorefield, C. N.; Newkome,G. R. New. J. Chem. 2007, 31, 1192−1217. (b) Fujii, S.; Masuno, H.;Taoda, Y.; Kano, A.; Wongmayura, A.; Nakabayashi, M.; Ito, N.;Shimizu, M.; Kawachi, E.; Hirano, T.; Endo, Y.; Tanatani, A.;Kagechika, H. J. Am. Chem. Soc. 2011, 133, 20933−20941. (c) Valliant,J. F.; Guenther, K. J.; King, A. S.; Morel, P.; Schaffer, P.; Sogbein, O.O.; Stephenson, K. A. Coord. Chem. Rev. 2002, 232, 173−230.(d) Hosmane, N. S. Boron Science. New Technologies and Applications;Taylor and Francis Books, CRC Press: Boca Raton, FL, 2011.(3) (a) Parrott, M. C.; Marchington, E. B.; Vallian, J. F.; Adronov, A.J. Am. Chem. Soc. 2005, 127, 12081−12089. (b) Jude, H.; Disteldorf,H.; Fisher, S.; Wedge, T.; Hawkridge, A. M.; Arif, A. M.; Hawthorne,M. F.; Muddiman, D. C.; Stang, P. J. J. Am. Chem. Soc. 2005, 127,12131−12139. (c) Djeda, R.; Ruiz, J.; Astruc, D.; Satapathy, R.; Dash,B. P.; Hosmane, N. S. Inorg. Chem. 2010, 49, 10702−10709. (d) Liang,L.; Rapakousiou, A.; Salmon, L.; Ruiz, J.; Astruc, D.; Dash, B. P.;Stapathy, R.; Sawichi, J. W.; Hosmane, N. S. Eur. J. Inorg. Chem. 2011,3043−3049. (e) Yao, Z.; Jin, G. Coord. Chem. Rev. 2013, 257 (17),2522−2535.(4) (a) Daniel, M. C.; Astruc, D. Chem. Rev. 2004, 104, 293−346.(b) Xia, Y.; Xiong, Y.; Lim, B.; Skabalak, S. E. Angew. Chem., Int. Ed.2009, 48, 60−103. (c) Giljohann, D. A.; Seferos, D. S.; Daniel, W. L.;Massich, M. D.; Patel, P. C.; Mirkin, C. A. Angew. Chem., Int. Ed. 2010,49, 3280−3294. (d) Gold Nanoparticles for Physics, Chemistry, Biology;Louis, C., Pluchery, O., Eds.; Imperial College Press: London, U.K.,2012.(5) (a) Alkilany, A. M.; Murphy, C. J. J. Nanopart. Res. 2010, 12,2313−2333. (b) Bardhan, R.; Lal, S.; Joshi, A.; Halas, N. J. Acc. Chem.Res. 2011, 44, 936−946. (c) Yang, X. C.; Samanta, B.; Agasti, S. S.;Jeong, Y.; Zhu, Z.; Rana, S.; Miranda, O. R.; Rotello, V. M. Angew.Chem., Int. Ed. 2011, 50, 477−481. (d) Llevot, A.; Astruc, D. Chem.Soc. Rev. 2012, 41, 242−257. (e) Jans, H.; Huo, Q. Chem. Soc. Rev.2012, 41, 2849−2866.(6) (a) Valliant, J. F.; Guenther, K. J.; King, A. S.; Morel, P.; Schaffer,P.; Sogbein, O. O.; Stephenson, K. A. Coord. Chem. Rev. 2002, 232,173−230. (b) Zhu, Y.; Peng, A. T.; Carpenter, K.; Maguire, J. A.;Hosmane, N. S.; Takagaki, M. J. Am. Chem. Soc. 2005, 127, 9875−9880. (c) Cioran, A. M.; Musteti, A. D.; Teixidor, F.; Krpetic, Z.; Prior,I. A.; He, Q.; Kiely, C. J.; Brust, M.; Vinas, C. J. Am. Chem. Soc. 2012,134, 212−221.(7) Walkey, C. D.; Olsen, J. B.; Guo, H.; Emili, A.; Chan, W. C. W. J.Am. Chem. Soc. 2012, 134, 2139−2147.(8) Wuelfing, W. P.; Gross, S. M.; Miles, D. T.; Murray, R. W. J. Am.Chem. Soc. 1998, 120, 12696−12697.(9) (a) Otsuka, H.; Nagasaki, Y.; Kataoka, K. Adv. Drug. Delivery Rev.2003, 55, 403−419. (b) Heo, D. N.; Yang, D. H.; Moon, H. J.; Lee, J.



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B.; Bae, M. S.; Lee, S. C.; Lee, W. J.; Sun, I. C.; Kwon, I. K.Biomaterials 2012, 33, 856−866.(10) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.Angew. Chem., Int. Ed. 2002, 41, 2596−2599. (b) Meldal, M.;Christensen, C.; Tornoe, C. W. J. Org. Chem. 2002, 67, 3057−3064.(c) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952−3015.(d) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302−1315.(e) Liang, L.; Astruc, D. Coord. Chem. Rev. 2011, 255, 2933−2945.(11) (a) Fleming, D. A.; Thode, C. J.; Williams, M. E. Chem. Mater.2006, 18, 2327−2334. (b) Thode, C. J.; Williams, M. E. J. ColloidInterface Sci. 2008, 320, 346−352. (c) Boisselier, E.; Salmon, L.; Ruiz,J.; Astruc, D. Chem. Commun. 2008, 5788−5790. (d) Boisselier, E.;Diallo, A. K.; Salmon, L.; Ornelas, C.; Ruiz, J.; Astruc, J. J. Am. Chem.Soc. 2010, 132, 2729−2742.(12) Liang, L.; Ruiz, J.; Astruc, D. Adv. Synth. Catal. 2011, 353,3434−3450.(13) (a) Zhao, P.; Grillaud, M.; Salmon, L.; Ruiz, J.; Astruc, D. Adv.Synth. Catal. 2012, 354, 1001−1011. (b) Astruc, D.; Liang, L.;Rapakousiou, A.; Ruiz, J. Acc. Chem. Res. 2012, 45, 630−640.(14) Brust, M.; Walker, M.; Bethell, D.; Schiffrin, D. J.; Whyman, R. J.Chem. Soc., Chem. Commun. 1994, 801−802.(15) Leites, L. A. Chem. Rev. 1992, 92, 279−323.(16) Leff, D. V.; Ohara, P. C.; Geath, J. R.; Gelbart, W. M. J. Phys.Chem. 1995, 99, 7036−7041.(17) Camponovo, J.; Ruiz, J.; Cloutet, E.; Astruc, D. Chem.Eur. J.2009, 15, 2990−3002.



44

Chapter 3

Triazole-stabilized AuNPs and their Applications

45

3.1 Introduction

Part A. A wide range of AuNP stabilizers including molecular and solid-state materials are

known since last century. We report here the first AuNP stabilization attempts using a simple

„„clicked‟‟ 1,2,3-triazole ligand with a PEG tail, indicating that it can provide a good

biocompatible platform towards various applications in water including catalysis and thiolate

coverage. This AuNP shows excellent performance in catalyzed nitrophenol reduction,

selective detection of Hg2+ and ligand substitution of thiolate ligands. This part was

accomplished in collaboration with Dr. Pengxing Zhao who actually initiated the project.

Part B. The one-step decoration of AuNPs with functional ligands is a priviledged topic

towards applications. Since “click” chemistry is one of the most well-known methods of

linking functionalities, a family of 1,2,3-triazole derivatives that contain both a PEG chain

and another functional fragment (polymer, dendron, alcohol, carboxylic acid, allyl, coumarin,

redox-robust metal complex or cyclodextrin) were synthesized and coordinated to AuNPs

surface in aqueous solution in a size range 3-11.2 nm. These AuNPs have potential

applications according to different functional groups.

Part C. Monofunctional triazoles linked to ferrocene, ferricenium or coumarin, easily

synthesized by “click” reactions between the corresponding functional azides and

trimethylsilylacetylene followed by silyl group deprotection, provide a variety of convenient

neutral ligands for the stabilization of functional gold nanoparticles (AuNPs) in polar organic

solvents. These triazole-AuNPs are very useful towards a variety of applications to synthesis,

sensing and catalysis.

46

3218 Chem. Commun., 2013, 49, 3218--3220 This journal is c The Royal Society of Chemistry 2013

Cite this: Chem. Commun.,2013,49, 3218

How a simple ‘‘clicked’’ PEGylated 1,2,3-triazole ligandstabilizes gold nanoparticles for multiple usage†

Pengxiang Zhao,ab Na Li,a Lionel Salmon,c Na Liu,d Jaime Ruiza and Didier Astruc*a

‘‘Click’’ chemistry now offers access to a great variety of triazoles,

and the first example of a strategy to stabilize gold nanoparticles

(AuNPs) with a new 1,2,3-triazole–mPEG ligand is developed here

together with preliminary examples of possible applications.

The growing field of gold nanoparticles (AuNPs) now occupies acentral place in nanoscience and nanotechnology because oftheir key applications in catalysis,1 materials science,2 opticalbiosensors,3 and nanomedical diagnostics and therapeutics(theranostics).4 A wide range of AuNP stabilizers includingmolecular and solid-state materials are known. Among them,citrate and cetyltrimethylammonium bromide (CTAB) offerremarkable key intermediate structures for further stabilizationby thiolates.5 Some undesired toxicity of ionic ligands some-times appears, however,3a,b and the search of additional usefulligands, in particular neutral ones, is called for. We wish toreport here the first AuNP stabilization attempts using a simple‘‘clicked’’ 1,2,3-triazole ligand, indicating that it can provide agood biocompatible platform towards various applications inwater including sensing, catalysis and thiolate coverage. Wehave selected a PEG tail, because it brings the solubility inaqueous media and biocompatibility, but ‘‘click’’ chemistry6

also further offers unlimited possibilities for terminal groups ofsuch AuNP frameworks. We explore here the aspects of theseAuNP assemblies including characterization by 1H NMR, TEM,HRTEM, EDS, Raman spectroscopy, UV-vis spectroscopy, anddynamic light scattering (DLS), and evaluate catalysis of 4-nitro-phenol reduction to 4-aminophenol, selective sensing of Hg2+,and usage as convenient starting materials for triazole/thiolateligand substitution and heterobifunctionalization.

The synthesis and post-treatment of triazole–mPEG cappedAuNPs are carried out in water (eqn (1)).

(1)

HAuIIICl4 is reduced to Au0 by dropwise addition of NaBH4 in thepresence of triazole–mPEG ligands at r.t. (ESI†). The threeAu:ligand (L) stoichiometries (Au/L = 0.5, 2 and 10) yield stableAuNPs for which the purple color and plasmon band remainunchanged even after refluxing the aqueous AuNPs for one hour.

The excess ligand and salts are removed from the solution of1 (Au/L = 2) by dialysis. The plasmon band is slightly red-shiftedfrom 535 to 538 nm (Fig. S4, ESI†), and the core size (TEM) largelyincreases from 6.0 to 17.5 nm upon increasing the Au/L ratio(Table S1, ESI† Fig. 1). The shape of the AuNP core in 1 shown byHRTEM in Fig. 1c is icosahedral. Dynamic light scattering providesa size of 12.6 � 3 nm in solution for 1. The Energy-Dispersive X-raySpectroscopy (EDS) of 1 (Fig. 1d) confirms the presence of Au andthe elements (i.e. C, N and O) contained in the triazole–mPEGligands. Determination of the number of Au atoms and cappedligands per AuNP using the TEM, 1H NMR and element analysisdata (from EDX)7 shows that the N/Au ratio is 0.03 and that the6 nm-cored AuNP 1 contains approximately 8850 Au atoms and1140 triazole–mPEG ligands.

Thiols are transformed to thiolates upon coordination to theAuNP surface in classic thiolate–AuNPs as recently proven byexperiment data,8 but triazoles are less acidic than thiols. Ramanspectroscopy shows here that the triazole is not transformed totriazolate upon coordination to the AuNPs 1. Compared to the freetriazole–mPEG (Fig. 1e, bottom), 1 (upper) undergoes a remark-able enhancement of the Raman absorbance at 559 cm�1 and1096 cm�1. The former corresponds to N–H wagging, and the

a ISM, Univ. Bordeaux, 351 Cours de la Liberation, 33405 Talence Cedex, France.

E-mail: [email protected] Science and Technology on Surface Physics and Chemistry Laboratory,

PO Box 718-35, Mianyang 621907, Sichuan, Chinac LCC, CNRS, 205 Route de Narbonne, 31077 Toulouse Cedex, Franced ICMCB, UPR CNRS No 9048, 87 avenue, Pey-Berland, 33608 Pessac Cedex, France

† Electronic supplementary information (ESI) available: Experimental details andcharacterization data. See DOI: 10.1039/c3cc00269a

Received 11th January 2013,Accepted 27th February 2013

DOI: 10.1039/c3cc00269a

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This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 3218--3220 3219

latter shows the N–N, NQN and C–H vibration in the triazolering.9 These two enhancements reflect the SERS effect provoked bythe coordination of the triazole N atoms onto the surface Au atomsof the AuNPs. However, the clear enhancement of the N–H waggingat 559 cm�1 shows that the H atom of the triazole ligand is notlost near the Au surface, which is opposite to what happenswith thiolate AuNP ligands. This key difference explains why thestabilization of AuNPs is weaker with triazole ligands than withthiolate ligands, and this distinction is at the origin of the specificproperties and applications of 1 in sensing, catalysis, ligand sub-stitution and multiple functionalizations.10

Reduction of 4-nitrophenol is an example to test the catalyticefficacy of the triazole–PEG-capped AuNPs (eqn (2)).

(2)

4-Aminophenol is very useful for a wealth of applications thatinclude analgesic and antipyretic drugs, photographic developer,corrosion inhibitor, anticorrosion lubricant, etc.11 The reductionof 4-nitrophenol to 4-aminophenol using aqueous NaBH4 isthermodynamically favorable, but the presence of the kineticbarrier due to the large structural transformation along theredox reaction between donor and acceptor molecules inhibitsthis reaction. The AuNPs catalyze this reaction because of thefavorable reactivity at the surface Au atoms of the AuNP coresthat are only weakly engaged with the neutral triazole ligands. Anaqueous solution (2.5 mL) containing 4-nitrophenol (0.37 mmol)

and NaBH4 (0.03 mmol) was mixed in a 3 mL standard quartzcuvette. This solution immediately changed from yellow toyellow-green (absorbance at 400 nm in Fig. 2a), which indicatedthe formation of 4-nitrophenolate ions. Then AuNPs containing0.5% Au catalyst were added, and the reaction was monitored byUV-vis spectroscopy. The intensity of the absorbance peak atabout 400 nm rapidly decreased after addition of the AuNPs,which indicated the consumption of 4-nitrophenol, while theappearance and increase of the absorbance peak at 300 nmshowed the formation of 4-aminophenol.

The reaction was nearly complete within 280 s at 25 1C. Theplasmon band at about 530 nm confirms the stability of thetriazole–mPEG-capped AuNPs during this reaction. The kineticconstant of this reaction follows kt = �ln(c/c0), and Fig. 2bshows the relation of �ln(c/c0) vs. reaction time for thereduction of 4-nitrophenol over triazole–mPEG-capped AuNPs,providing k = 5.2 � 10�3 s�1. Further, this reaction was carriedout with various amounts of the AuNP catalyst 1, and the kvalues are gathered in Table S1 (ESI†). Compared with recentreports,11 the triazole–mPEG-capped AuNPs 1 shows among thevery best catalytic activities for this reaction.

The AuNPs are also an excellent optical sensor for the selectivedetection of Hg2+. The plasmon band shift of AuNPs in thepresence of various metal ions including Mg2+, Ca2+, Ag2+, K+,Fe2+, Cu2+, Na+, and Hg2+ was investigated and no shift wasobserved. Enhancement of the absorbance with Fe3+ and Cu2+ isdue to their own colors. A clear plasmon-band red shift of 12 nm(Fig. S11, ESI†) was only observed by adding Hg2+ (Fig. 3).

It is known that the triazole ring strongly and selectivelycoordinates to Hg2+, compared with other ions.12 The weakAu–triazole linkage opens the possibility for this Hg2+ ion todisplace triazole from the AuNP surface and to form a Au–Hg2+

bond or a triazole-bridging heterobimetallic interaction with bothAu and Hg2+. The selective red shift of the AuNP plasmon bandcan thus be taken into account by this coordination change at theAuNP surface of 1. During the Hg2+ titration, the AuNP solutionremains homogeneous, i.e. no AuNP aggregation occurs.

Finally, one of the key properties of the AuNPs 1 is theirfunction as a precursor for a variety of functionalizations,13 aseasily as with citrate ions that undergo, however, some trans-formation upon coordination. The weak AuNP–triazole bondsopen the route to facile ligand-substitution reactions, whereasthe well-known substitution of strongly bonded thiolate ligands

Fig. 1 TEM of triazole–mPEG capped AuNPs 1 (a); size distribution of 1 (b);HR-TEM of 1 (c) and its EDS spectrum (EDS peaks of Cu and Si belong to the gridtemplate used for the analysis) (d). Raman spectra of triazole–mPEG (bottom)and triazole–mPEG capped AuNPs 1 (upper) (e).

Fig. 2 (a) UV-vis absorption spectra during the reduction of 4-nitrophenolcatalyzed by 1 (quartz cuvette, path length: 1 cm). (b) Plot of �ln(c/c0) vs.reaction time during the reduction of 4-nitrophenol catalyzed by 1 at 25 1C.

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3220 Chem. Commun., 2013, 49, 3218--3220 This journal is c The Royal Society of Chemistry 2013

is tedious.6c For instance, complete triazole ligand substitution byfunctional thiols in methanol and water is fast and facile withoutany aggregation or core size change for Au : L ratio = 0.5 and 2.The triazole–mPEG ligands were substituted with a mixture of11-mercaptoundecanoic acid and thiol–mPEG, with a pre-determined ratio of 1 : 1 that remained the same on the Au surface(Scheme 1 Fig. S14, ESI†). Another example deals with the moredifficult problem of the introduction of a polyfunctional dendronthat possesses a single thiol group at the focal point, and a stericallybulky nonaferrocenyl thiol dendron with 1 - 3 connectivityhas been chosen.14 The exchange reaction between 1 and 3 isconducted in the presence of dodecanethiol (Scheme 1), yieldingthe stable dendrimer-shape AuNPs 4 that contains 40% ofdendronic thiolates, as determined by 1H NMR (Fig. S19, ESI†),which corresponds to approximately 1000 ferrocenyl groups aroundthe 6 nm AuNP core (size from DLS: 16.3 � 3 nm).

The TEM data show that this core size remains almostunchanged (slight increase) upon ligand substitution in 2 and4 vs. 1. The DLS data provide sizes of 16.3 � 3 nm and 13.1 �3 nm for 2 and 4 respectively. The cyclic voltammogram of the

AuNP-cored dendrimer 4 was recorded on a Pt electrode inCH2Cl2 with decamethylferrocene (FeCp*2) as the internalreference.15,16 It shows a chemically and electrochemicallyreversible anodic oxidation to polyferricinium at E1/2 = 0.610 Vvs. [FeCp*2]+/0 with strong cathodic adsorption due to the largesize, also characterized by a Epa � Epc value of 40 mV, lowerthan the 59 mV expected at 25 1C in the absence of adsorption(Fig. S22, ESI†).16

In conclusion, a simple ‘‘1,2,3-triazole’’ ligand resultingfrom the extensively used ‘‘click’’ chemistry stabilizes AuNPs withvarious core sizes, specific properties and possible applications.Given the broad scope of ‘‘click’’ chemistry, many variationsshould be open for multiple usages.

Financial support from the China Scholarship Council (CSC)(PhD grants to P. Zhao and N. Li), the Universities Bordeaux 1and Toulouse III, and the CNRS is gratefully acknowledged.

Notes and references1 (a) M. Haruta, Nature, 2005, 437, 1098; (b) A. Corma and P. Serna,

Science, 2006, 313, 332; (c) N. Dimitratos, J. A. Lopez-Sanchez andG. J. Hutchings, Chem. Sci., 2012, 3, 20.

2 (a) Y. Xia, Y. Xiong, B. Lim and S. E. Skrabalak, Angew. Chem., Int. Ed.,2009, 48, 60; (b) Gold Nanoparticles for Physics, Chemistry, Biology,ed. C. Louis and O. Pluchery, Imperial College Press, 2012.

3 (a) C. J. Murphy, A. M. Golet, J. W. Stone, P. N. Sisco, A. M. Alkilany,E. C. Goldsmith and S. C. Baxter, Acc. Chem. Res., 2008, 41, 1721;(b) A. M. Alkilany and C. J. Murphy, J. Nanopart. Res., 2010, 12, 2313;(c) R. Bardhan, S. Lal, A. Joshi and N. J. Halas, Acc. Chem. Res., 2011,44, 936.

4 X. C. Yang, B. Samanta, S. S. Agasti, Y. Jeong, Z. Zhu, S. Rana,O. R. Miranda and V. M. Rotello, Angew. Chem., Int. Ed., 2011,50, 477.

5 (a) M. Giersig and P. Mulvaney, Langmuir, 1993, 9, 3408; (b) M. Brust,M. Walker, D. Bethell, D. J. Schiffrin and R. J. Whyman, J. Chem.Soc., Chem. Commun., 1994, 801; (c) A. C. Templeton, W. P. Wuelfingand R. W. Murray, Acc. Chem. Res., 2000, 33, 27; (d) M. C. Daniel andD. Astruc, Chem. Rev., 2004, 104, 293.

6 (a) M. Meldal and C. W. Tornøe, Chem. Rev., 2008, 108, 2952;(b) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302;(c) L. Liang and D. Astruc, Coord. Chem. Rev., 2011, 255, 2933.

7 For the determination of the ligand number from the AuNP core sizeand elemental analysis, see: (a) D. V. Leff, P. C. Ohara, J. R. Heathand W. M. Gelbart, J. Phys. Chem., 1995, 99, 7036; (b) A. Labande,J. Ruiz and D. Astruc, J. Am. Chem. Soc., 2002, 124, 1782.

8 Y. Li, O. Zaluzhna, B. Xu, Y. Gao, J. M. Modest and Y. J. Tong, J. Am.Chem. Soc., 2011, 133, 2092.

9 A. A. Jbarah, A. Ihle, K. Banert and R. Holze, J. Raman Spectrosc.,2006, 37, 123.

10 It is expected that two adjacent N atoms of the PEGylated triazole arecoordinated to the AuNP core. Thus the AuNP-binding energyshould be higher than with amines (6 kcal mol�1), (ref. 6d) probablyof the order of 10 kcal mol�1. Note the thermal stability in boilingwater; on the other hand attempts to remove the solvent (water ororganic) results in agglomeration, preventing thermogravimetricanalysis.

11 (a) Z. Zhang, C. Shao, P. Zou, P. Zhang, M. Zhang, J. Mu, Z. Guo,X. Li and C. Wang, Chem. Commun., 2011, 47, 3906; (b) A. Gangula,R. Podila, M. Ramakrishna, L. Karanam, C. Janardhana andA. M. Rao, Langmuir, 2011, 27, 15268; (c) I. Biondi, G. Laurenczyand P. J. Dyson, Inorg. Chem., 2011, 50, 8038.

12 Y. H. Lau, J. R. Price, M. H. Todd and P. J. Rutledge, Chem.–Eur. J.,2011, 17, 2850.

13 A. Llevot and D. Astruc, Chem. Soc. Rev., 2012, 41, 242.14 G. R. Newkome and C. Shreiner, Chem. Rev., 2010, 110, 6338.15 J. Ruiz and D. Astruc, C. R. Acad. Sci., Ser. IIc: Chim., 1998, 21.16 F. Barriere and W. E. Geiger, Acc. Chem. Res., 2010, 43, 1030.

Fig. 3 Plasmon band shift (vs. 535 nm) of 1 (0.4 mM) with MgCl2, CaCl2, KCl,Fe(C6H5O7), Ag2CO3, CuCl2, Hg(O2CCH3)2 or NaCl (all 0.05 mM).

Scheme 1 Ligand-substitution reactions of triazole–mPEG in 1.

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& Nanotechnology

“Click” Chemistry Mildly Stabilizes Bifunctional GoldNanoparticles for Sensing and Catalysis

Na Li,[a] Pengxiang Zhao,[b] Na Liu,[c] Mar�a Echeverria,[d] Sergio Moya,[d] Lionel Salmon,[e]

Jaime Ruiz,[a] and Didier Astruc*[a]

Abstract: A large family of bifunctional 1,2,3-triazole deriva-tives that contain both a polyethylene glycol (PEG) chainand another functional fragment (e.g. , a polymer, dendron,alcohol, carboxylic acid, allyl, fluorescence dye, redox-robustmetal complex, or a b-cyclodextrin unit) has been synthe-sized by facile “click” chemistry and mildly coordinated tonanogold particles, thus providing stable water-soluble gold

nanoparticles (AuNPs) in the size range 3.0–11.2 nm with var-ious properties and applications. In particular, the sensingproperties of these AuNPs are illustrated through the detec-tion of an analogue of a warfare agent (i.e. , sulfur mustard)by means of a fluorescence “turn-on” assay, and the catalyticactivity of the smallest triazole–AuNPs (core of 3.0 nm) is ex-cellent for the reduction of 4-nitrophenol in water.

Introduction

Gold nanoparticles (AuNPs) have emerged as a key field ofnanoscience due to their quantum-related and supramolecularproperties,[1] with promising applications in catalysis,[2] sens-ing,[3] and nanomedicine, in particular.[4] A variety of ligandshave been shown to stabilize AuNPs since the citrate methodof synthesis reported in 1952 by Turkevich et al. that allowedthe formation of water-soluble AuNPs in the range 15–50 nm,which are still currently used in biomedical applications.[5]

Sulfur ligands are popular stabilizers, in particular thiolate li-gands in the Brust–Schiffrin method, which provide small mon-odisperse AuNPs (2–6 nm).[6] Cetyltrimethylammonium bro-mide (CTAB),[7] a remarkable Au-nanorod stabilizer, has restric-tions in biological applications due to the biotoxicity of thisfree surfactant.[8] Besides, many other nitrogen donors, such asimidazoles,[9] pyridines,[10] and others, have also been intro-duced for the stabilization of AuNPs, with the advantage of

a modest AuNP–ligand bond strength that allows the AuNPsurface to be reached by ready ligand displacement. Such anintroduction of substrates onto the AuNP surface upon weakligand displacement leads to possibilities in optical, sensing,and catalytic applications.[11] For AuNP stabilizers, the use ofa large class of biocompatible neutral and water-solubilizing li-gands that are heterobifunctional is now considered to bea new, general, and environmentally friendly strategy that canproduce a variety of side products and overcome the limita-tions indicated above.

The CuI-catalyzed azide–alkyne cycloaddition (CuAAC) reac-tion (“click” reaction) is one of the most well-known methodsof linking functionalities,[12] and this reaction forms 1,4-hetero-bifunctional 1,2,3-triazoles, which are very useful ligands. The1,2,3-triazole ring is an amphoteric p-electron-rich aromatic,which is completely biocompatible and stable toward both ox-idizing and reducing agents. So far, click chemistry has beenone of the numerous methods to functionalize thiolate ligandsof nanoparticles.[13] Herein, we show that the clicked 1,2,3-tria-zoles can be used as excellent neutral ligands to stabilizeAuNPs with the following great advantages: 1) these ligandsare neutral and mild and involve a weaker bond with theAuNP cores than the thiolate ligands, a property that will beshown to be crucial in sensing and catalysis ; 2) the great po-tential of click synthesis allows the introduction of a large vari-ety of functional groups; 3) the heterobifunctionality of the1,2,3-triazole ligands synthesized by click reactions allows theintroduction of two functional groups at a time, which makesthem superior to, for instance, thiolate and amine ligands;4) water-soluble AuNPs can be synthesized in this way bychoosing the biocompatible polyethylene glycol (PEG) groupas one of the triazole substituents, whereas the other substitu-ent will lead to a specific property, function, and application inwater. The 1,2,3-triazole ring can associate with AuNP surfacesthrough the lone pair of electrons on the sp2-hybridized nitro-

[a] N. Li, Dr. J. Ruiz, Prof. Dr. D. AstrucISM, UMR CNRS 5255Universit� Bordeaux, 351 Cours de la Lib�ration33405 Talence Cedex, (France)E-mail : [email protected]

[b] Dr. P. ZhaoScience and Technology on Surface Physics and Chemistry LaboratoryPO Box 718-35, Mianyang 621907, Sichuan (China)

[c] Dr. N. LiuICMCB, UPR CNRS 9048, Universit� Bordeaux, 87 AvenuePey-Berland, 33608 Pessac Cedex (France)

[d] M. Echeverria, Dr. S. MoyaCIC biomaGUNE, Paseo Miram�nno182, Edif. “C”20009 Donostia-San Sebasti�n (Spain)

[e] Dr. L. SalmonLCC, UPR CNRS 8241, 205 Route de Narbonne31077 Toulouse Cedex (France)

Supporting information for this article is available on the WWW underhttp ://dx.doi.org/10.1002/chem.201402652.

Chem. Eur. J. 2014, 20, 8363 – 8369 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim8363

Full PaperDOI: 10.1002/chem.201402652

50

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gen atoms.[14] In addition, dendrimers that incorporate triazolerings have been shown to have an excellent ability to encapsu-late and stabilize noble-metal NPs.[15]

These new 1,2,3-triazole–AuNPs synthesized in this studywith a biologically benign PEG chain (Mw = 2000) and varioususeful functional groups are anticipated to potentially undergovarious applications based upon their electrochemical, optical,fluorescent, supramolecular, encapsulating, and catalytic prop-erties. For the purpose of utilizing the properties of triazole–AuNPs, including the properties of the ligand and AuNP core,each compound contains two groups on each triazole unit,that is, a solubilizing PEG chain and a functional fragment.

Results and Discussion

Design of bifunctional triazole-stabilized AuNPs

The functional fragments of 1–5 include polymeric and den-dronic groups with various functionalities (Figure 1). A couma-rin fragment, which was expected to have excellent photolu-minescence properties, was introduced in 6.

Redox-robust organometallic compounds that contain a fer-rocenyl group, tris-ferrocenyl dendron, or the “electron-reser-voir” complex [CpFe(h6-C6Me6)][PF6] (Cp = cyclopentadienyl)complex[16] were introduced to combine electrochemical and

Figure 1. Structures of the disubstituted 1,2,3-triazoles 1–10, and the stabilization of AuNPs with these disubstituted 1,2,3-triazole molecules. mPEG = methox-ypolyethylene glycol.

Chem. Eur. J. 2014, 20, 8363 – 8369 www.chemeurj.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim8364

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optical properties in triazole–AuNPs in 7–9, respectively(Figure 1). These iron sandwich complexes are redox catalyststhat have been used as glucose biosensors in the case of ferro-cene[16b,c] and as redox catalysts for the reduction of nitrateand nitrite moieties in water in the case of the mixed sandwichcomplex. The presence of a large number of these species inwater-soluble NPs should further facilitate their use as redoxcatalysts and redox sensors. In addition, 10 has been assem-bled with a b-cyclodextrin (b-CD) unit, that is, a rigid cylindricalamphiphilic molecule, and has been extensively used to in-clude hydrophobic molecules, such as anticancer drugs, to in-crease their solubility in water. Hence, AuNP-10 is a promisingcandidate for drug-delivery vehicles. The synthesis of the dis-ubstituted triazole-stabilized AuNPs was conducted by usingtetrachloroauric acid and a 1,2,3-triazole dissolved in deionizedwater in a standard molar ratio 1:2 of AuIII/triazole (AuNP-6 =

1:0.5, AuNP-2 = 1:5) and followed by the addition of sodiumborohydride as the reductant.

Characterization of the AuNPs

The triazole–AuNPs were characterized by using UV/Vis spec-troscopy, TEM, and dynamic light scattering (DLS). Particularproperties of AuNP-5, -6, -7, and -10 with special functionalgroups were displayed separately from the correspondingmeasurements. The TEM images depict the core size of theAuNPs to be in the range 3.0–11.2 nm.

Variations in the core size relies on the ratio between theAuIII center and the triazole in the preparation, and secondarydeterminants of this variation are the rate of reduction, whichresult from the addition of the reductant, and the slight influ-ence of the distinctive functional fragments in each triazolecompound. For instance, AuNP-6 (d = 11.2 nm) is much largerthan other AuNPs because it was prepared with a ratio of AuIII/triazole ligand of 1:0.5, thus leading to an assembly of the Auatoms that proceeds much faster than the AuNP stabilizationby the triazole ligands until a certain point. In addition, a traceof anisotropic nanocrystals was produced during this synthesis(Figure 2). With a diameter over 10 nm, AuNPs-6 should showprominent efficiency in fluorescence quenching assays. In con-trast, AuNPs-2 was prepared with a low AuIII/triazole ratio (i.e. ,1:5) to obtain smaller AuNPs that could reveal excellent catalyt-ic properties. The AuNPs that were prepared with the ratio ofAuIII/triazole of 1:2 displayed similar diameters (AuNPs-1 = 6.1,AuNPs-4 = 6.0, AuNPs-5 = 5.9, AuNPs-8 = 5.2, AuNPs-9 = 5.7,AuNPs-10 = 5.2 nm), except for AuNPs-3 and AuNPs-7 (4.0and 3.8 nm, respectively). The location of the surface plasmonband (SPB) in the UV/Vis spectra (see the Supporting Informa-tion for details) of various AuNPs corresponds well to the core-size distribution of these AuNPs.

The behavior of AuNP-1–AuNP-10 in water were revealedthrough DLS analysis. The diameter obtained for each AuNP issubjected to deviations according to the nature of the func-tional groups (see the Supporting Information). AuNP-1 ag-glomerates in a large cluster, which includes many individualAuNPs due to extensive aggregating supramolecular interac-tions among the PEG tails of both triazole substituents (d =

396 nm) in aqueous solution. The PEG chains dominate the be-havior of the AuNPs in solution because of their long flexiblechain and interweave with one another among several adja-cent AuNPs. On the other hand, AuNP-2–AuNP-6 that containorganic fragments on one triazole substituent only give mobili-ty diameters in the range 140–250 nm because intermolecularPEG-chain interweaving proceeds only on one triazole side. Fi-nally, AuNP-7–AuNP-9 that bear a ferrocenyl unit and relatedgroups are well dispersed in water and show a mobility diame-ter of lower than 30 nm (see Figures S48, S50, and S51 in theSupporting Information). Consequently, it is concluded that theferrocenyl group and its derivatives inhibit the gathering of in-dividual AuNPs.

The electrochemical properties of AuNP-7 were recognizedupon recording cyclic voltammograms (see Figure S50 in theSupporting Information). Both the electrochemical and opticalproperties of AuNP-7 have proven to be valuable for thedesign of sensory devices that are devoted to the selective rec-ognition of extensively studied oxo anions (especially HSO4

� ,H2PO4

� , and ATP2� ions).[17]

The surface-enhanced Raman scattering (SERS) effect of tria-zole–AuNPs was investigated by comparison between theRaman spectra of 5 and AuNP-5 (Figure 3). This comparisonshows a distinct enhancement at l= 539 (N�N wagging) and1100 cm�1 (C�N, C=C, and N=N stretching), both of these sig-nals correspond to the triazole ring.[14b,c] In the Raman spec-trum of AuNP-5, these two signals of the triazole ring were so

Figure 2. TEM images of AuNP-2 and AuNP-6 (core diameter = 3.0 and11.2 nm, respectively).

Figure 3. Raman spectra of 5 (upper curve) and AuNP-5 (lower curve).


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drastically amplified that one cannot clearly distinguish theother signals relative to the same position in the spectrum of 5.

This phenomenon shows that the triazole C�N and N=Nbonds are much closer to the AuNPs surface than any otherpart of the triazole group. Therefore, this finding indicates thatthe triazole neutral ligands stabilize the AuNPs by coordinationof their nitrogen atoms to the AuNP surface.

These AuNPs are thermally stable at 100 8C in aqueous solu-tion, which is indicated by the absence of plasmon-band varia-tion after several hours at 100 8C (see Figure S46 in the Sup-porting Information), but these AuNPs agglomerate in the con-densed phase, which inhibits thermogravimetric studies. Theirstability to variations in pH values in aqueous solution was fur-ther studied by using UV/Vis spectroscopic analysis to recordthe SPB band of AuNP-5 at 25 8C (see Figure S46 in the Sup-porting Information), whereby various pH values were adjustedby the addition of NaOH or HCl solution. As a result, no obvi-ous plasmon-band shift was observed in the range pH 4–9,that is, the range of physiological pH values in the cellular en-vironment, thus indicating that the triazole–AuNPs are stablein a physiological pH environment.

Fluorescence sensing of 2-CEMS

Triazole–AuNPs were also used as excellent fluorescencequenchers for fluorescence-based assays because of their ex-traordinary high molar extinction coefficients and broadenergy bandwidth. The fluorescent dye coumarin-containingtriazole 6 exhibits fluorescence under UV light (Scheme 1).After combination with AuNPs, the fluorescence of the donorligand is decreased or even totally quenched (see Figure S47 inthe Supporting Information, which shows the photographs ofthe fluorescent 6 and AuNP-6 under illuminance of UV light atl= 365 nm). Compound 6 displays an intense band witha wavelength of maximum emission lmax = 472 nm, in the

emission spectrum with excitation at lex = 405 nm (Figure 4 a ).After stabilization of the AuNPs with 6 (see the preparation de-tails in the Experimental Section), the fluorescent emission isdramatically quenched. The fluorescence quenching phenom-enon is due to the short distance between the coumarin unitand the AuNPs surface, thus indicating that AuNP-6 has poten-tial applications in biosensing or metal-ion detection by usingthis fluorescence “turn-on” method upon the substitution offluorescent ligands.

AuNP-6 was employed in the fluorescent sensing of 2-chlor-oethyl methyl sulfide (2-CEMS), which is a widely employed an-alogue of bis(2-chloroethyl) sulfide (2-CEES), a mortiferouschemical weapon that is commonly known as “mustard gas”and was infamous in World War II. For security, the detectionof 2-CEES has always been used instead of its less toxic ana-logues.[9b, 18] The sensing capability of AuNP-6 was verifiedthrough a ligand-displacement process through progressive ti-tration of a solution of 2-CEMS in methanol into a solution ofAuNPs-6 in water/methanol 7:3 in a standard quartz cuvette(path length: 1 cm), which were mixed by inversion for 10 sec-onds (see the Experimental Section). The obtained solutionwas recorded by means of fluorescence emission spectroscopyimmediately or afterwards (Figure 4 b). As expected, the fluo-

Scheme 1. A sketch that illustrates the fluorescence quenching of 6 by con-jugation with AuNPs and the fluorescence “turn-on” detection of the sulfur-mustard analogue 2-CEMS through ligand displacement from the AuNP sur-face.

Figure 4. a) Emission spectra of 6 (0.4 mm, upper curve) and AuNP-6(0.4 mm, lower curve) in aqueous solution. b) Emission spectra of AuNP-6without titration of 2-CEMS, with 5 equivalents of 2-CEMS, with 10 equiva-lents of 2-CEMS, and 5, 10, and 15 min after the addition of 10 equivalentsof 2-CEMS, respectively (lex = 405 nm).


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rescence band of AuNP-6 raiseswith an increase of the 2-CEMSconcentration. Indeed, a strongincrease in band intensity wasobserved when 2-CEMS wasadded in a 10-fold concentra-tion, and the ligand displace-ment reached equilibrium within10 minutes of the titration.

As a comparison, the titrationof 1-dodecanethiol was carriedout by following the same pro-cedure, and a similar per-formance was observed as moni-tored by emission spectroscopicanalysis (see Figure S48 in theSupporting Information). Substi-tution of the triazole ligands by the sulfide or thiol analytes onthe AuNP surface results in the release of fluorescence, whichhad been quenched by the AuNPs surface-energy-transfereffect. Facile bonding of the Au–triazole moiety to 2-CEMSmeans that the AuNPs can detect the chemical-warfare-agentsulfur mustard by using a fluorescence “turn-on” assay.

Catalytic performance of AuNPs-2 in the reduction of 4-ni-trophenol

The reduction of 4-nitrophenol is widely used for the evalua-tion of the catalytic activity of various metal NPs owing to thehigh sensitivity of this reaction to the metal catalyst and theconvenient determination of the reaction rate by UV/Vis spec-troscopic analysis.[19] The triazole-stabilized AuNP-2 with a coresize of d = 3.0 nm (that is, smaller than other triazole–AuNPs)were probed as catalysts for the reduction of nitrophenol inso-far as the AuNP surface was expected to be readily availablefor the activation of adsorbed substrates subsequent to thesubstitution of weakly coordinated triazole ligands by the sub-strates. Briefly, a solution of 4-nitrophenol (0.09 mmol) andsodium borohydride (7.5 mmol) in water was prepared in a stan-dard quartz cuvette (3 mL). This solution immediately turnedyellow and showed a strong absorption at l= 400 nm in theUV/Vis spectrum. An aqueous solution of AuNP-2 (0.5 %) wasinjected into the quartz cuvette, and the reduction reactionwas monitored by UV/Vis spectroscopic analysis (Figure 5).

The absorption of 4-nitrophenol at l= 400 nm was shownto rapidly decrease with the reaction time (Figure 5 a). The plotof the consumption rate of 4-nitrophenol �ln (C/C0) versus thereaction times provided the rate constant k = 7.0 � 10�3 s�1 (at22 8C).

Comparatively, AuNP-2 is much more active in the catalyticreduction of 4-nitrophenol by sodium borohydride than AuNPscapped with monosubstituted triazole–PEG, which is attributedto the small size of AuNP-2 and possibly also to the ready dis-placement of disubstituted triazole ligands by the substrates.All in all, the triazole-stabilized AuNPs reveal a remarkable cata-lytic activity in the reduction of 4-nitrophenol, which is largelydue to the flexibility of the mild AuNP–triazole bonding.

Encapsulation of the hydrophobic compound 1-adamanta-nol with AuNP-10

The encapsulation properties of AuNP-10 containing b-CDwere investigated by titration of AuNP-10 into 1-adamantanol(AD) in solution (Figure 6).

First, AD and AuNPs-10 were separately prepared in D2O/[D6]DMSO (7:3; 5 mm in each case), followed by the stepwisetitration of AuNP-10 into the solution of AD. After beingmixed by inversion, the obtained solution with various molarratios of AD/b-CD (1:0.5, 1:1, or 1:1.5) was monitored by1H NMR spectroscopic analysis (see the full-scale spectra in Fig-ure S54 in the Supporting Information).

Three characteristic peaks of AD at d= 2.25, 1.82, and1.75 ppm for Hg, Hb, and Hd, respectively, showed chemical-shift changes due to the chemical environment of the protonsin AD as a result of the formation of the b-CD/AD host–guestinclusion complex formed by trapping AD inside the b-CDcavity (Figure 6). The largest shifts for these three peaks (d=

2.36, 1.87, and 1.78 ppm for Hg, Hb, and Hd) were observed inthe AD/b-CD ratio of 1:1.5, and no further shift emerged whenmore AuNP-10 was added.

This result is in accord with reports of this well-documentedhost–guest inclusion phenomena.[20] Moreover, no SPB shiftwas observed in the UV/Vis spectrum before and after the as-sociation (see Figure S52 in the Supporting Information). Thisstudy suggests that AuNP-10 could potentially be used asa promising drug carrier in cancer therapy without the need tochemically modify a drug because most commercially availabledrugs are hydrophobic compounds. The delivery potential ofsuch drugs by b-CD and other carriers is well known, and thecombination of this species in a AuNP cargo has been high-lighted for combined diagnosis and therapy.[21]

Conclusion

Nanogold chemistry has benefitted from the widespread useof “click” chemistry, which not only stabilizes AuNPs, but alsoprovides a remarkably mild coverage that permits uses and ap-plications that are more difficult to conduct with thiolate-typeanionic ligands. The series of disubstituted 1,2,3-triazoles syn-

Figure 5. a) UV/Vis spectra in which the reaction is monitored every 40 seconds (at 22 8C). b) Consumption rate of4-nitrophenol �ln(C/C0) versus reaction time.


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thesized in this study by using straightforward CuAAC “click”reactions contain a PEG chain, which contributes to the watersolubility and biocompatibility of the triazole-stabilized AuNPs,and a polymer, dendron, alcohol, carboxylic acid, tris-allyl den-dron, fluorescent dye, ferrocene complex, or b-CD moiety. Therange of AuNP sizes obtained (i.e. , 3.0–11.2 nm) leads to a size-dependent selective choice of applications. The SERS proper-ties of the triazole–AuNPs have been illustrated by comparingthe Raman spectrum of AuNP-5 and 5, thus providing evi-dence that the triazole ring was very close to AuNPs surface,that is to say, coordinated. The stability of these triazole–AuNPs under the physiological pH range 4–9 suggests thatthey are qualified to be used in further studies in the cellularenvironment, in particular because of the PEG tail, which is notonly biocompatible but also provides enhanced permeabilityand a retention (EPR) effect. The fluorescence-emission de-crease of AuNP-6 relative to ligand 6 alone as a result of thequenching effect of AuNPs successfully designated the AuNPs-6 as a fluorescent sensor of the sulfur-mustard analogue 2-CEMS. In catalysis, the facile removal of the triazole ligands bythe substrate from the small AuNP-2 (3.0 nm core) is responsi-ble for faster catalysis in the reduction of 4-nitrophenol (k =

7.0 � 10�3 s�1, when 0.5 % AuNPs is employed) than with thio-late AuNPs from which thiolate-ligand removal is more difficult.Finally, the excellent encapsulation ability of the trapping ofhydrophobic molecules of AuNP-10 has a potential applicationin biomedicine.

In summary, this new generalstrategy that involves the use ofcommon click chemistry to stabi-lize PEG-tailed bifunctionalAuNPs with clicked 1,2,3-triazoleligands opens promising applica-tions toward sensing, supra-molecular encapsulation, synthe-sis of highly functionalized thio-late–AuNPs, and catalysis of vari-ous types of reactions.

Experimental Section

CuAAC click synthesis of tria-zoles 1–10

PEG (Mw = 2000) azide or PEG–alkyne (1 g, 0.5 mmol) and a givenamount of a specific alkyne orazide were dissolved in THF(10 mL). CuSO4·5 H2O (0.25 mmol,62 mg) in aqueous solution wasadded to the reaction mixture, fol-lowed by the dropwise addition ofa freshly prepared aqueous solu-tion of sodium ascorbate(0.5 mmol, 99 mg) to obtain a THF/water in a ratio of 1:1. The solutionwas stirred overnight at room tem-perature under nitrogen. After re-moval of THF in vacuo, CH2Cl2

(5 mL) and concentrated (30 %) aqueous ammonia solution (5 mL)were added to the reaction mixture, which was stirred for 30 minto remove the Cu ions trapped inside the polymer as [Cu(NH3)2-(H2O)2]2 +. The organic layer was collected and washed with water.After drying with anhydrous Na2SO4, the solvent was removed invacuo. Compounds 1–9 were obtained as white powders in highyields (>95 %) after reprecipitation. Compound 10 was synthesizedby using the click reaction between the alkyne (1 g, 0.5 mmol) andazide (580 mg, 0.5 mmol) moeities in water/DMSO (1:1), with CuI(11.6 mg, 0.06 mmol) as the catalyst. The catalyst was subsequentlyremoved by filtration.

Synthesis of 1,2,3-triazole-mPEG-capped AuNPs 1–10

General procedure for the synthesis of the AuNPs 1–6, 9, and10 : Tetrachloroaurate acid (8.5 mg, 0.025 mmol) and the triazoleligand (0.05 mmol; 0.125 and 0.0125 mmol for AuNPs-2 andAuNPs-6, respectively) were dissolved in deionized water (10 mL),and the obtained solution was stirred for 10 min. Freshly preparedsodium borohydride (0.1 mmol) aqueous solution (1 mL) wasadded dropwise to the reaction mixture with vigorous stirring for5 min. AuNPs-7 and -8 were prepared with a reverse addition toavoid reduction of the AuIII center by the ferrocenyl groups. Anaqueous solution of tetrachloroaurate acid (5 mL, 8.5 mg,0.025 mmol) was added dropwise to aqueous solutions of the tria-zole derivative (6 mL, 0.05 mmol) and sodium borohydride (6 mL,0.1 mmol). After further stirring for 30 min, the AuNPs were puri-fied by dialysis for 24 h to remove the excess ligands and salts. Thetriazole–AuNPs were kept in aqueous solution at 22 8C

Figure 6. Illustration of AD encapsulation with PEG-triazole-cyclodextrin stabilized AuNP-10. 1H NMR spectra ofAD (in D2O/[D6]DMSO (7:3), 25 8C) and AD mixed with various amounts of AuNP-10 after titration (molar ratios ofAD/CD = 1:0.5, 1:1, and 1:1.5).


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Fluorescence detection of 2-CEMS with AuNPs-6

A gradually increasing amount of 2-chloroethyl methyl sulfide(40 mm ; 0.5, 1, 2, 3, 4, 5, 7, 10, 15 and 20 equivalents) in methanolwas added to a solution of AuNPs-6 (2.5 mL, 0.08 mm) in water/methanol (3:7) in a standard quartz cuvette (path length = 1 cm),and monitored directly by fluorescence spectroscopic analysis. Thesolution with 10 equivalents of analyte (50 mL) was monitored after5, 10, and 20 min, respectively.

Catalytic reduction of 4-nitrophenol with AuNPs-2

An aqueous solution (2.5 mL) containing 4-nitrophenol (0.09 mmol)and NaBH4 (7.2 mmol) was prepared in a standard quartz cuvette(3 mL, path length = 1 cm). The AuNP catalyst (0.5 %, 0.45 � 10�3

mmol) was injected into this solution, and the reaction progresswas detected by UV/Vis spectroscopic analysis every 40 s at 22 8C.

Encapsulation of 1-adamantanol in AuNPs-10

Solutions of AD and AuNP-10 were prepared separately in D2O/[D6]DMSO (7:3, 5 mm in each case), followed by the dropwise titra-tion of the AuNP-10 solution into the AD solution. After mixing byinversion, solutions of AD and b-CD in various molar ratios (1:0,1:0.5, 1:1, and 1:1.5) were studied by 1H NMR spectroscopic analy-sis.

Acknowledgements

Financial support from the China Scholarship Council (CSC)(Ph.D. grants to N.L.), the Universities of Bordeaux and Tou-louse III, the CNRS, and L’Or�al is gratefully acknowledged.

Keywords: click chemistry · fluorescence · gold ·nanoparticles · reduction · sulfur-mustard analogues

[1] a) M. R. Jones, K. D. Osberg, R. J. MacFarlane, M. R. Langille, C. A. Mirkin,Chem. Rev. 2011, 111, 3736 – 3827; b) N. J. Halas, S. Lal, W. S. Chang, S.Link, P. Nordlanser, Chem. Rev. 2011, 111, 3913 – 3961; c) L. M. Liz-Marz�n, Chem. Commun. 2013, 49, 16 – 18; d) N. Li, P. Zhao, D. Astruc,Angew. Chem. 2014, 126, 1784 – 1818; Angew. Chem. Int. Ed. 2014, 53,1756 – 1789.

[2] a) M. Haruta, Nature 2005, 437, 1098 – 1099; b) A. Corma, P. Serna, Sci-ence 2006, 313, 332 – 334; c) M. Stratakis, H. Garcia, Chem. Rev. 2012,112, 4469 – 4506; d) Y. Zhang, X. Cui, F. Shi, Y. Deng, Chem. Rev. 2012,112, 2467 – 2505.

[3] a) C. M. Cobley, J. Chen, E. C. Cho, L. V. Wang, Y. Xia, Chem. Lett. Chem.Soc. , Rev. 2011, 40, 44 – 56; b) K. Saha, S. S. Agasti, C. Kim, X. Li, V. M. Ro-tello, Chem. Rev. 2012, 112, 2739 – 779; c) H. Jans, Q. Huo, Chem. Soc.Rev. 2012, 41, 2849 – 2866.

[4] a) R. A. Sperling, P. Rivera Gil, M. Zhang, W. J. Parak, Chem. Lett. Chem.Soc. , Rev. 2008, 37, 1896 – 1908; b) R. Bardhan, S. Lal, A. Joshi, N. J.Halas, Acc. Chem. Res. 2011, 44, 936 – 946; c) S. Rana, A. Bajaj, R. Mout,V. M. Rotello, Adv. Drug Deliv. Rev. 2012, 64, 200 – 216; d) S. E. Lohse, C. J.Murphy, J. Am. Chem. Soc. 2012, 134, 15607 – 15620.

[5] a) J. Turkevich, P. C. Stevenson, J. Hillier, Discuss. Faraday Soc. 1951, 11,55 – 75; b) G. Frens, Nature Phys. Sci. 1973, 241, 20 – 22; c) J. Kimling, M.Maier, B. Okenve, V. Kotaidis, H. Ballot, A. Plech, J. Phys. Chem. B 2006,110, 15700 – 15707; d) S. D. Perrault, W. C. W. Chan, J. Am. Chem. Soc.2009, 131, 17042 – 17043.

[6] a) M. Brust, M. Walker, D. Bethell, D. J. Schiffrin, R. Whyman, J. Chem.Soc. Chem. Commun. 1994, 801 – 802; b) M. J. Hostetler, J. E. Wingate, C.J. Zhong, J. E. Harris, R. W. Vachet, M. R. Clark, J. D. Londono, S. J. Green,

J. J. Stokes, G. D. Wignall, G. L. Glish, M. D. Porter, N. D. Evans, R. W.Murray, Langmuir 1998, 14, 17 – 30; c) B. Hvolbæk, T. V. W. Janssens, B. S.Clausen, H. C. Falsig, H. Christensen, J. K. Nørskov, Nanotoday 2007, 2,14 – 18.

[7] a) B. Nikoobakht, M. A. El-Sayed, Chem. Mater. 2003, 15, 1957 – 1962;b) J. P�rez-Juste, I. Pastoriza-Santos, L. M. Liz-Marz�n, P. Mulvaney, Coor.Chem. Rev. 2005, 249, 1870 – 1901; c) K. Kwon, K. Y. Lee, Y. W. Lee, M.Kim, J. Heo, S. J. Ahn, S. W. Han, J. Phys. Chem. C 2007, 111, 1161 – 1165.

[8] a) J. L. Ferry, P. Craig, C. Hexel, P. Sisco, R. Frey, P. L. Pennington, M. H.Fulton, I. G. Scott, A. W. Decho, S. Kashiwada, C. J. Murphy, T. Shaw, J.Nat. Nanotechnol. 2009, 4, 441 – 444; b) A. M. Alkilany, C. J. Murphy, J.Nanopart. Res. 2010, 12, 2313 – 2333; c) N. Khlebtsov, L. Dykman, Chem.Soc. Rev. 2011, 40, 1647 – 1671.

[9] a) C. J. Serpell, J. Cookson, D. Ozkaya, P. D. Beer, Nat. Chem. 2011, 3,478 – 483;b) R. C. Knighton, M. R. Sambrook, J. C. Vincent, S. A. Smith,C. J. Serpell, J. Cookson, M. S. Vichers, P. D. Beer, Chem. Commun. 2013,49, 2293 – 2295; c) C. J. Serpell, J. Cookson, A. L. Thompson, C. M. Brown,P. D. Beer, Dalton Trans. 2013, 42, 1385 – 1393.

[10] a) A. Yu, Z. Liang, J. Cho, F. Caruso, Nano Lett. 2003, 3, 1203 – 1207; b) A.Devadoss, A.- M. Spehar-D�l�ze, D. A. Tanner, P. Bertoncello, R. Marthi,T. E. Keyes, R. J. Forster, Langmuir 2010, 26, 2130 – 2135; c) H. Lange, J.Maultzsch, W. Meng, D. Mollenhauer, B. Paulus, N. Peica, S. Schlecht, C.Thomsen, Langmuir 2011, 27, 7258 – 7264.

[11] a) C. Kinnear, H. Dietsch, M. J. D. Clift, C. Endes, B. Rothen-Rutishauser, A.Petri-Fink, Angew. Chem. 2013, 125, 1988 – 1992; Angew. Chem. Int. Ed.2013, 52, 1934 – 1938; b) S. Rucareanu, V. J. Gandubert, R. B. Lennox,Chem. Mater. 2006, 18, 4674 – 4680; c) R. P. BriÇas, M. Maetani, J. J.Barchi Jr. , J. Colloid Interf. Sci. 2013, 392, 415 – 421.

[12] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem.2002, 114, 2708 – 2711; Angew. Chem. Int. Ed. 2002, 41, 2596 – 2599;b) M. Meldal, C. W. Tornoe, Chem. Rev. 2008, 108, 2952 – 3015; c) J. E.Hein, V. V. Fokin, Chem. Soc. Rev. 2010, 39, 1302 – 1315; d) L. Liang, D.Astruc, Coord. Chem. Rev. 2011, 255, 2933 – 2945.

[13] a) R. A. Sperling, W. J. Parak, Phil. Trans. R. Soc. A. 2010, 368, 1333 – 1383;b) A. Gole, C. J. Murphy, Langmuir 2008, 24, 266 – 272; c) J. L. Brennan,N. S. Hatzakis, T. R. Tshikhudo, N. Dirvianskyte, V. Razumas, S. Patkar, J.Vind, A. Svendsen, R. J. Nolte, A. E. Rowan, M. Brust, Bioconjugate Chem.Bioconj. Chem. 2006, 17, 1373 – 1375; d) Y. Zhou, S. Wang, X. Jiang,Angew. Chem. 2008, 120, 7564 – 7566; Angew. Chem. Int. Ed. 2008, 47,7454 – 7456.

[14] a) K. E. Sapsford, W. R. Algar, L. Berti, K. B. Gemmill, E. Oh, M. H. Stewart,I. L. Medintz, Chem. Rev. 2013, 113, 1904 – 2074; b) B. Pergolese, M.Muniz-Miranda, A. Bigotto, J. Phys. Chem. B 2004, 108, 5698 – 5702;c) A. A. Jbarah, A. Ihle, K. Banert, R. Holze, J. Raman Spectrosc. 2006, 37,123 – 131.

[15] E. Boisselier, A. K. Diallo, L. Salmon, C. Ornelas, J. Juiz, D. Astruc, J. Am.Chem. Soc. 2010, 132, 2729 – 2742.

[16] a) J.-R. Hamon, D. Astruc, P. Michaud, J. Am. Chem. Soc. 1981, 103, 758 –766; b) A. Heller, Acc. Chem. Res. 1990, 23, 128 – 126; c) D. Astruc, Elec-tron transfer and radical processes in transition metal chemistry, Wiley-VCH, Weinheim, 1995, Chapter 7.

[17] a) M. Daniel, J. Ruiz, S. Nlate, J. C. Blais, D. Astruc, J. Am. Chem. Soc.2003, 125, 2617 – 2628; b) F. Ot�n, A. Espinosa, A. T�rraga, C. R. de Arel-lano, P. Molina, Chem. Eur. J. 2007, 13, 5742 – 5725.

[18] L. A. Patil, A. R. Bari, M. D. Shinde, V. Deo, M. P. Kaushik, Sens. Act. B2012, 161, 372 – 380.

[19] P. Herv�s, M. Per�z-Lorenzo, L. M. Liz-Marz�n, J. Dzubiella, Y. Lu, M. Bal-lauff, Chem. Prod. Chem. Soc. , Rev. 2012, 41, 5577 – 5587.

[20] a) P. Mukhopadhyay, A. Wu, L. Isaacs, J. Org. Chem. 2004, 69, 6157 –6164; b) H. Goto, Y. Furusho, E. Yashima, J. Am. Chem. Soc. 2007, 129,109 – 112.

[21] a) C. Burda, X. Chen, M. A. El-Sayed, Chem. Rev. 2005, 105, 1025 – 1102;b) C. J. Murphy, A. M. Gole, J. W. Stone, P. N. Sisco, A. M. Alkilany, E. C.Goldsmith, S. C. Baxter, Acc. Chem. Res. 2008, 41, 1721 – 1730;

Received: March 18, 2014Published online on May 30, 2014


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http://dx.doi.org/10.1039/c2cc35720h



http://dx.doi.org/10.1002/ange.201300441



http://dx.doi.org/10.1002/anie.201300441




http://dx.doi.org/10.1038/4371098a

http://dx.doi.org/10.1038/4371098a

http://dx.doi.org/10.1038/4371098a

http://dx.doi.org/10.1126/science.1128383








http://dx.doi.org/10.1021/cr200260m




http://dx.doi.org/10.1039/b821763g







http://dx.doi.org/10.1039/c1cs15280g




http://dx.doi.org/10.1039/b712170a




http://dx.doi.org/10.1021/ar200023x



http://dx.doi.org/10.1016/j.addr.2011.08.006



http://dx.doi.org/10.1021/ja307589n



http://dx.doi.org/10.1039/df9511100055

http://dx.doi.org/10.1039/df9511100055

http://dx.doi.org/10.1039/df9511100055

http://dx.doi.org/10.1039/df9511100055

http://dx.doi.org/10.1038/physci241020a0



http://dx.doi.org/10.1021/jp061667w




http://dx.doi.org/10.1021/ja907069u




http://dx.doi.org/10.1039/c39940000801

http://dx.doi.org/10.1039/c39940000801

http://dx.doi.org/10.1039/c39940000801

http://dx.doi.org/10.1039/c39940000801

http://dx.doi.org/10.1021/la970588w



http://dx.doi.org/10.1016/S1748-0132(07)70113-5

http://dx.doi.org/10.1016/S1748-0132(07)70113-5

http://dx.doi.org/10.1016/S1748-0132(07)70113-5

http://dx.doi.org/10.1016/S1748-0132(07)70113-5

http://dx.doi.org/10.1021/cm020732l



http://dx.doi.org/10.1021/jp064317i



http://dx.doi.org/10.1038/nnano.2009.157




http://dx.doi.org/10.1007/s11051-010-9911-8

http://dx.doi.org/10.1007/s11051-010-9911-8

http://dx.doi.org/10.1007/s11051-010-9911-8

http://dx.doi.org/10.1007/s11051-010-9911-8

http://dx.doi.org/10.1039/c0cs00018c








http://dx.doi.org/10.1039/c2dt31984e



http://dx.doi.org/10.1021/nl034363j



http://dx.doi.org/10.1021/la902676p



http://dx.doi.org/10.1021/la200919m










http://dx.doi.org/10.1021/cm060793+



http://dx.doi.org/10.1016/j.jcis.2012.06.042



http://dx.doi.org/10.1002/1521-3757(20020715)114:14%3C2708::AID-ANGE2708%3E3.0.CO;2-0




http://dx.doi.org/10.1002/1521-3773(20020715)41:14%3C2596::AID-ANIE2596%3E3.0.CO;2-4









http://dx.doi.org/10.1016/j.ccr.2011.06.028



http://dx.doi.org/10.1098/rsta.2009.0273



http://dx.doi.org/10.1021/la7026303



http://dx.doi.org/10.1021/bc0601018











http://dx.doi.org/10.1021/cr300143v



http://dx.doi.org/10.1021/jp0377228



http://dx.doi.org/10.1002/jrs.1476




http://dx.doi.org/10.1021/ja909133f




http://dx.doi.org/10.1021/ja00394a006



http://dx.doi.org/10.1021/ar00173a002



http://dx.doi.org/10.1016/j.snb.2011.10.047




http://dx.doi.org/10.1021/jo049976a



http://dx.doi.org/10.1021/ja065477a




http://dx.doi.org/10.1021/cr030063a



http://dx.doi.org/10.1021/ar800035u




1

Stabilization of AuNPs by Monofunctional

Triazole Linked to Ferrocene, Ferricenium or

Coumarin and Applications to Synthesis,

Sensing and Catalysis

Na Li,† Pengxiang Zhao,†,‡ María Echeverría,§ Amalia Rapakousiou,† Lionel Salmon,║

Sergio Moya,§ Jaime Ruiz,† Didier Astruc*,†

† ISM, Univ. Bordeaux, 351 Cours de la Libération, 33405 Talence Cedex, France.

‡Science and Technology on Surface Physics and Chemistry Laboratory, PO Box

718-35, Mianyang 621907, Sichuan, China.

§ CIC biomaGUNE, Unidad Biosuperficies, Paseo Miramónnº 182, Edif."C", 20009

Donostia-San Sebastián, Spain.

║LCC, CNRS, 205 Route de Narbonne, 31077 Toulouse Cedex, France.

ABSTRACT

Monofunctional triazoles linked to ferrocene, ferricenium or coumarin, easily

synthesized by copper catalyzed azide alkyne (CuAAC) “click” reactions between

the corresponding functional azides and trimethylsilylacetylene followed by silyl

group deprotection, provide a variety of convenient neutral ligands for the

stabilization of functional gold nanoparticles (AuNPs) in polar organic solvents.

These triazole-AuNPs are very useful towards a variety of applications to synthesis,

sensing and catalysis. Both ferrocenyl (Fc) and isostructural ferricenium linked-

triazoles give rise to AuNP stabilization, although by different synthetic routes.

Indeed, the first direct synthesis and stabilization of AuNPs by ferricenium is obtained

by reduction of HAuCl4 upon reaction with a ferrocene derivative, AuNP stabilization

resulting from a synergy between electrostatic and coordination effects. The

ferricenium/ferrocene triazole-AuNP redox couple is fully reversible as shown by

cyclic voltammograms that was recorded with both redox forms. These triazole-

AuNPs are stable for weeks in various polar solvents, but in the same time the

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advantage of triazole-AuNPs is the easy substitution of the neutral triazole ligands by

thiols and other ligands giving rise to applications. Indeed this ligand substitution of

triazole at the AuNP surface yields a stable ferrocenyl-terminated nanogold-cored

dendrimer upon reaction with a ferrocenyl-terminated thiol dendron, substitution of

coumarin- linked triazole with cysteine, homocysteine and glutathione provides

remarkably efficient biothiol sensing, and a ferricenium-linked triazole-AuNP catalyst

is effective for NaBH4 reduction of 4-nitrophenol to 4-aminophenol. In this catalytic

exemple, the additional electrostatic AuNP stabilization modulates the reaction rate

and induction time.

KEYWORDS: triazole, gold nanoparticle, ferrocene, ferricenium, coumarin,

biological thiol, sensing, catalysis, nitrophenol.

INTRODUCTION

In the past few decades, a variety of ligands1-9 have been synthesized and used to

stabilize gold nanoparticles (AuNPs)9 either in organic solvents or in water. The

surface properties, including ligand type, binding force of Au with other atoms, as

well as the ligand coverage of AuNPs control the solubility, stability and applications

of AuNPs. For example, in thiolate-stabilized AuNPs, covalent bonding between the

gold and sulfur atoms contributes to the passivation of the surface of thiolate-

stabilized AuNPs and makes AuNPs stable in solid state,1 whereas citrate stabilized

AuNPs were usually prepared in aqueous solution due to the multi-package of ionic

species on the AuNPs surface.2 In addition, the influence of the surface properties of

AuNPs was also observed in several examples on the coordination- induced

stabilization of AuNPs with nitrogen donors, particularly dendritic supramolecules.9

Indeed PAMAM dendrimers show significant template effects in the formation of

NPs in various solvents.3 Copper-catalyzed azide alkyne (CuAAC) “click” chemistry

has generated supermolecules4 such as PEG-terminated dendrimers and polymers5

also stabilizing AuNPs in aqueous solution.6 Besides, other nitrogen ligands such as

imidazoles,7 pyridines8 have also been utilized for the stabilization of AuNPs.9 The

dual property of triazole-AuNPs (trz-AuNPs) that on one hand are stable and on the

other hand have modest AuNP-N bond strength allowing facile ligand substitution of

trzs by other ligands for various applications makes this family of AuNPs particularly

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attractive. Indeed, upon trz ligand substitution, it is possible to synthesize various

other liganded AuNPs, to use the ligand-exchange processes for sensing and to

provide catalytically efficient AuNP surfaces.10 Stabilization and uses of water-

soluble PEGylated triazole-AuNPs have recently been shown.11 Here we focus on the

stabilization of trz-AuNPs linked to ferrocene,12, 13 ferricenium and coumarin termini

using these monofunctional triazole-AuNPs that are not synthesized in water and are

soluble in organic solvents.

For applications, ferrocenes have attracted attention due to the sensing and biomedical

applications of the ferrocenyl (Fc) derivatives related to their reversible redox

properties.14 Catalytic properties will also be shown to result from fast triazole

removal by substrates at the AuNP surface. Indeed, noble metal nanoparticles,15 in

particular AuNPs, are excellent catalysts for the reduction of 4-nitrophenol (4-NP)

that is toxic and inhibitory in nature, in order to produce 4-aminophenol (4-AP) that

has properties and applications as corrosion inhibitor, dying agent, and in particular

intermediate for the synthesis of paracetamol.16 Finally, coumarin (Cou) is a well-

known fluorescent dye17 that we are linking to triazole-AuNPs fort he investigation of

fluorescent sensing properties based on AuNP ligand substitution by biologically-

relevant thiols. Indeed the thiols, cysteine (Cys), homocysteine (Hcy) and glutathione

(GSH) play key roles in the biological systems.18 Many diseases are relevant to the

abnormal contents of Cys or Hcy in the human body. For instance, an abnormal level

of cysteine may cause skin lesions and liver damage.19 Furthermore, Hcy is a risk

factor for Alzheimer’s and cardiovascular diseases.20 Excess Cys has been associated

with neurotoxicity and many other diseases.21 Accordingly, the development of

chemo-sensors for biological thiol derivatives (biothiols) is of great importance as

recently indicated.22 Sensing biological thiols using the fluorescence “turn-on”

method on the surface of AuNPs either results from the formation of new fluorescent

species or the release of dye adsorbed on the AuNPs as recently reported.23

RESULTS AND DISCUSSION

In order to easily incorporate the redox complex and other functionalities into AuNPs

in organic solution, two kinds of small mono-substituted trz molecules, Fc-trz and

Cou-trz, were synthesized taking into account their electrochemical or photochemical

properties. Each functional unit was linked to the trz ring by an ether group that

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increased the flexibility of the trz ligand to make sure that trzs smoothly arrange on

the surface of AuNPs.

Ferrocene- and ferricenium-trz-stabilized AuNPs.

Late transition-metal sandwich complexes are known for their stability in several

oxidation states and ability to effect efficient stoichiometric and catalytic electron-

transfer processes24 for multiple applications.25,26 They are also rather easy to

functionalize on the ligands,25 and thus the introduction of alkynyl or azido groups has

been reported in view of further CuAAC “click” functionalizing chemistry.27 The

ferrocenyl- linked 1,2,3-triazole (Fc-trz, see Figure 1) was synthesized using the

CuAAC “click” reaction between trimethylsilylazide and propargyl-

oxymethylferrocene in a DMF/MeOH solution at 100 oC with CuI as catalyst

(Experimental Section). Fc-trz was characterized by 1H, 13C NMR, IR spectroscopies,

ESI mass spectrometry, elemental analysis and cyclic voltammetry (Supplementary

Information). Cou-trz was synthesized according to the literature,28 but its

photochemical property and applications were not reported.

Figure 1. AuNPs stabilized by Fc-trz (AuNP-1) or oxidized Fc+-trz Cl

- (AuNP-2) in organic

solution.

A one-step process to functionalize AuNPs with Fc-trz was carried out in organic

solution. As compared to the above-mentioned ligand-substitution method, Fc-trz was

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used as stabilizer instead of ferrocene thiolate ligands.12a The preparation of AuNPs

stabilized by Fc-trz was performed using two pathways. In the first method, Fc-trz

and NaBH4 were dissolved in ethanol, a HAuCl4 ethanol solution was slowly injected

into this solution under nitrogen atomosphere with stirring. After being further stirred

for 2 hours, AuNP-1 was purified by dialysis against a large volume of ethanol. In

this process, Au(III) was reduced by NaBH4 while Fc-trz played the role of stabilizer.

No oxidation of Fc was found according to UV-vis. spectroscopy analysis of AuNP-1,

which is well taken into account by the fact that NaBH4 is a much stronger and faster

reducing agent than ferrocene. Indeed, as shown in Figure 2a, two bands at 321 nm

and 430 nm belong to the ferrocene unit.

On the other hand, during the preparation of AuNP-2, no external reductant was

involved. Then Fc group does not only work as the capping agent in ist oxidized form

but also as the reductant. In this reaction, the Fc group was oxidized to ferricenium

chloride, AuIII being reduced to Au0 atoms that form AuNPs. These AuNP-2 are

stabilized by the ferricenium chloride-trz ligand, stabilization resulting from the

positive synergy between the electrostatic factor and the trz ligand coordination to the

AuNP surface (Figure 1). The oxidation of ferrocene to ferricenium was sucessfully

recorded by UV-vis. spectroscopy, the band at 637 nm in Figure 2b corresponding to

the ferricenium unit. In Figure 2a, a shoulder band around 560 nm corresponds to the

surface plasmon band (SPB) of AuNP-1, and the SPB of AuNP-2 overlaps with the

ferricenium band, which is deduced from the comparison with the SPB band of

AuNP-3. Both methanol and THF were suitable solvents in the one-step preparation

of AuNPs-1 and AuNPs-2.

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Figure 2. UV-vis. spectra revealing the characteristic band of a) the Fc group in AuNP-1

(321 nm, 430 nm) and b) the ferricenium group in AuNP-2 (627 nm) (both were recorded in

ethanol solution).

The TEM images shown in Figure 3 revealed the sizes of the Fc-trz-capped AuNPs

that were prepared with or without NaBH4, indicating that AuNP-1 (5 nm) was

slightly larger than AuNP-2 (4.4 nm). The size difference between AuNP-1 and

AuNP-2 in core size may arise from the difference of reduction rate and stabilization

rate in each case. Indeed the stabilization in AuNP-2 is stronger compared to AuNP-1

due to the additional electrostatic stabilization of AuNP-2. Both AuNP-1 and

AuNP-2 are monodispersed in ethanol solution, as disclosed by TEM and DLS

analyses. The multi- ionic layers of AuNP-2 led to the formation of small clusters (9.8

nm) in solution compared to AuNP-1 which formed relatively larger clusters (12 nm).

The electrochemical characterization of AuNP-1 and AuNP-2 was conducted by

cyclic voltammetry. As shown in Figure S7 (Supporting Information) on the cyclic

votammogram of AuNP-1, the expected chemically and electrochemically reversible

waves of the ferricenium/Fc redox system were observed. The difference between the

anodic and cathodic peak potentials (ΔE) is 0.06 V, and the intensity ratio ia/ic is 1.0,

showing the chemical reversibility of the FeIII/II system without being marred by

adsorption. The measured redox potential value of this multiferrocenyl redox system,

i.e. the average of the anodic and cathodic wave potentials [E1/2 = (Epa + Epc)/2], is

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0.44 V vs. decamethylferrocene.24c Both AuNPs-1 and AuNPs-2 are qualified for

redox-sensing applications.

Figure 3. TEM images of AuNP-1 (d = 5 nm) and AuNP-2 (d = 4.4 nm) prepared using two

distinct methods.

4- Nitrophenol reduction

AuNP-2 was selected, because it was the only AuNP in this series that was water

soluble, which facilitated the catalytic experiments. The lability of the AuNP-trz and

AuNP-Cl- connections on the surface of AuNP-2 was employed to catalyze 4-NP

reduction in water/ethanol (95/5) in the presence of NaBH429 with catalyst amounts of

0.5% or 1%. This reaction was carried out in a standard quartz cuvette (path lengh: 1

cm) and was monitored by UV-vis. spectroscopy in every 40 s (Supporting

Information, Figure S11). The plots of the decrease rate of 4-NP [−ln(C/C0)] vs. the

reaction times (Figure 4) were collected (C and C0 being the 4-NP concentrations at

times t resp. t = 0). The rate constant k of the catalytic reduction of 4-NP was found

to be 1.1×10-3 s-1 with 0.5% of AuNP-2 as catalyst, and the k value increased to

1.6×10-3 s-1 with the increase of catalyst amount to 1%. Moreover, an induction

period (200 s) was required, due to the AuNP surface organization of the substrates in

the mixed solvent.30 As compared to the catalysis of 4-NP reduction with bulky water-

soluble PEG-triazole ligands which provided k = 5.2 ×10-3 s-1 (cat. 0.5%),13a the

catalytic efficiency of AuNP-2 that was stabilized by the present triazole ligands was

relatively lower (1.1×10-3 s-1) although the core of AuNP-2 is slightly smaller than

that of AuNPs with PEG-triazole ligands. However, AuNPs-2 remained superior for

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4-NP reduction to triazole-stabilized AuNPs of close size stabilized by other ligands

such as thiolate and citrate due to the labile character of the AuNP-triazole bonds.

Figure 4. Plots of the decreasing rate of 4-NP [−ln(C/C0)] vs. the reaction times using two

distinct amounts of catalyst AuNP-2 (0.5% cat. in black curve and 1% cat.in red curve).

Cou-trz stabilized AuNPs

Cou-trz stabilized AuNPs (AuNP-3) were prepared in ethanol with sodium

borohydride as reductant to reduce Au(III) to Au(0). Thus HAuCl4 and Cou-trz were

dissolved together in ethanol solution, and an ethanol solution of NaBH4 was added

dropwise into the mixture under nitrogen atomosphere. The yielded solution was

further stirred for 2 hours. These AuNPs precipitated in ethanol in 24 h, and they were

redissolved in DMSO. After precipitation-redissolution 3 times, excess Cou-trz was

easily removed with the supernatant. The size of the AuNP-3 core shown by TEM is

6.3 nm, i.e. slightly larger than those of AuNP-1 and AuNP-2. TEM and DLS

(average diameter size: d = 16 nm) analyses showed that AuNP-3 has lower

dispersion than AuNP-1 and AuNP-2, presumably due to the precipitation-

redissolution purification process.

According to the fluorescence quenching effect of the AuNP core of AuNP-3, the

very high molar extinction coefficients and broad energy bandwidth of AuNPs result

in emission-extinction of a fluorescent dye that is relatively close to the surface of

AuNP-3. As shown in Figure 5 in which the fluorescence emission spectra of Cou-trz

and AuNP-3 are presented the emission band (λmax) of Cou-trz at 537 nm is of high

intensity (λex = 405 nm in DMSO/H2O solution). On the other hand dramatic decrease

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was observed after capping AuNPs with Cou-trz ligands (see the red curve in Figure

5), that is the emission of Cou-trz was quenched by the AuNP core of AuNP-3.

Figure 5. Fluorescent emission spectra of Cou-trz (0.2 mM) and Cou-trz-capped AuNP-3,

(both in DMSO/H2O solution. λex = 405 nm, recorded at 22 oC).

Given the combination of the fluorescence quenching effect of AuNPs and the

flexible bonding of AuNPs to trz rings facilitating trz substitution at the AuNP surface,

it was reasoned that sensing by dramatic change of fluorescence intensity upon ligand

substitution should be efficient. It was indeed possible to easily detect the presence in

solution of thiol or sulfide compounds in this way. Three biological thiols that are

known to cause illness in human body were taken as models to verify the sensing

property of AuNP-3. As illustrated in Scheme 1, an aqueous solution of biothiol (Hcy,

Cys or GSH) was progressively titrated upon increasing the concentration in a

DMSO/H2O solution of AuNP-3 in a standard quartz cuvette (path length = 1 cm).

Along with the progress of ligand substitution, Cou-trz-AuNP-3 was removed from

the solution and replaced by AuNPs bound to biothiols. The recovery of

photochemical emission of Cou-trz was consequently observed. The emission

intensity of AuNP-3 increased distinctly with the increase of biothiols (up to 10

equivalents) after being mixed during 10 min after titration (Figure 6). The same

phenomena were observed in sensing Cys and GSH (Supporting Information, Figure

S12 and S13), demonstrating the photochemical application of AuNP-3 in sensing of

biothiols.

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Scheme 1. General illustration of fluorescent sensing of biothiols (Cys, Hcy and GSH) with

AuNP-3 via ligand substitution on the surface of AuNPs inducing fluorescence “turn-on”

phenomenon. The green color represents the recovery of the coumarin fluorescence property.

Figure 6. Fluorescent emission spectra of AuNP-3 mixed with various amount of

homocysteine (1 eq. analyte = 0.05 mM in the solution, λex = 405 nm, standard quartz cuvette:

path length = 1 cm, recorded at 25 oC).

Synthesis of a nanogold-cored Fc-terminated dendrimer

Another way to utilize the lability of triazole in monosubstituted trz-stabilized AuNPs

for the synthesis of Fc-containing AuNPs was achieved by facile reaction of the trz-

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AuNPs with Fc-terminated dendrons containing a thiol focal point as potential AuNP

thiolate ligand. Thus the nona-branched Fc-terminated thiol dendron 6 was

synthesized and utilized to substitute the trz ligand from the surface of AuNPs. This

method allows the formation of the very stable thiolate AuNPs containing a bulky Fc-

loaded surface.13a

The nona-ferrocene dendron 6 with 1→3 directionalites31 was synthesized via

CuAAC “click” reaction of azidomethyl-Fc with a nona-alkyne dendron.13a This

dendron was easily grafted onto the surface of AuNPs by fast and quantitative trz

ligand substitution to give AuNP-5 (Scheme 2). In order to limit the Fc bulk at the

dendrimer periphery the dendron 6 was introduced together with linear dodecanethiol

that were found in 70% of total of 540 ± 80 32 thiol per AuNP-5. The AuNP-5

retained its core size and monodispersity during the reaction in organic solvent, which

resulted in a AuNP-cored dendrimer containing about 140 ± 25 thiol dendrons, i.e.

1260 ± 180 Fc termini and displayed chemical and electrochemical reversibility

together with significant adsorption in its cyclic voltammogram (Supporting

Information).33

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Scheme 2. Ligand-substitution of the triazole-capped AuNP-4 by nona-Fc thiol dendron on

the AuNP surface yielding the AuNP-thiolate polyferrocenyl-terminated dendrimer (AuNP-5).

CONCLUSION

In this work, the first trz-AuNPs that are soluble in organic media have been

synthesized in a size range of 4.4 to 6.3 nm with narrow dispersities in ethanol with

ferrocene, ferricenium and coumarin groups linked to the trz ligands. The first

ferricenium-stabilized AuNPs have been synthesized by direct redox reaction between

the trz- linked Fc and HAuCl4 without any other reductant. The excellent stabilization

of these AuNPs results from the synergistic stabilization by both the electrostatic

effect and trz coordination. This excellence of stabilization is confirmed by the slower

catalysis of 4-NP reduction by NaBH4 than with other trz-AuNP catalysts. In addition

the retention time characterized here was not found with other trz-AuNPs, indicating a

higher reorganization energy at the AuNP surface than with neutral trz ligands. The

two FeII and FeIII redox forms of the trz-AuNPs with closely related AuNP core sizes

were independently synthesized and shown to reversibly interconvert by cyclic

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voltammetry. Easy trz ligand substitution has been shown to usefully apply to

dendrimer synthesis, biothiol fluorescence “turn-on” sensing assay and nitrophenol

reduction by NaBH4. Finally, concerning the synthetic aspect, facile AuNP-cored

dendrimer construction is demonstrated upon triazole substitution by a thiol dendron.

These remarkable applications show the versatility and applicability of the trz-AuNP

in organic media. The strategy that consists in stabilizing stable AuNPs by easily-

synthesized 1,2,3-triazoles is conclusively powerful due to the complementarity

between the stability of these AuNPs and the multiple applications resulting from

facile triazole substitution at the AuNP-surfaces.

EXPERIMENTAL SECTION

General data

All solvents and chemicals were used as purchased. Dialysis was performed with a

Spectra/Por 6 dialysis membrane. NMR spectra were recorded at 25 °C with a Bruker

300 (300 MHz) spectrometer. All the chemical shifts are reported in parts per million

(δ, ppm) with reference to Me4Si for the 1H and 13C NMR spectra. The infrared (IR)

spectra were recorded on an ATI Mattson Genesis series FT-IR spectrophotometer.

UV-vis. absorption spectra were measured with Perkin-Elmer Lambda 19 UV-vis.

spectrometer. Elemental analyses were recorded on a PAR 273 potentiostat under

nitrogen atmosphere. The DLS measurements were made using a Malvern Zetasizer

3000 HSA instrument at 25 °C at an angle of 90°. Fluorescence emission spectra were

recorded by Spex FluoroLog 2 Spectrofluorometer. Cyclic voltammetry (CV)

measurements: All electrochemical measurements were recorded under nitrogen

atmosphere at 25 °C.

Synthesis of the 1,2,3-triazoles.

Synthesis of Fc-trz: trimethylsilyl azide (0.23 mL, 1.8 mmol) was added to a DMF

and MeOH solution (3 mL, 9:1) of CuI (7.5 mg, 0.04 mmol) and

propargyloxymethylferrocene (300 mg, 1.18 mmol) under N2 in a pressure vial. The

reaction mixture was stirred at 100 oC for 12 h. The mixture was cooled to room

temperature (r.t.) and then filtered and concentrated. The residue was purified by

silica gel column chromatography (n-hexane/EtOAc, 5:1 to 2:1) to afford Fc-trz in 60%

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yield. 1H NMR (300MHz, CDCl3) δppm = 7.66 (1H, CHtrz), 4.65 (2H, CH2-trz), 4.35

(2H, CH2-Fc), 4.24 (2H, CHCp), 4.15 (2H, CHCp), 4.13 (5H, CHCp). 13C NMR (75

MHz, CDCl3) δppm = 145, 122.2, 82.7, 69.1, 68.9, 62.4, 50.2. IR: νCp at 819 cm-1,

disappearance of σC≡C band at 2100 cm-1. MS (ESI, m/z) [M + Na+]: Calcd. for

C14H15FeN3O, 320.12; found 320.0. Analysis (calcd., found for C14H15FeN3O): C

(56.59, 56.70), H (5.09, 5.34), N (14.14, 13.87) .

Coumarin-triazole (Cou-trz) was synthesized according to the literature.28

Synthesis of the AuNPs

AuNP-1: Fc-trz (19 mg, 0.06 mmol) and NaBH4 (2.5 mg, 0.06 mmol) was dissolved

in 20 mL EtOH in a Schlenk flask, a HAuCl4 (4.3 mg, 0.012 mmol) EtOH solution

(10 mL) was then injected dropwise into the flask in a N2 atmosphere with vigorous

stirring. The solution was further stirred for 1 h, purified by dialysis against a large

volume of EtOH before analysis. AuNPs were prepared in MeOH or THF with the

same procedure.

AuNP-2: Fc-trz (11.5 mg, 0.04 mmol) was dissolved in 20 mL EtOH in a Schlenk

flask, a HAuCl4 (4.3 mg, 0.012 mmol) EtOH solution (10 mL) was then injected into

the flask under a N2 atmosphere with stirring. The solution was further stirred for 1 h,

purified by dialysis against a large volume of EtOH before analysis. AuNPs were

prepared in MeOH or THF with the same procedure.

AuNP-3: Cou-trz (30 mg, 0.06 mmol) and HAuCl4 (4.3 mg, 0.012 mmol) was

dissolved in 20 mL EtOH in a Schlenk flask that is refilled with N2. A NaBH4 (2.5 mg,

0.06 mmol) EtOH soltion (10 mL) was then added dropwise into the flask under a N2

atmosphere with stirring. The solution was further stirred for 1 h. AuNP-3 was

purified by precipitation in EtOH and redissolution in DMSO three times.

Catalytic reduction of 4-nitrophenol

A typical procedure follow: An aqueous solution (2.5 mL) containing NaBH4 (7.2

μmol) and 4-nitrophenol (0.09 μmol) was prepared in 3 mL a standard quartz cuvette

(path lengh: 1 cm). AuNP-2 (0.5%, 0.45 × 10−3 μmol; 1%, 0.9× 10−3 μmol) in

EtOH was injected into the cuvette. The reaction progress was detected by UV−vis.

spectroscopy every 40 s.

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Sensing of homocysteine, cysteine and glutathione.

A gradually increasing amount of homocysteine (40 mM, 0.5, 1, 2, 5, 10 equivalents)

in water was added to a 2.5 mL solution of AuNP-3 (0.05 mM, water/DMSO 3:7) in a

standard quartz cuvette (path length: 1 cm). The solution was monitored using a

fluorometer after 10 min after mixing. The titration of cysteine and glutathione were

conducted according to the same process.

Ligand-substitution reaction of AuNP-4 by a mixture of thiolate-nonaferrocenyl

dendron 6 and dodecanethiol to synthesize AuNPs-5.

3 mL of THF solution of the thiol-nonaferrocenyl dendron13a (150 mg, 0.25 mmol)

and dodecanethiol (10 mg, 0.05 mmol, 12 μL) was added into 3 mL (1mM) thiazole-

mPEG stabilized AuNPs (AuNP-4)13a and stirred for 10 min. Then 10 mL

dichloromethane was added into the mixed solution, the organic phase was then

separated and dried over Na2SO4. After evaporating the solvent, AuNPs was washed

with acetone and then ethanol followed by precipitation in dichloromethane/methanol.

1H NMR (CDCl3, 200 MHz) δ = 7.61 (9H, CH in triazole), 6.71 (8H, HAr), 5.28, 5.16

(24 H, Ar-O-CH2-), 4.91 (18H, -CH2-Cp), 4.24-4.12 (81H, CHCp), 1.83, 1.59. 1.24

(22H, CH2- in alkyl chain), 0.86 (3H, CH3-CH2-); UV-vis. spectroscopy: plasmon

band at 535 nm. DLS: 16.3 ± 3 nm.

Using Leff’s method,32 the number of AuNP atoms in AuNP-5 and the number of

ligands, 540 thiol ligands on the surface of AuNP-5, were determined. From the

integration of H-1 (CH3 in dodecanethiolate) and H-2 (CH in Cp) in the 1H NMR

spectrum (Supporting Information, Figure S14) of AuNP-5, the ratio of the numbers

of the two ligands (Fc-dendron/dodecanethiolate) was calculated to be about 1:2.8,

that is 70% of thiolates on the surface of AuNP-5 are dodecanethiolate ligands (about

400 ± 70 dodecanethiolates per AuNP). Meanwhile, approximately 140 ± 25 Fc-

dendrons in average are located on each AuNP surface. The calculations indicate that

there are in average about 1260 ± 180 ferrocenyl units surrounding every single

AuNP-5 (Supporting Information).

71

16

ASSOCIATED CONTENT

Supporting Information

Characterization and data of compounds and AuNPs. This material is available free of

charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

E-mail: [email protected]

ACKNOWLEDGEMENT

Financial support from the China Scholarship Council (CSC) (Ph.D. grants to N. Li),

the Université de Bordeaux and the CNRS is gratefully acknowledged.

REFERENCES

(1) (a) Giersig, M.; Mulvaney, P. Langmuir 1993, 9, 3408-3413. (b) Brust, M.;

Walker, M.; Bethell, D.; Schiffrin, D. J.; Whyman, R. J. J. Am. Chem. Soc. Commun.

1994, 801-802. (c) Rongchao, J. Nanoscale 2010, 2, 343-362.

(2) (a) Turkevitch, J.; Stevenson, P. C. Discuss. Faraday Soc. 1951, 11, 55-75. (b)

Frens, G. Nature: Phys. Sci. 1973, 132, 20-22. (c) Connor, E. E.; Mwamuka, J.; Gole,

A.; Murphy, C. J.; Wyatt, M. D. Small 2005, 1, 325-327. (d) Kimling, J.; Maier, M.;

Okenve, B.; Kotaidis, V.; Ballot, H.; Plech, A. J. Phys. Chem. B 2006, 110, 15700-

15707.

(3) Scott, R. W. J.; Wilson, O. M.; Oh, S.-K.; Kenik, E. A.; Crooks, R. M. J. Am.

Chem. Soc. 2004, 126, 15583-15591.

(4) (a) Boisselier, E.; Diallo, A. K.; Salmon, L.; Ornelas, C.; Astruc, D. J. Am. Chem.

Soc. 2010, 132, 2729-2742. (b) Astruc, D. Nat. Chem. 2012, 4, 255-267 .

(5) C. Deraedt, A. Rapakousiou, Y. Wang, L. Salmon, M. Bousquet, D. Astruc,

Angew. Chem., Int. Ed. 2014, 52, 8445-8449.

72

http://pubs.acs.org/


17

(6) Li, N.; Echeverría, M.; Moya, S.; Ruiz, J.; Astruc, D. Inorg. Chem. 2014, 53,

6954-6961.

(7) (a) Serpell, C. J.; Cookson, J.; Ozkaya, D.; Beer, P. D. Nat. Chem. 2011, 3, 478-

483. (b) Knighton, R. C.; Sambrook, M. R.; Vincent, J. C.; Smith, S. A.; Serpell, C. J.;

Cookson, J.; Vichers, M. S.; Beer, P. D. Chem. Commun. 2013, 49, 2293 -2295;

(8) (a) Yu, A.; Liang, Z.; Cho, J.; Caruso, F. Nano Lett. 2003, 3, 1203-1207. (b)

Devadoss, A.; Spehar-Délèze. A. -M.; Tanner, D. A.; Bertoncello, P.; Marthi, R.;

Keyes, T. E.; Forster, R. J. Langmuir 2010, 26, 2130 -2135;

(9) (a) Chen, X.; Mao, S. S. Chem. Rev. 2007, 107, 2891- 2959. (b) Xia, Y.; Xiong, Y.;

Lim, B.; Skrabalak, S. E. Angew. Chem., Int. Ed. 2009, 48, 60-103. (c) Louis, C.;

Pluchery, O. Gold Nanoparticles for Physics, Chemistry, Biology, Imperial College

Press, 2012.

(10) Astruc, D.; Liang, L.; Rapakousiou, A.; Ruiz, J. Acc. Chem. Res. 2012, 45, 630-

640.

(11) (a) Zhao, P.; Li, N.; Salmon, L.; Liu, N.; Ruiz, J.; Astruc, D. Chem. Commun.

2013, 49, 3218-3220. (b) Li, N.; Zhao, P.; Liu, N.; Echeverría, M.; Moya, S.; Salmon,

L.; Ruiz, J.; Astruc, D. Chem. Eur. J. 2014, 20, 8363-8369.

(12) (a) A. Labande, J. Ruiz, D. Astruc, J. Am. Chem. Soc. 2002, 124, 1782-1789. (b)

Daniel, M.; Ruiz, J.; Nlate, S.; Blais, J. C.; Astruc, D. J. Am. Chem. Soc. 2003, 125,

2617-2628. (c) Otón, F.; Espinosa, A.; Tárraga, A.; de Arellano, C. R.; Molina, P.

Chem. Eur. J. 2007, 13, 5742-5725. (d) Wang, Y.; Salmon, L.; Ruiz, J.; Astruc, D.

Nat. Commun. 2014, 5, doi: 10.1038/ncomms4489.

(13) (a) Sardar, R.; Beasley, C. A.; Murray, R. W. J. Am. Chem. Soc. 2010, 132,

2058-2063. (b) Mars, A.; Parolo, C.; Raouafi, N.; Boujlel, K.; Merkoçi, A., J. Mater.

Chem. B 2013, 1, 2951-2955.

(14) (a) Ornelas, C. New. J. Chem. 2011, 35, 1973-1985. (b) Gasser, G.; Ott, I.;

Metzler-Nolte, N. J. Med. Chem. 2011, 54, 3-25. (c) Hillard, E. A.; Jaouen, G.

Organometallics 2011, 30, 20-27. (d) Hartinger, C. G.; Metzler-Nolte, N.; Dyson, P. J.

Organometallics 2012, 31, 5677-5685.

(15) (a) Herves, P.; Perez-Lorenzo, M.; Liz-Marzán, L. M.; Dzubiella, J.; Lu, Y.;

Ballauff, M. Chem. Soc. Rev. 2012, 41, 5577-5587. (b) Shivhare, A.; Ambrose, S. J.;

Zhang, H.; Purves, R. W.; Scott, R. W. J. Chem. Commun. 2013, 49, 276-278. (c)

Pachfule, P.; Kandambeth, S.; Díaz, D.; Banerjee, R. Chem. Commun. 2014, 50,

3169-3172. (d) Zhang, Y.; Cui, X.; Shi, F.; Deng, Y. Chem. Rev. 2012, 112, 2467-

73

18

2505.

(16) (a) Woo, Y. -T.; Lai, D. Y. Aromatic Amino and Nitro–Amino Compounds and

Their Halogenated Derivatives. Patty's Toxicology, pp. 1-96. Wiley-VCH, New York,

2001. (b) Mitchell, S. C. ; Waring, R. H. “Aminophenols.” In Ullmann’s Encyclopedia

of Industrial Chemistry, Wiley-VCH. 2002.

(17) Mizukami, S.; Nagano, T.; Urano, Y.; Odani, A.; Kikuchi, K. J. Am. Chem. Soc.

2002, 124, 3920-3925. (b) Xu, Z.; Liu, X.; Pan, J.; Spring, D. R. Chem. Commun.

2012, 48, 4764-4766.

(18) Zhang, S. Y.; Ong, C. -N.; Shen, H. -M. Cancer Lett. 2004, 208, 143-153.

(19) Shahrokhian, S. Anal. Chem., 2001, 73, 5972–5978.

(20) Seshadri, S.; Beiser, A.; Selhub, J.; Jacques, P. F.; Rosenberg, I. H.; D’Agostino,

R. B.; Wilson P. W. F.; Wolf, P. A. N. Engl. J. Med., 2002, 346, 476-483.

(21) Kleinman W. A.; Richie, J. P. Biochem. Pharmacol. 2000, 60, 19-29.

(22) (a) Li, Y.; Li, Z.; Gao, Y.; Gong, A.; Zhang, Y.; Hosmane, N. S.; Shen, Z.; Wu,

A. Nanoscale 2014, 6, 10631-10637. (b) Long, L.; Zhou, L.; Wang, L.; Meng, S.;

Gong, A.; Du, F. Org. Biomol. Chem. 2013, 11, 8214-8220.

(23) (a) Jung, H. S.; Chen, X.; Kim, J. S.; Yoon, J. Chem. Soc. Rev. 2013, 42, 6019-

6031. (b) Lin, J. -H.; Chang, C. -W.; Tseng, W. -L. Analyst 2010, 135, 104-110.

(24) (a) A. Madonik, D. Astruc, J. Am. Chem. Soc. 1984, 106, 2437-2439. (b) Desbois,

M. -H.; Astruc, D.; Guillin, J.; Varret, F. ; Trautwein, A.X. ; Villeneuve, G. J. Am.

Chem. Soc. 1989, 111, 5800-5809. (c) Ruiz, J.; Astruc, D. C. R. Acad. Sci. Paris, t. 1,

Série Π c, 1998, 21-27.

(25) (a) Moinet, C.; Román, E.; Astruc, D. J. Electroanal. Interfac. Chem. 1981, 121,

241-246. (b) Green, J. C.; Kelly, M. R.; Payne, M. P.; Seddon, E. A.; Astruc, D.;

Hamon, J. -R.; Michaud, P. Organometallics 1983, 2, 211-218.

(26) (a) Abd-El-Aziz, A.; Bernardin, S. Coord. Chem. Rev. 2000, 203, 219-267. (b)

Manners, I. Science 2001, 294, 1664-1666. (c) Abd-El-Aziz, A. S. Coord. Chem. Rev.

2002, 233-234, 177-191. (d) Geiger, W. E. Organometallics 2007, 26, 5738-5765. (e)

Abd-El-Aziz, A. S.; Winram, D. J.; Shipman, P. O.; Bichler, L. Macromol. Rapid

Commun. 2010, 31, 1992-1997.

(27) (a) Tornøe, C.W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-

3064. (b) Devadoss, A.; Chidsay, C. E. D. J. Am. Chem. Soc. 2007, 129, 5370-5371.

(c) Rapakousio, A.; Wang, Y.; Belin, C.; Pinaud, N.; Ruiz, J.; Astruc, D. Inorg. Chem.

2013, 52, 6685-6693.

74

19

(28) Robilotto, T. J.; Deligonul, N.; Updegraff, J. B.; Gray, T. G. Inorg. Chem. 2013,

52, 9659-9668.

(29) (a) Wunder, S.; Lu, Y.; Albrecht, M.; Ballauff, M. ACS Catal. 2011, 1, 908-916.

(b) Pradhan, N.; Pal, A.; Pal, T. Colloid Surf. A 2002, 196, 247-257. (c) Esumi, K.;

Isono, R.; Yoshimura, T.; Langmuir 2004, 20, 237-243;

(30) Mei, Y.; Sharma, G.; Lu, Y.; Drechsler, M.; Irgang, T.; Kempe R.; Ballauff, M.

Langmuir, 2005, 21, 12229-12234.

(31) (a) Newkome, G. R.; Yao, Z.; Baker, G. R.; Gupta, G. K., J. Org. Chem. 1985,

50, 2003-2004. (b) Newkome, G. R. ; Shreiner, C. Chem. Rev. 2010, 110, 6338-6442.

(32) Leff, D. V.; Ohara, P. C.; Geath, J. R.; Gelbart, W. M. J. Phys. Chem. 1995, 99,

7036-7041.

(33) For reviews on ferrocenyl-terminated dendrimers, see : (a) Casado, C. M. ;

Cuadrado, I.; Moran, M.; Alonso, B.; Garcia, B.; Gonzales, B.; Losada, J.; Coord.

Chem. Rev. 1999, 185-6, 53-79. (b) Casado, C. M.; Alonso, B.; Losada, J.; Garcia-

Armada M. P. In Designing Dendrimers, Campagna, S. ; Ceroni, P. ; Puntoriero,

F. eds., John Wiley&Sons, Hoboken, NJ, 2012, pp. 219-262.

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Ferrocene- and coumarin-triazole were utilized to stabilize AuNPs. The first

ferricenium-stabilized gold nanoparticle was directly obtained by reaction between

the trz- linked ferrocene and HAuCl4. Ferrocene and Ferricenium appended AuNP-1

and AuNP-2 reversibly interconvert. The triazole- linked ferricenium chloride

stabilization of AuNP-2 is also characterized by slower catalysis in 4-nitrophenol

reduction by NaBH4 than with other triazole-AuNPs. AuNP-3 capped with coumarin-

triazole is a fluorescent nanosensor for biological thiols. Easy ligand substitution was

also applied to dendrimer synthesis.

76

Chapter 4

Dendrimer-stabilized AuNPs and their Catalytic Application for

p-Nitrophenol Reduction

77

4.1 Introduction

Part A. Dendrimers are classic branched single macromolecules that have been demonstrated

to have extraordinary ability to hold hydrophobic guests by noncovalent bonding. A ligand

site, such as triazole ring in the interior of dendrimers, enhances the interaction between the

host and the guest. PEG-terminated dendrimers have a hydrophilic periphery that provides

water solubilization of dendrimer-stabilized materials. With variious lengths of PEG

branches, dendrimers have significant influence in stabilization of AuNPs and catalytic

activity of 4-nitrophenol reduction reaction.

Part B. Among the transition metal-catalyzed redox reactions, reduction of nitroaromatics is

one of the most crucial ones. Indeed, 4-nitrophenol (4-NP) is anthropogenic, toxic and

inhibitory in nature. Its reduction product, 4-aminophenol (4-AP), finds applications as a very

important substrate in industry and medicine. It has reported that surface functional groups of

NPs influenced the catalytic behavior. We compared catalytic activities of different ligands

(triazole, citrate or thiolate) capped AuNPs in uniform size in 4-NP reduction. The weak

bonding of the trz ligands, compared to the stronger bonding of thiolate and citrate ligands, is

responsible for their easy displacement from the AuNP surface by substrates. All the 1,2,3-

triazole (trz)-stabilized AuNPs that are examined here are much more efficient catalysts than

standard AuNPs that are stabilized by the formally anionic thiolate and citrate ligands. This

part was essentially conducted by Dr. Roberto Ciganda with whom we collaborated, with

contributions from Christophe Deraedt and Sylvain Gatard.

78

“Click” Synthesis of Nona-PEG-branched Triazole Dendrimers andStabilization of Gold Nanoparticles That Efficiently Catalyzep‑Nitrophenol ReductionNa Li,† María Echeverría,‡ Sergio Moya,‡ Jaime Ruiz,† and Didier Astruc*,†

†ISM, UMR CNRS 5255, University of Bordeaux, 351 Cours de la Liberation, 33405 Talence Cedex, France‡CIC biomaGUNE, Unidad Biosuperficies, Paseo Miramon no. 182, Edif. “C”, 20009 Donostia-San Sebastian, Spain

*S Supporting Information

ABSTRACT: Two new water-soluble 1,2,3-triazole-containing nona-PEG-branched dendrimers are obtained with nine intradendritic 1,2,3-triazoles(trz). Addition of HAuCl4 in water to these dendrimers quantitatively leads tothe intradendritic formation of AuCl3(trz) moieties subsequent to complete Cl−

substitution by trz on Au(III), whereas the analogous complexation reaction ofAuCl3 with a linear PEG trz ligand forms only an equilibrium between trz-coordinated Au(III) and Au(III) that is not coordinated to trz. Reduction of thedendrimer-Au(III) complexes to Au0 by NaBH4 then leads to stabilization ofgold nanoparticles (AuNPs) in water. The sizes of the AuNPs stabilized by thedendritic macromolecules are further controlled between 1.8 and 12 nm uponselecting the stoichiometry of Au(III) addition per dendritic trz followed byNaBH4 reduction. With a 1:1 Au/trz stoichiometry, the AuNP size depends onthe length of the PEG tether of the dendrimer; small dendrimer-encapsulatedAuNPs are formed with PEG2000, whereas large AuNPs are formed withPEG550. With Au/trz stoichiometries larger than unity, Au(III) is reduced outside the macromolecule, resulting in the formationof large interdendritically stabilized AuNPs. The formation of very small and only mildly stabilized AuNPs by neutral hydrophilictriazole ligands offers an opportunity for very efficient p-nitrophenol reduction by NaBH4 in water at the AuNP surface.

■ INTRODUCTION

Dendrimers that are classic synthetic macromolecules with well-defined topological flower-like structures have been demon-strated to have an extraordinary ability to hold hydrophobicguests by noncovalent bonding including physical encapsula-tions, van der Waals forces, hydrogen-bond interactions, andhydrophobic interactions.1 The dendrimer−metal nanoparticle(NP) host−guest composites are synthesized through atemplate approach in which metal ions are entrapped in theinterior of dendrimers due to the functional groups and thesteric embedding effects and then reduced chemically. Thesedendrimer−NP composites have been modified to exhibitsufficient solubility and stability, resulting in their potentialapplications inter alia in catalysis,2 photophysics,3 diagnosis,4

and sensing.5

Catalysis by dendrimer-encapsulated metal NPs waspioneered by Crooks’ group6 using polyamidoamine(PAMAM) dendrimers.7 Subsequently, many reports haveappeared on the stabilization of and catalysis by precious metalNPs (Pd, Pt, and Au) in various dendrimers.8 In particular,attention has been focused on the dendrimer-stabilized AuNPsthat have applications in both drug delivery and surfaceplasmon-based photothermal diagnosis and therapy,9 whereasthe catalytic properties of dendrimer-stabilized AuNPs were

often investigated in the form of bimetal alloys or nano-composites.10

“Click” dendrimers terminating with triethylene glycol(TEG) branched tris-dendrons11 have been used for thestabilization of AuNPs subsequent to coordination of their trzligands. It was supposed that AuNPs are either encapsulated inthe dendrimers or surrounded by several dendrimers, whichdepends on both the size of the AuNPs and the morphology ofthe dendrimers.11 It was also reported that the TEG dendron-terminated “click” dendrimer-stabilized PdNPs displayedimpressive activity in the Suzuki−Miyaura reaction in aqueousmedium.12 Significantly, numerous studies in catalysis undervarious “green” conditions have shown that the dendrimer playsthe role of the nanoreactor and nanofilter.2

One of our general goals is to design water-soluble andbiocompatible nanomaterials in order to apply them to sensing,catalysis, and biomedicine.13 For this purpose, PEG-terminateddendrimers fulfill these requirements and moreover provide thepossibility to benefit from the enhanced permeability andretention (EPR) effect upon accumulating in tumoral tissues.14

The association of AuNPs15 with dendrimers is of particularinterest given their multiple applications in catalysis,16

Received: April 11, 2014Published: June 9, 2014

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photonics,17 and biomedicine.18 The activation of aromaticsupon temporary π complexation by late transition metalgroups,19 in particular in the [Fe(η5-C5H5)(arene)]

+ com-plexes,20 provides a powerful means of functionalization and, inparticular, for the synthesis of dendritic cores, dendrons, anddendrimers with 1 → 3 connectivity.21 Thus, we have appliedthe η5-C5H5Fe

+-induced polyallylation20,22 of polymethylben-zene, in particular the nona-allylation of mesitylene giving 1(Scheme 1),22 for the construction of nona-PEG-terminateddendrimers.23

Therefore, the nona-allylated core 1 obtained as shown inScheme 1 was hydrosilylated with dimethylchloromethylsilane,and the product 2 was submitted to nucleophilic substitution ofchloride by azide via reaction with NaN3 to yield 3 (Scheme2).23

The known nona-azide 3 is a very practical starting materialfor a variety of copper-catalyzed alkyne azide cycloaddition(CuAAC) “click” reactions and was applied here in the

investigation of such reactions in order to introduce PEGtethers together with triazole (trz) rings onto the dendrimersusing propargyl-PEG derivatives. Herein we report thesesyntheses and characterizations of the 1,2,3-triazole dendrimersobtained in this way, the complexation of Au(III) to theintradendritic trz ligands upon reaction with HAuCl4, andfurther introduction of AuNPs of catalytic interest by reductionof AuIII using NaBH4. The variation of parameters leading tothese AuNP syntheses has been examined for further catalysisof p-nitrophenol reduction by these AuNPs that are only mildlystabilized by the trz ligands, as well as the influence of theAuNP core size on the catalytic reduction rate.

■ RESULTS AND DISCUSSIONSynthesis of Dendrimers. As a versatile substrate, the

known arene-cored, nonabranched dendrimer with azidotermini 3 was synthesized according to Schemes 1 and 2.11

Synthesis of PEG-branched nonadendrimers was then con-

Scheme 1. η5-C5H5Fe+-Induced Nona-allylation of Mesitylene Yielding the Nona-allylated Core 1

Scheme 2. Synthesis of the Nona-azide 3 from the Nonaolefin Core 1 via 2


dx.doi.org/10.1021/ic500861f | Inorg. Chem. 2014, 53, 6954−69616955

80

veniently carried out by a selective “click” reaction (Scheme 3)through grafting PEG alkyne onto an azido-terminatednonadendrimer. The classic Sharpless catalyst was used, andthe “click” reaction was launched in THF/H2O solution. Thesereactions were completed within 48 h, this long reaction timebeing necessary because of the steric bulk of the PEG tethersand the modest reactivity of Cu(I) under these conditions. Byemploying PEG alkyne with different chain lengths (PEG550and PEG2000), two corresponding PEG-branched dendrimers(abbreviated as DEND550 and DEND2000) were obtained insatisfactory yields and characterized by 1H, 13C, and 29Si NMR,IR spectroscopy, elemental analysis, size exclusion chromato-graph, and mass spectrometry for DEND550 (see details in theSupporting Information).Preparation and Characterization of the Dendrimer-

Stabilized AuNPs. AuNPs stabilized by DEND550 andDEND2000 were prepared in aqueous solution with sodiumborohydride as reductant as shown in Scheme 4. Thedendrimer and HAuCl4 were dissolved together in deionizedwater and stirred for 30 min in order to ensure access of AuCl4

−

to the trz ring that is wrapped by the PEG chains. A freshlyprepared NaBH4 aqueous solution was then added dropwiseinto the as-prepared solution. The color of the solutiongradually turned deep red or purple as AuNPs formed. For thepurpose of synthesizing AuNPs with various sizes, the molarratio of Au(III)/trz was varied as 1:1, 5:1, 10:1, and 20:1.

Accordingly, the obtained AuNPs with DEND550 are namedAu-DEND550-1, Au-DEND550-5, Au-DEND550-10, and Au-DEND550-20, respectively, whereas with DEND2000 they arenamed Au-DEND2000-1, Au-DEND2000-5, Au-DEND2000-10, and Au-DEND2000-20, respectively.Complexation of Au(III) with triazole molecules has been

investigated by Bortoluzzi and co-workers.24 In order tounderstand the complexation process between Au(III) andthe trz dendrimers, a titration process was carried out by addingvarious amounts of HAuCl4 into an as-prepared D2O solutionof dendrimer. After stirring for 20 min, the reaction wasmonitored by 1H NMR spectroscopy. The ratio of trz/Au(III)was progressively set to 1:0, 1:1, and 1:2. 1H NMRspectroscopy demonstrated that with both DEND2000 andDEND550 the complexation of Au(III) was complete afteraddition of 1 equiv of Au(III) per dendritic branch. As depictedin the 1H NMR spectrum of DEND2000 in Figure 1, thechemical shift of the trz proton (Htrz) is 7.9 ppm in pure D2Osolution. After addition of 1 equiv of Au(III) per dendriticbranch, the Htrz signal is entirely shifted to 8.37 ppm, indicatingcompletion of the complexation. No further shift was observedafter addition of another equivalent of Au(III) precursor. Thesame result was obtained upon complexation of Au(III) withDEND550 (Supporting Information, Figure S11). Forcomparison, a monomeric trz derivative containing PEG2000and an alkyl chain was synthesized, and with this monomer

Scheme 3. Synthesis of PEG-Branched Dendrimers DEND550 (n = 11, 12) and DEND2000 (n = 40−44) by “Click” Reactions

Scheme 4. Synthesis of AuNPs: Complexation Process of Au(III) with trz Ring, Reduction of Au(III) by NaBH4, and Gatheringof Au(0) into AuNPs



81

incomplete complexation resulting from an equilibrium wasobserved with the use of 1 equiv of Au(III) (SupportingInformation, Figure S12). This comparison shows the benefit ofthe dendrimer structure over a linear analogue, owing to theadditional driving force provided by encapsulation of theCl3Au-trz moieties.UV−vis spectroscopy also revealed that during the trz

complexation the absorbance intensity of Au(III) at 302 nmdecreased with time in both Au(III)/DEND2000 and Au(III)/DEND550 solutions. No further decrease of the absorbancewas observed after 20 min, suggesting that the complexationreached the equivalence point (Supporting Information, FigureS13). Therefore, it was necessary to leave enough time for thecomplexation, because the steric effect of both the dendriticstructure and the package of PEG chain surrounding the trzring slowed the coordination process.In the case of the preparation of AuNPs involving lower

Au(III)/trz ratios, the Au atoms were coordinated by trz,leading to the formation of AuNPs of small size with narrowdispersity. It seems reasonable to infer that, given their smallsize and formation from Cl3Au-trz moieties localized inside thedendrimers, these small AuNPs were encapsulated inside thedendrimers that were much larger than these AuNP cores

(Figure 2, left). On the contrary, the AuNPs that were preparedwith a high Au(III)/trz ratio mostly resulted from theformation of Au atoms outside the dendrimers because of theexcess of Au(III) precursors over the number of trz rings. Inthis case the interdendritic AuNP stabilization does not preventthe formation of large AuNPs, and such AuNPs are much toolarge to be encapsulated inside the dendrimers. Thus, thestabilization of these latter AuNPs is due to several surroundingdendrimers (Figure 2, right).The morphology and the core size of AuNPs were revealed

by TEM images, in which the core diameter of the AuNPs wasshown to regularly increase as the Au(III)/trz ratio was raised(Table 1 and Supporting Information, Figure S17−20). It was

also found that with a certain Au(III)/trz ratio AuNPsstabilized by several dendrimers were diverse in core size,which was attributable to the difference in package density ofdendrimers that influenced the mobility of Au(III), NaBH4, andAuNPs, as well as the leaching of Au atoms and small Auclusters. Upon stoichiometric addition of Au(III) to thedendrimeric trz bearing long PEG-2000 tethers followed byreduction with NaBH4, the formed AuNPs have a diameter of1.8 nm, with about 180 Au atoms, which corresponds to oneAuNP formed from Au atoms coming from 20 dendriticmacromolecules on average. On the other hand, with shortPEG-550 tethers AuNPs are interdendritically formed andstabilized with a 3.2 nm AuNP core, i.e., contain about 1000 Auatoms provided by more than 100 dendrimers (Figure 3 andTable 1). From these experiments, it is concluded that the Auatoms and very small primary Au clusters show a great mobility

Figure 1. 1H NMR spectrum of DEND2000 (in red) and 1H NMRspectra of DEND2000 after titration of HAuCl4 (to form a trz/Au(III)ratio of 1:1 (in blue) and 1:2 (in black), individually). All the sampleswere prepared in D2O, and a few drops of acetone-d6 were added inthe case of 1:2 DEND2000/Au(III) in order to solubilize all thecomponents.

Figure 2. Dendrimer-encapsulated small AuNP (left) and large AuNP surrounded by several dendrimers (right).

Table 1. TEM and SPB Data for the Dendrimer-StabilizedAuNPs

AuNPs SPB (nm) TEM (d = nm) Au atoms/NP25

Au-DEND550-1 516 3.2 1000Au-DEND550-5 535 7.3 12 000Au-DEND550-10 537 9 22 000Au-DEND550-20 538 12 53 000Au-DEND2000-1 1.8 180Au-DEND2000-5 526 5.7 5700Au-DEND2000-10 529 8.7 20 200Au-DEND2000-20 538 11.4 45 000



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before definitive stabilization. The filtering effect of the PEGtethers is also clearly demonstrated upon comparing theinfluence of two PEG tether lengths on the limitation of theAuNP size.The UV−vis spectra of the AuNPs displayed changes in the

surface plasmon band (SPB) along with the variety of sizes. Forinstance, the SPB of Au-DEND550-1 was observed at amaximum of 516 nm, while the SPB of Au-DEND550-20 wasfound at 538 nm (Supporting Information, Figure S14). Thedifference in SPB was in agreement with the variation of corediameter as revealed by TEM. The plasmon band of Au-DEND2000-1 was weak and unresolved in the UV−visspectrum, indicating that Au-DEND2000-1 has a small coresize (1.8 nm). These AuNPs were also narrowly dispersed inaqueous solution, as revealed by the DLS measurements(Supporting Information, Figures S15 and S16). This resultsuggests promising applications of click-PEG-dendrimer-stabi-lized AuNPs in aqueous media.Catalytic Reduction of p-Nitrophenol. Nitrophenols are

toxic and hazardous micropollutants, and their degradation is

challenging for environmental purposes. On the other hand, p-aminophenol is a potential industrial intermediate inmanufacturing various analgesic and antipyretic drugs, anti-corrosion lubricants, and hair-drying agents; thus efficientPdNP catalysis of p-nitrophenol reduction is of great value. p-Nitrophenol reduction also is a versatile reaction that is usefulfor the evaluation of the catalytic activity of various metal NPs,owing to its high sensitivity to metal catalyst and theconvenient determination of the reaction rate through UV−vis spectroscopy.26 It has been previously reported that AuNPspossessed prominent catalytic activity in p-nitrophenolreduction.27 In this context the loose coordination of trzligands to the AuNP core surface provides a very favorablesituation for efficient catalysis. The influence of the morphologyof dendrimers, the size of AuNPs, and the catalyst amount onthe kinetics of p-nitrophenol reduction was investigated in thisstudy. Thus, the relatively smaller AuNPs, Au-DEND550-1 (d= 3.2 nm) and Au-DEND550-5 (7.3 nm), as well as Au-DEND2000-1 (1.8 nm) and Au-DEND2000-5 (5.7 nm), wereprovided as catalysts for the p-nitrophenol reduction. A typicalcatalytic reaction was processed as follows: a p-nitrophenol(0.09 μmol) aqueous solution was mixed with sodiumborohydride (7.2 μmol) in a 3 mL standard quartz cuvette,to form a total volume of 2.5 mL. This solution immediatelyturned yellow and showed an intense absorption at 400 nm inthe UV−vis spectrum. Various molar percentages of AuNPs(0.5%, 1%, 2%, and 5%, separately) in aqueous solution werethen injected into the above-mentioned quartz cuvette, and thereduction reaction was monitored by UV−vis spectroscopyevery 40 s throughout the reduction process (see SupportingInformation, Figures S21−24).The plot of the consuming rate [−ln(C/C0)] of p-

nitrophenol versus the reaction times is presented in Figure4, and the k values of the reduction under various conditions

Figure 3. TEM images of Au-DEND550-1 (d = 3.2 nm) and Au-DEND2000-1 (d = 1.8 nm).

Figure 4. Plots of the consuming rate of p-nitrophenol [−ln(C/C0)] vs the reaction times with various AuNPs as catalysts: (a) Au-DEND550-1, (b)Au-DEND550-5, (c) Au-DEND2000-1, (d) Au-DEND2000-5.



83

are summarized in Figure 5. The catalysis results obtained withAu-DEND550-1 (3.2 nm) and Au-DEND550-5 (7.3 nm) show

that the k value increases upon raising the amount of catalyst,and the k value decreases upon raising the AuNP size (Figure5). Likewise, the large dendrimer (DEND2000)-stabilizedAuNPs, Au-DEND2000-1 (1.8 nm) and Au-DEND2000-5(5.7 nm), exhibit a similar trend.Upon comparing the catalysis results of four AuNPs (Figure

5), it obviously appears that AuNPs stabilized by the smalldendrimer (DEND550) exhibit higher catalytic activity thanAuNPs stabilized by the larger dendrimer (DEND2000). Thisis taken into account by the less bulky periphery of the smalldendrimer (DEND550) that allows easier access of thesubstrates to the AuNP core surface and makes their reactioneasier on this surface. On the other hand, the filtering effect ofthe large PEG tethers in the case of PEG2000 causes kineticlimitations. In other reported examples of AuNP-catalyzed p-nitrophenol reduction, the structural transformation at theAuNP surface was found to be rate limiting,27 whereas here thediffusion of the substrate through the ligand shell can controlthe kinetics when the PEG tethers are long enough. Inparticular, Au-DEND550-1 (3.2 nm) displays a remarkablecatalytic efficiency (k = 5.1 × 10−3 s−1, with the catalyst amount0.5%) in such a low concentration of p-nitrophenol. Thisefficiency is among the best ever observed for this reaction,which can be attributed to the very mild interaction betweenthe trz nitrogen ligand and the AuNP core surface, causing avery easy ligand exchange between the trz ligand and thesubstrate (p-nitrophenol and NaBH4).Concluding Remarks. The facile “click” synthesis of nona-

PEG-branched macromolecules offers a valuable straightfor-ward application of the η5-C5H5Fe

+-induced nona-allylation ofmesitylene. Then a positive and productive dendritic effect wasdisclosed for the quantitative intradendritic trz complexation toAu(III) upon reaction of the click dendrimers with HAuCl4 inwater according to AuCl4

− + trz → AuCl3(trz) + Cl−, whereasunder analogous conditions complexation of a nondendritictriazole analogue leads only to an equilibrium.Another original dendritic effect is that involving the

influence of the PEG tether length on the formation of theAuNPs, in particular on their size. The NaBH4 reduction oftriazole-coordinated Au(III) was shown to lead to relativelysmall AuNPs, contrary to the reduction of free HAuCl4 (whenthe Au(III)/triazole ratio was larger than unity), which led to

large AuNPs. The influence of the parameters involved in theAuNP formation leads to the conclusion that interdendriticmobility of Au atoms (or native Au clusters) occurs morereadily than in the case of PdNPs, which is of interest for latetransition metal nanoparticle engineering for catalysis. Finallythese trz dendrimer-stabilized AuNPs are excellent p-nitro-phenol reduction catalysts.In summary, the stabilization of metal NPs by easily

synthesized “click” arene-cored trz dendritic macromoleculesproduces nanoreactors for nanoparticle catalysis with greatefficiency thanks to the combination of the dendrimer-supported nanoreactor and the flexible Au−trz bonding. Thecontrol of the fate of native Au atoms and small Au clusters bythe structural and reaction parameters including “forced”leaching from the dendrimers has led to an understanding ofhow to optimize the catalytic efficiencies.

■ EXPERIMENTAL SECTIONChemicals and Characterization Tools. All solvents and

chemicals were used as purchased. Milli-Q water (18.2 MΩ) wasused in the preparation of AuNPs. NMR spectra were recorded at 25°C with a Bruker 300 (300 MHz) spectrometer. All the chemical shiftsare reported in parts per million (δ, ppm) with reference to Me4Si forthe 1H and 13C NMR spectra. The infrared (IR) spectra were recordedon an ATI Mattson Genesis series FT-IR spectrophotometer. UV−visabsorption spectra were measured with a PerkinElmer Lambda 19UV−vis spectrometer. Elemental analyses were recorded on a PAR273 potentiostat under a nitrogen atmosphere. The DLS measure-ments were made using a Malvern Zetasizer 3000 HSA instrument at25 °C at an angle of 90°. Size exclusion chromatography of dendrimerswas performed using a JASCO HPLC pump type 880-PU,TOSOHAAS TSK gel columns (G4000, G3000, and G2000 withpore sizes of 20, 75, and 200 Å, respectively, connected in series), anda Varian (series RI-3) refractive index detector, with THF as themobile phase and calibrated with polystyrene standards

Synthesis of DEND550 and DEND2000. A general procedurewas employed and is described below: the azido-terminated non-abranch dendrimer 311 (0.08 mmol, 121 mg) and propargyl PEG (0.72mmol) were dissolved in 5 mL of THF. CuSO4·5H2O (0.72 mmol,180 mg) in aqueous solution was then added. The obtained solutionwas deaerated and refilled with N2, followed by dropwise addition of afreshly prepared aqueous solution of sodium ascorbate (1.44 mmol,285 mg) to obtain a 1:1 THF/water ratio. The solution was stirred for48 h at room temperature under a N2 atmosphere. After removal ofTHF in vacuum, 5 mL of CH2Cl2 and 5 mL of concentrated (30%)aqueous ammonia solution were added. The mixture was stirred for 30min to release the Cu ions trapped inside the polymer as[Cu(NH3)2(H2O)2]

2+. Then the organic layer was collected andwashed with brine. After drying with anhydrous Na2SO4, the solventwas removed under vacuum. DEND2000 was recovered and purifiedby reprecipitation in CH2Cl2 and diethyl ether. The PEGylateddendrimers were obtained in 91% (DEND550) and 88%(DEND2000) yields, respectively.

Titration of HAuCl4 into the D2O Solution of Dendrimers (orMonomer). Taking Au(III)/DEND2000 as an example, HAuCl4(0.01 mmol, 2 mg, 1 equiv per branch) was added into a D2Osolution of DEND2000 (0.0011 mmol, 21 mg, in 1 mL of D2O). Afterstirring for 20 min, the 1H NMR spectrum (300 MHz) was recorded.Then, another equivalent of HAuCl4 was added into the above-mentioned solution, this solution was further stirred for 20 min, andthe 1H NMR spectrum was recorded again. The same operation wasfollowed in the titration of HAuCl4 with DEND550 (or the trzmonomer) in D2O solution.

Preparation of Dendrimer-Stabilized AuNPs. AuNPs stabilizedby dendrimers DEND550 (respectively DEND2000) were preparedunder various Au(III)/trz ratios (1:1, 5:1, 10:1, and 20:1, respectively).Typically, HAuCl4·3H2O (0.009 mmol, 3.5 mg) and DEND550 (0.001mmol, 6.5 mg) were dissolved in 5 mL of Milli-Q water. After being

Figure 5. Bar graph showing the kinetic constant (k value) of p-nitrophenol reduction with various AuNP catalysts.



84

stirred for 10 min, 1 mL of freshly prepared NaBH4 (0.045 mmol, 1.7mg) water solution was added dropwise into the solution withvigorous stirring. The Au-DEND550-1 solution that was obtained wasfurther stirred for 30 min and was dialyzed against a large volume ofwater (2 × 4 h). Subsequently, Au-DEND550-5, Au-DEND550-10,Au-DEND550-20, Au-DEND2000-1, Au-DEND2000-5, Au-DEND2000-10, and Au-DEND2000-20 were prepared following thesame procedure. These dendrimer-stabilized AuNPs were kept inaqueous solution and were diluted before characterization and use incatalytic reactions.Catalytic Reduction of p-Nitrophenol with Dendrimer-

Stabilized AuNPs. An aqueous solution (2.5 mL) containing 0.09μmol of p-nitrophenol and 7.2 μmol of NaBH4 was prepared in a 3 mLstandard quartz cuvette (path length: 1 cm). Then AuNP (0.5%, 0.45× 10−3 μmol) catalyst was injected into the as-prepared solution, andthe reaction progress was detected by UV−vis spectroscopy every 40 s.The same processes were carried out with an increasing catalystamount, successively 1%, 2%, and 5%.

■ ASSOCIATED CONTENT*S Supporting InformationCharacterization data of dendrimers and AuNPs and UV−visspectroscopic studies of the catalytic p-nitrophenol reductionreactions. This material is available free of charge via theInternet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected] authors declare no competing financial interest.

■ ACKNOWLEDGMENTSFinancial support from the China Scholarship Council (CSC)(Ph.D. grants to N.L.), the University of Bordeaux, and theCNRS is gratefully acknowledged.

■ REFERENCES(1) (a) Newkome, G. R.; He, E.; Moorefield, C. N. Chem. Rev. 1999,99, 1689−1746. (b) Bosman, A. W.; Janssen, H. M.; Meijer, E. W.Chem. Rev. 1999, 99, 685−688. (c) Dufes, C.; Uchegbu, I. F.;Schatzlein, A. G. Adv. Drug Delivery Rev. 2005, 57, 2177−2202.(d) Mintzer, M. A.; Simanek, E. E. Chem. Rev. 2009, 109, 259−302.(e) Astruc, D.; Boisselier, E.; Ornelas, C. Chem. Rev. 2010, 110, 1857−1959. (f) Hu, J.; Xu, T.; Cheng, Y. Chem. Rev. 2012, 112, 3856−3891.(2) (a) Crooks, R. M.; Zhao, M.; Sun, L.; Chechik, V.; Yeung, L. K.Acc. Chem. Res. 2001, 34, 181−190. (b) Astruc, D.; Heuze, K.; Gatard,S.; Mery, D.; Nlate, S.; Plault, L. Adv. Syn. Catal. 2005, 347, 329−338.(c) Myers, V. S.; Weir, M. G.; Carino, E. V.; Yancey, D. F.; Pande, S.;Crooks, R. M. Chem. Sci. 2011, 2, 1632−1646. (d) Wang, D.; Astruc,D. Coord. Chem. Rev. 2013, 257, 2317−2334. (e) Maity, P.; Yamazoe,S.; Tsukuda, T. ACS Catal. 2013, 3, 182−185.(3) (a) Balzani, V.; Bergamini, G.; Ceroni, P.; Voegtle, F. Coord.Chem. Rev. 2007, 251, 525−535. (b) Lo, S.-C.; Burns, P. L. Chem. Rev.2007, 107, 1097−1116. (c) Lo, S.-C.; Harding, R. E.; Brightman, E.;Burns, P. L.; Samuel, L. D. W. J. Mater. Chem. 2009, 19, 3213−3227.(d) Kim, H. N.; Guo, Z.; Zhu, W.; Yoon, J.; Tian, H. Chem. Soc. Rev.2011, 40, 79−93. (e) Wen, S.; Li, K.; Cai, H.; Chen, Q.; Shen, M.;Huang, Y.; Peng, C.; Hou, W.; Zhu, M.; Zhang, G.; Shi, X. Biomaterial2013, 34, 1570−1580.(4) (a) Caravan, P.; Ellison, J. J.; McMurray, T. J.; Lauffer, R. B.Chem. Rev. 1999, 99, 2293−2352. (b) Toht, E.; Helm, L.; Merbach, A.E. Top. Curr. Chem. 2002, 221, 61−101. (c) Longmire, M.; Choyke, P.L.; Kobayashi, H. Curr. Top. Med. Chem. 2008, 8, 1180−1186.(d) Alumatairi, A.; Rossin, R.; Shokeen, M.; Hagooly, A.; Ananth, A.;Capoccia, B.; Guillaudeu, S.; Abendschein, D.; Anderson, C. J.; Welch,

M. J.; Frechet, J. M. J. Proc. Natl. Acad. Sci. 2009, 106, 685−690.(e) Shen, M.; Shi, X. Nanoscale 2010, 2, 1596−1610.(5) (a) Choi, Y.; Mecke, A.; Orr, B. G.; Banaszak Holl, M. M.; Baker,J. R. Nano Lett. 2004, 4, 391−397. (b) Li, Y.; Cu, Y. T. H.; Luo, D.Nat. Biotechnol. 2005, 23, 885−889. (c) Rosi, N. L.; Mirkin, C. A.Chem. Rev. 2005, 105, 1547−1562. (d) Caminade, A.-M.; Padie, C.;Laurent, R.; Maraval, A.; Majoral, J.-P. Sensors 2006, 6, 901−914.(e) Zhao, P.; Li, N.; Astruc, D. Coord. Chem. Rev. 2013, 257, 638−665.(6) (a) Zhao, M.; Sun, L.; Crooks, R. M. J. Am. Chem. Soc. 1998, 120,4877−4878. (b) Scott, R. W. J.; Wilson, O. M.; Crooks, R. M. Phys.Chem. B 2005, 109, 692−704.(7) (a) Scott, R. W. J.; Wilson, O. M.; Oh, S.-K.; Kenik, E. A.;Crooks, R. M. J. Am. Chem. Soc. 2004, 126, 15583−15591. (b) Mandal,T.; Dasgupta, C.; Maiti, P. K. J. Phys. Chem. C 2013, 117, 13627−13636. (c) Boni, A.; Albertazzi, L.; Innocenti, C.; Gemmi, M.; Bifone,A. Langmuir 2013, 29, 10973−10979. (d) Iyyamperumal, R.; Zhang,L.; Henkelman, G.; Crooks, R. M. J. Am. Chem. Soc. 2013, 135, 5521−5524.(8) (a) Juttukonda, V.; Paddock, R. L.; Raymond, J. E.; Denomme,D.; Richardson, A. E.; Slusher, L. E.; Fahlman, B. D. J. Am. Chem. Soc.2006, 128, 420−421. (b) Chen, A. M.; Taratula, O.; Wei, D.; Thomas,T.; Thomas, T. J.; Minko, T.; He, H. ACS Nano 2010, 4, 3679−3688.(c) Hermes, J. P.; Sander, F.; Peterle, T.; Urbani, R.; Pfohl, T.;Thompson, D.; Mayor, M. Chem.Eur. J. 2011, 17, 13473−13481.(d) Bergamini, G.; Ceroni, P.; Balzani, V.; Gingras, M.; Raimundo, J.-M.; Morandi, V.; Merli, P. G. Chem. Commun. 2007, 4167−4169.(e) Thompson, D.; Hermes, J. P.; Quinn, A. J.; Mayor, M. ACS Nano2012, 6, 3007−3017.(9) (a) Wang, X.; Cai, X.; Hu, J.; Shao, N.; Wang, F.; Zhang, Q.;Xiao, J.; Cheng, Y. J. Am. Chem. Soc. 2013, 135, 9805−9810. (b) Shan,Y.; Luo, T.; Peng, C.; Sheng, R.; Cao, A.; Cao, X.; Shen, M.; Guo, R.;Tomas, H.; Shi, X. Biomaterials 2012, 33, 3025−3035. (c) Kasturir-angan, V.; Nair, B. M.; Kariapper, M. T. S.; Lesniak, W. G.; Tan, W.;Bizimungu, R.; Kanter, P.; Toth, K.; Buitrago, S.; Rustum, Y. M.;Hutson, A.; Balogh, L. P.; Khan, M. K. Nanotoxicology 2013, 7, 441−451. (d) Peng, C.; Zheng, L.; Chen, Q.; Shen, M.; Guo, R.; Wang, H.;Cao, X.; Zhang, G.; Shi, X. Biomaterials 2012, 33, 1107−1119.(10) (a) Chandler, B. D.; Long, C. G.; Gilbertson, J. D.; Pursell, C. J.;Vijayaraghavan, G.; Stevenson, K. J. J. Phys. Chem. C 2010, 114,11498−11508. (b) Lang, H.; Maldonado, S.; Stevenson, K. J.;Chandler, B. D. J. Am. Chem. Soc. 2004, 126, 12949−12956.(c) Scott, R. W. J.; Wilson, O. M.; Oh, S.-K.; Kenik, W. A.; Crooks,R. M. J. Am. Chem. Soc. 2004, 126, 15583−15591.(11) (a) Boisselier, E.; Diallo, A. K.; Salmon, L.; Ornelas, C.; Astruc,D. J. Am. Chem. Soc. 2010, 132, 2729−2742. (b) Astruc, D.; Liang, L.;Rapakousiou, A.; Ruiz, J. Acc. Chem. Res. 2012, 45, 630−640.(12) (a) Deraedt, C.; Salmon, L.; Etienne, L.; Ruiz, J.; Astruc, D.Chem. Commun. 2013, 49, 8169−8171. (b) Deraedt, C.; Astruc, D.Acc. Chem. Res. 2014, 47, 494−503.(13) (a) Astruc, D. Nat. Chem. 2012, 4, 255−267. (b) Zhao, P.;Astruc, D. ChemMedChem 2012, 7, 952−972. (c) Llevot, A.; Astruc, D.Chem. Soc. Rev. 2012, 41, 242−257.(14) (a) Fang, J.; Nakamura, H.; Maeda, H. Adv. Drug Delivery Rev.2011, 63, 136−151. (b) Jokerst, J. V.; Lobovkina, T.; Zare, R. N.;Gambhir, S. S. Nanomedicine 2011, 6, 715−728. (c) Hatakeyama, H.;Akita, H.; Harashima, H. Biol. Pharm. Bull. 2013, 36, 892−899.(15) (a) Murphy, C. J. Science 2002, 298, 2139−2141. (b) Daniel,M.-C.; Astruc, D. Chem. Rev. 2004, 104, 293−346. (c) GoldNanoparticles for Physics, Chemistry, Biology; Louis, C.; Pluchery, O.,Eds.; Imperial College: London, 2012.(16) (a) Haruta, M. Nature 2005, 437, 1098−1099. (b) Corma, A.;Garcia, H. Chem. Soc. Rev. 2008, 37, 2096−2126. (c) Sue Myers, V.;Weir, M. G.; Carino, E. V.; Yancey, D. F.; Pande, S.; Crooks, R. M.Chem. Sci. 2011, 2, 1632−1646.(17) (a) Gawlitza, K.; Turner, S. T.; Polzer, F.; Wellert, S.; Karg, M.;Mulvaney, P.; Klitzing, R. V. Phys. Chem. Chem. Phys. 2013, 15,15623−15631. (b) Sepulveda, B.; Angelome, P. C.; Lechuga, L. M.;Liz-Marzan, L. M. Nano Today 2009, 4, 244−251.



85

http://pubs.acs.org


(18) (a) Seferos, D. S.; Giljohann, D. A.; Hill, H. D.; Prigodich, A. E.;Mirkin, C. A. J. Am. Chem. Soc. 2007, 129, 15477−15479. (b) Lal, S.;Clare, S. E.; Halas, N. Acc. Chem. Res. 2008, 41, 1842−1851.(c) Huang, X.; Jain, P. K.; El-Sayed, I. H.; El-Sayed, M. A. Lasers Med.Sci. 2008, 23, 217−228. (d) Lohse, S. E.; Murphy, C. J. J. Am. Chem.Soc. 2012, 134, 15607−15620.(19) (a) Moinet, C.; Roman, E.; Astruc, D. J. Electroanal. Chem.1981, 121, 241−253. (b) Madonik, A. M.; Astruc, D. J. Am. Chem. Soc.1984, 106, 2437−2439. (c) Gloaguen, B.; Astruc, D. J. Am. Chem. Soc.1990, 112, 4607−4609.(20) (a) Moulines, F.; Astruc, D. Angew. Chem., Int. Ed. 1988, 27,1347−1349. (b) Moulines, F.; Gloaguen, B.; Astruc, D. Angew. Chem.,Int. Ed. Engl. 1992, 31, 458−460.(21) Moulines, F.; Djakovitch, L.; Boese, R.; Gloaguen, B.; Thiel, W.;Fillaut, J.-L.; Delville, M.-H.; Astruc, D. Angew. Chem., Int. Ed. Engl.1993, 32, 1075−1077.(22) (a) Newkome, G. R.; Yao, Z.; Baker, G. R.; Gupta, V. K. J. Org.Chem. 1985, 50, 2003−2004. (b) Newkome, G. R.; Shreiner, C. D.Chem. Rev. 2010, 110, 6338−6442.(23) (a) Ruiz, J.; Lafuente, G.; Marcen, S.; Ornelas, C.; Lazare, S.;Cloutet, E.; Blais, J.-C.; Astruc, D. J. Am. Chem. Soc. 2003, 125, 7250−7257. (b) Ornelas, C.; Ruiz, J.; Belin, C.; Astruc, D. J. Am. Chem. Soc.2009, 131, 590−601.(24) Bortoluzzi, M.; Scrivanti, A.; Reolon, A.; Amadio, E.; Bertolasi,V. Inorg. Chem. Commun. 2013, 33, 82−85.(25) Leff, D. V.; Ohara, P. C.; Geath, J. R.; Gelbart, W. M. J. Phys.Chem. 1995, 99, 7036−7041.(26) (a) Zhang, Y.; Cui, X.; Shi, F.; Deng, Y. Chem. Rev. 2012, 112,2467−2505. (b) Herves, P.; Perez-Lorenzo, M.; Liz-Marzan, L. M.;Dzubiella, J.; Lu, Y.; Ballauff, M. Chem. Soc. Rev. 2012, 41, 5577−5587.(c) Gangula, A.; Podila, R.; Karanam, R. M. L.; Janardhana, C.; Rao, A.M. Langmuir 2011, 27, 15268−15274. (d) Antonels, N. C.; Meijboom,R. Langmuir 2013, 29, 13433−13442.(27) (a) Kuroda, K.; Ishida, T.; Haruta, M. J. Mol. Catal. A: Chem.2009, 298, 7−11. (b) Wunder, S.; Polzer, F.; Lu, Y.; Ballauf, M. J. Phys.Chem. C 2010, 114, 8814−8820. (c) Wang, S.-N.; Zhang, M.-C.;Zhang, W. Q. ACS Catal. 2011, 1, 207−211. (d) Wunder, S.; Lu, Y.;Albrecht, M.; Ballauff, M. ACS Catal. 2011, 1, 908−916. (e) Li, J.; Liu,C.-Y.; Liu, Y. J. Mater. Chem. 2012, 22, 8426−8430. (f) Zhang, J.; Han,D.; Zhang, H.; Chaker, M.; Zhao, Y.; Ma, D. Chem. Commun. 2012, 48,11510−11512. (g) Shivhare, A.; Ambrose, S. J.; Zhang, H.; Purves, R.W.; Scott, R. W. J. Chem. Commun. 2013, 49, 276−278.



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10126 | Chem. Commun., 2014, 50, 10126--10129 This journal is©The Royal Society of Chemistry 2014

Cite this:Chem. Commun., 2014,

50, 10126

Gold nanoparticles as electron reservoir redoxcatalysts for 4-nitrophenol reduction: a strongstereoelectronic ligand influence†

Roberto Ciganda,ab Na Li,a Christophe Deraedt,a Sylvain Gatard,a Pengxiang Zhao,ac

Lionel Salmon,d Ricardo Hernandez,b Jaime Ruiza and Didier Astruc*a

The stereoelectronic properties of the stabilizing ligands of

gold nanoparticles (AuNPs) are shown to play a considerable role

in their catalytic efficiency for 4-nitrophenol reduction by NaBH4,

consistent with a mechanism involving restructuration of the AuNP

surface that behaves as an ‘‘electron reservoir’’.

Gold nanoparticles (AuNPs) have recently received considerableinterest for a variety of applications owing to their uniquephysical and chemical properties.1 In particular, their extensiveuse in catalysis2 has followed the seminal discovery of low-temperature CO oxidation by small AuNPs by Haruta.3 Amongthe transition metal-catalyzed redox reactions, the reductionof nitroaromatics is one of the most crucial ones.4 Indeed,4-nitrophenol (4-NP) is anthropogenic, toxic and inhibitory innature. Its reduction product, 4-aminophenol (4-AP), finds appli-cations as a photographic developer of black and white films, acorrosion inhibitor, a dying agent, a precursor for the manufac-ture of analgesic and antipyretic drugs, and in particular, as anintermediate for the synthesis of paracetamol.5 Noble metalnanoparticle catalysts are widely employed for the reduction of4-NP to 4-AP,6–8 and this reaction, with an excess amount ofNaBH4, has often been used as a model reaction to examinethe catalytic performance of metal NPs,6,7 as first shown by Palet al.8 AuNP catalysts that have been examined so far are solid-supported AuNPs7 or various thiolate-AuNPs. The reactionmechanism is still unknown, although Ballauff’s group providedstrong evidence for a process fitting the Langmuir–Hinshelwood

(LH) model. This mechanism involves adsorption of both reactantson the surface of the catalyst for AuNPs or PdNPs that areimmobilized on the surface of spherical polyelectrolyte brusheswith an induction time caused by dynamic restructuring ofthe nanoparticle surface.6c,7b,d,9 For other AuNPs, Pal’s groupalso showed that the catalytic reaction took place at the AuNPsurface.10 Ghosh’s group showed that the rate constant increasedwith a decrease in the size of AuNPs and was proportional tothe total surface area of AuNPs,9 as reported by Ballauff’sgroup;11 and Liu et al. reported that surface functional groupsinfluenced the catalytic behavior.12 Katz suggested a completelydifferent mechanism in which the active site was a leached goldspecies that was present in exceedingly small concentrations.13

Zhang et al. suggested that the borohydride salt transferred ahydride to the AgNPs in the case of TiO2-supported AgNPs.14

Scott’s group showed that in the presence of excess borohydride salts,thiolate–AuNPs that catalyze 4-NP reduction grew to larger sizes.15

Here we show the dramatic influence of the stereoelectroniceffects of the ligand on the reaction rate, and we emphasize theelectron reservoir behavior of the gold nanoparticle catalysts.Therefore, we compare, under identical conditions, the rates ofthe homogeneous 4-NP reduction by excess NaBH4 catalyzed inwater by water-soluble AuNPs stabilized by citrate, polyethyleneglycol (PEG) thiolate of different lengths, and mono, bifunc-tional, polymeric and dendritic 1,2,3-triazoles terminated withPEG 400 or 2000 (Fig. 1). The catalytic 4-NP reduction is easilymonitored via UV-vis spectroscopy by the decrease of the strongadsorption of the 4-nitrophenolate anion at 400 nm, directlyleading to the rate constant.8 Isosbestic points in the spectra ofthe reacting mixtures demonstrate that no side reaction occurs.6c

The various stable AuNPs that are studied have sizes around3 nm, but larger AuNPs have also been examined for comparison(Table 1). The reduction rate has been observed, as in manypreceeding cases, to be pseudo-first order in the presence ofa large molar excess of NaBH4 (here 81 equiv. NaBH4 per mol4-NP). All the apparent kinetic constants are summarized inTable 1. In order to obtain data that are independent of thesurface, the rate constant (k1 = kapp/S) was also estimated

a Univ. Bordeaux, ISM, UMR 5515, 33405 Talence Cedex, France.

E-mail: [email protected] Facultad de Quımica de San Sebastian, Universidad del Paıs Vasco, Apdo. 1072,

20080 San Sebastian, Spainc Science and Technology on Surface Physics and Chemistry Laboratory, PO Box

718-35, Mianyang 621907, Sichuan, Chinad LCC UPR 241, 205 Route de Narbonne, 31077 Toulouse Cedex, France

† Electronic supplementary information (ESI) available: UV-vis spectra of thereduction of 4-NP by AuNPs, the corresponding plots of �ln(Ct/C0) as a functionof time and ln kapp vs. 1/T and AuNP synthesis and characterization. See DOI:10.1039/c4cc04454a

Received 11th June 2014,Accepted 14th July 2014

DOI: 10.1039/c4cc04454a

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normalized to the surface (S) with the assumption of the LHmechanistic model7b,16 (see Table 1). The results clearly showthat the best stabilizers, thiolates, provide the slowest AuNPcatalysts, followed by the citrate. Citrate-AuNPs are large, butthe comparison between thiolate-AuNPs and citrate-AuNPs of thesame size (diameter: 13.5 nm) shows that the citrate-AuNPs areslightly less slow catalysts than the thiolate-AuNPs. The similarityof results with these two types of ligands, however, reveals asimilarity of bonding to the AuNP, i.e. the citrate–AuNP bondshould reflect the coordination of citrate to the AuNP surface, asthe thiolate–AuNP bond, in spite of the difference in electro-negativity and polarizability between these two chalcogen atoms.

All the 1,2,3-triazole (trz)-stabilized AuNPs17 that are examinedhere are much more efficient catalysts than the AuNPs that are

stabilized by the formally anionic thiolate and citrate ligands.This reveals the considerable advantage, in terms of catalyticreaction rates, of neutral ligands such as triazoles that formonly weak coordination bonds with the AuNP surface giventhe impossibility of back bonding due to high-lying nitrogenp* orbitals. This weak bonding of the trz ligands, compared tothe stronger bonding of thiolate and citrate ligands, is respon-sible for their easy displacement from the AuNP surface bysubstrates. It is also striking that the induction time (t0), whichis usually directly connected to the surface rearrangementon the AuNP surface,7b,d is found only with the thiolate–AuNPsand citrate–AuNPs.

With these ligands, they are rather long, and by contrast,under these conditions, no induction times are found for allthe trz-AuNPs, confirming the very facile trz displacement bythe substrates. Among the trz-AuNPs, the dendrimer-stabilizedtrz-AuNPs are the less efficient catalysts. The polymer-stabilizedtrz-AuNPs are more efficient than the related dendrimer-stabilizedtrzAuNPs, but less so than the non-dendritic mono- and dis-ubstituted trz ligands. Thus, it appears that this order ofcatalytic efficiency of the trz-AuNPs is related to their stericeffects, the largest steric bulk being provided by the dendrimerframework that is bulkier than that of the polymer, whereasthe less bulky non-macromolecular trz ligands provide by farthe most efficient AuNP catalysts. These two AuNPs catalyzereactions that are so fast, under the same conditions as theother liganded AuNP catalysts, that they are too fast to observe ameasurable rate at 25 1C. It is possible to compare these twoAuNP catalysts, however, at lower temperatures. Then the mono-substituted trz-AuNPs appear to be more efficient than thebulkier disubstituted trz-AuNPs, as expected.

These results confirm that ligand displacement by substrateson the AuNP surfaces is the dominant feature of the mechanismthat involves restructuration of the surface. This is in accord withthe mechanism proposed by Ballauff and others following theLH kinetic model, which in particular also discards a leachingmechanism. With the series of trz-AuNPs, it also appears thatdiffusion of substrates towards the trz-AuNPs shows the filtra-tion effect of the dendrimer and polymer frameworks, becausethe order of reaction rates follows the order of steric bulk of thetrz-containing frameworks.

These data also confirm that the AuNPs play the role of aninner-sphere redox catalyst,18 because BH4

� transfers a hydrideto the AuNP surface, resulting in the formation of a covalentAu–H bond.7d This means that the negative charge is trans-ferred to the AuNP, as already suggested,7d,19 charge delocaliza-tion being largely facilitated by the low-lying conduction bandof the AuNPs. Indeed, addition of NaBH4 to the trz-AuNPs leadsto a color change corresponding to a blue shift of the surfaceplasmon band (SPB) that indicates the accumulation of severalnegative charges at the AuNP surface. Such a shift that has beenalready observed in particular for thiolate–AuNPs is shown herefor trz-AuNPs (Fig. 2).

This effect is accompanied by another effect, AuNP aggrega-tion, i.e. AuNP size increase (Ostwald ripening),20 upon NaBH4

addition, that is characterized by a red shift of the SPB.

Fig. 1 Various AuNPs under study. See the diameters (D) in Table 1. Theligands of 7 and 8 are respectively HS-PEG400 and HS-PEG2000.

Table 1 Catalytic AuNP activity in the reduction of 4-NP at 20 1C

AuNPsstabilized D (nm) kapp (s�1) t0 (s) k1 (L s�1 m�2) Ea (kJ mol�1)

1 3 Fasta 0 — 242 3 Fastb 0 — 293 6 1.4 � 10�2 0 4.3 � 10�2 374 6 6.7 � 10�3 0 2 � 10�2 405 3.5 7.5 � 10�3 0 1.2 � 10�2 —6 3.6 1.1 � 10�2 0 1.9 � 10�2 —7 3.5 7 � 10�4 900 1 � 10�3 1328 13.5 4 � 10�4 2100 3 � 10�3 —9 13.5 6 � 10�4 1200 4 � 10�4 —

a At 13 1C: kapp = 1.2 � 10�2 s�1, k1 = 1.7 � 10�2 L s�1 m�2. b At 13 1C:kapp = 9.6 � 10�3 s�1, k1 = 1.4 � 10�2 L s�1 m�2.


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After observation of the blue shift upon NaBH4 addition, thisred shift appears upon addition of more NaBH4. Gold precipi-tation then occurs when the amount of added NaBH4 becomestoo high (Fig. 2).

The accumulation of negative charges at the AuNP surfaceproceeds along with the Au–H bond formation until the resultingelectrostatic effect becomes too important. Along this line, electro-chemical experiments conducted by Quinn’s group by differentialpulse voltammetry using well-defined thiolate–Au147NPs showed aseries of 15 electrochemically and chemically reversible singleelectron transfer steps with Coulomb blockades (only limited bythe electrochemical window) leading to stable multiply chargedAuNPs.21 In the presence of nitrophenolate anions on the AuNPsurface, the electrochemical peak spacing that corresponds tothe quantized capacitance charging was found to be decreasedcompared to that obtained in its absence, which corresponds to asmall decrease of the AuNP capacitance.22 This shows that theAuNPs behave as ‘‘electron reservoirs’’.23 This role is efficientlyfulfilled by the AuNP redox catalysts for 4-NP reduction in thetransformation of inner-sphere single electron transfers fromborohydride ions to the surface into a multi-electron transfer.A multi-electron transfer is necessary for each 4-NP reduction to4-AP. The citrate anions, as hydrides, form coordination bondswith the AuNP surface involving partial charge transfer from theligand to the AuNP surface. Such a coordination with a tripod ofdihapto carboxylates that are coordinated to Au(111) is known,24

although the degree of AuNP–O covalency and charge transferhas not been addressed.

In conclusion, the role of the stabilizing ligands in the AuNPcatalyzed 4-NP reduction has been shown here to be crucial. Itis involved both in the restructuration at the AuNP surfacefollowing the LH kinetic model with considerable variation ofefficiency from ‘‘anionic’’ thiolate or citrate ligands to neutraltrz ligands and the steric or filtering effect25 of the substratethrough the bulk of the trz ligand framework. The difficulty inexchanging the thiolate ligands does not inhibit Suzuki–Miyaura cross carbon–carbon coupling reactions with analogousPdNPs,26a because a leaching mechanism is involved.26b On theother hand, it considerably slows down AuNP-catalyzed 4-NPreduction in contrast to the situation involving easily exchangedtrz ligands.17 The data and apparent accumulation of severalnegative charges in the AuNPs that occurs while the Au–H bondsform upon NaBH4 reaction emphasize the role of ‘‘electronreservoirs’’ of these redox catalysts. Well-known precedentsare found for instance in the role of PtNPs as redox catalysts

in water photosplitting.27 These findings should significantlycontribute to shed light on the surface mechanism and optimizethe design of effective catalysts for this intensively searched‘‘green’’ aqueous reaction.

Financial support from Gobierno Vasco (R. C., post-dotoralscholarship), Universidad del Paıs Vasco, Chinese ScholarshipCouncil (N. L., PhD grant), Ministere de la Recherche et de laTechnologie (C. D., PhD grant), the CNRS (S. G. delegation), andthe University of Bordeaux is gratefully acknowledged.

Notes and references1 (a) M.-C. Daniel and D. Astruc, Chem. Rev., 2004, 104, 293;

(b) X. Chen and S. S. Mao, Chem. Rev., 2007, 107, 2891; (c) Y. Xia,Y. Xiong, B. Lim and S. E. Skrabalak, Angew. Chem., Int. Ed., 2009,48, 60; (d) Gold Nanoparticles for Physics, Chemistry, Biology,ed. C. Louis and O. Pluchery, Imperial College Press, 2012.

2 (a) M. Haruta and M. Date, Appl. Catal., A, 2001, 222, 227; (b) F. Porta,L. Prati, M. Rossi and G. Scari, J. Catal., 2002, 210, 464; (c) M. Haruta,Nature, 2005, 437, 1098; (d) D. I. Enache, J. K. Edwards, P. Landon,B. Solsona-Espriu, A. F. Carley, A. A. Herzing, M. Watanabe, C. J. Kiely,D. W. Knight and G. J. Hutchings, Science, 2006, 311, 362;(e) C. D. Pina, E. Falletta, L. Prati and M. Rossi, Chem. Soc. Rev.,2008, 37, 2077; ( f ) A. Corma and H. Hermenegildo, Chem. Soc. Rev.,2008, 37, 2096; (g) A. Corma, A. Leyva-Perez and J. Maria Sabater,Chem. Rev., 2011, 111, 1657; (h) N. Dimitratos, J. A. Lopez-Sanchezand G. J. Hutchings, Chem. Sci., 2012, 3, 20.

3 (a) M. Haruta, T. Kobayashi, H. Sano and N. Yamada, Chem. Lett.,1987, 405; (b) M. Haruta, N. Yamada, T. Kobayashi and S. Ijima,J. Catal., 1989, 115, 301; (c) M. Haruta, Catal. Today, 1997, 36, 153;(d) M. Haruta, Angew. Chem., Int. Ed., 2014, 53, 52.

4 A. Corma and P. Serna, Science, 2006, 313, 332.5 (a) Y.-T. Woo and D. Y. Lai, Aromatic Amino and Nitro–Amino Com-

pounds and Their Halogenated Derivatives. Patty’s Toxicology, Wiley,New York, 2001, pp. 1–96; (b) S. C. Mitchell and R. H. Waring,Aminophenols, in Ullmann’s Encyclopedia of Industrial Chemistry,Wiley-VCH, 2002.

6 (a) A. Gangula, R. Podila, R. M. L. Karanam, C. Janardhana andA. M. Rao, Langmuir, 2011, 27, 15268–15274; (b) Y. Zhang, X. Cui,F. Shi and Y. Deng, Chem. Rev., 2012, 112, 2467–2505; (c) P. Herves,M. Perez-Lorenzo, L. M. Liz-Marzan, J. Dzubiella, Y. Lu andM. Ballauff, Chem. Soc. Rev., 2012, 41, 5577–5587; (d) N. C. Antonelsand R. Meijboom, Langmuir, 2013, 29, 13433–13442.

7 (a) K. Kuroda, T. Ishida and M. Haruta, J. Mol. Catal. A: Chem., 2009,298, 7–11; (b) S. Wunder, F. Polzer, Y. Lu and M. Ballauff, J. Phys.Chem. C, 2010, 114, 8814–8820; (c) S.-N. Wang, M.-C. Zhang andW. Q. Zhang, ACS Catal., 2011, 1, 207–211; (d) S. Wunder, Y. Lu,M. Albrecht and M. Ballauff, ACS Catal., 2011, 1, 908–916; (e) J. Li,C.-Y. Liu and Y. Liu, J. Mater. Chem., 2012, 22, 8426–8430;( f ) J. Zhang, D. Han, H. Zhang, M. Chaker, Y. Zhao and D. Ma,Chem. Commun., 2012, 48, 11510–11512; (g) A. Shivhare,S. J. Ambrose, H. Zhang, R. W. Purves and R. W. J. Scott, Chem.Commun., 2013, 49, 276–278; (h) P. Pachfule, S. Kandambeth,D. Dıaz and R. Banerjee, Chem. Commun., 2014, 50, 3169.

8 N. Pradhan, A. Pal and T. Pal, Colloids Surf., A, 2002, 196, 247–257.9 S. Panigrahi, S. Basu, S. Praharaj, S. Pande, S. Jana, A. Pal,

S. K. Ghosh and T. Pal, J. Phys. Chem. C, 2007, 111, 4596.10 S. Saha, A. Pal, S. Kundu, S. Basu and T. Pal, Langmuir, 2010, 26,

2885–2893.11 Y. Mei, G. Sharma, Y. Lu, M. Drechsler, T. Irgang, R. Kempe and

M. Ballauff, Langmuir, 2005, 21, 12229–12234.12 (a) W. Liu, X. Yang and W. Huang, J. Colloid Interface Sci., 2006,

304, 160; (b) W. Liu, X. Yang and L. Xie, J. Colloid Interface Sci., 2007,313, 494.

13 M. M. Nigra, J.-M. Ha and A. Katz, Catal. Sci. Technol., 2013, 3, 2976–2983.14 H. Zhang, X. Li and G. Chen, J. Mater. Chem., 2009, 19, 8223–8231.15 M. Dasog, W. Hou and R. W. J. Scott, Chem. Commun., 2011, 47, 8569–8571.16 S. Panigrahi, S. Basu, S. Praharaj, S. Pande, S. Jana and A. Pal,

J. Phys. Chem. C, 2007, 111, 4596–4605.17 (a) D. Astruc, L. Liang, A. Rapakousiou and J. Ruiz, Acc. Chem. Res.,

2012, 45, 630–640; (b) D. Astruc, Nat. Chem., 2012, 4, 255–267.

Fig. 2 Trz-AuNPs 3 after addition from left to right of 0, 0.1, 0.2, 0.3, 0.4,0.5, 1, 1.5 and 2 equiv. of NaBH4 per gold atom. The blue shift upon NaBH4

addition is emphasized by values of lmax (SPB).

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18 (a) H. Taube, H. Myers and R. L. Rich, J. Am. Chem. Soc., 1953, 75, 4118;(b) J.-M. Saveant, Acc. Chem. Res., 1980, 13, 25; (c) J.-M. Lehn, Science, 1985,227, 849; (d) D. Astruc, Electron Transfer and Radical Processes in Transition-Metal Chemistry, VCH, New York, 1995, ch. 7, pp. 479–506.

19 (a) P. Mulvaney, Langmuir, 1996, 12, 788–800; (b) M. Brust andC. Kiely, Colloids Surf., A, 2002, 202, 175–186.

20 (a) W. Ostwald, Z. Phys. Chem., 1897, 22, 289–330; (b) N. G. Bastus,J. Comenge and V. Puntes, Langmuir, 2011, 27, 11098–11105.

21 B. M. Quinn, P. Lijeroth, V. Ruiz, T. Laaksonen and K. Kontturi,J. Am. Chem. Soc., 2003, 125, 6644–6645.

22 S. Chen and K. Huang, Langmuir, 2000, 16, 2014–2018.23 (a) J.-R. Hamon, D. Astruc and P. Michaud, J. Am. Chem. Soc., 1981,

103, 758–766; (b) C. Ornelas, J. Ruiz, C. Belin and D. Astruc, J. Am.Chem. Soc., 2009, 131, 590–601.

24 (a) S. Floate, M. Hosseini, M. R. Arshadi, D. Ritson, K. L. Young andR. J. Nichols, J. Electroanal. Chem., 2003, 542, 67–71; (b) Y. Lin,G.-B. Pan, G.-J. Su, X.-H. Fang, L.-J. Wan and C.-L. Bai, Langmuir,2003, 19, 10000–10003.

25 (a) R. M. Crooks, M. Zhao, L. Sun, V. Chechik and L. K. Yeung, Acc.Chem. Res., 2001, 34, 181–190; (b) V. S. Myers, M. W. Weier,E. V. Carino, D. F. Yancey and R. M. Crooks, Chem. Sci., 2011, 2,1632–1646.

26 (a) F. Lu, J. Ruiz and D. Astruc, Tetrahedron Lett., 2004, 9443–9445;(b) A. Diallo, C. Ornelas, L. Salmon, J. Ruiz and D. Astruc, Angew.Chem., Int. Ed., 2007, 46, 8644–8648.

27 (a) J.-M. Lehn and J.-P. Sauvage, Nouv. J. Chim., 1977, 1,449–451; (b) A. Hagfeldt and M. Gratzel, Chem. Rev., 1995, 95,49–68.


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Chapter 5

A Bibliographical Review of Anisotropic AuNPs and their

Applications

91

5.1 Introduction

The last chapter of this thesis is a review article that focuses on the synthesis, properties and

applications of anisotropic AuNPs. Over 420 references are involved in this bibliographical

work and more than 150 of them are in last 5 years. The investigations of anisotropic shapes

and morphologies of AuNPs in particular have increased during the last years. Such syntheses

of anisotropic AuNPs have attracted interest because the structural, optical, electronic,

magnetic, and catalytic properties are different from, and most often superior to, those of

spherical AuNPs and have potential applications. The recent development of preparation and

applications of anisotropic AuNPs in catalysis, sensing, theranostics and drug delivery as well

as the toxicity of AuNPs in biological system was reviewed therein with emphasis on

historical aspects as well as recent literature reports. The preparation of this review article was

essentially organized under the direction of Prof. Didier Astruc and Dr Pengxiang Zhao.

92

NanoparticlesDOI: 10.1002/anie.201300441

Anisotropic Gold Nanoparticles: Synthesis, Properties,Applications, and ToxicityNa Li, Pengxiang Zhao,* and Didier Astruc*

AngewandteChemie

Keywords:anisotropy · gold nanoparticles ·nanocatalysis · nanomedicine ·plasmon

Dedicated to Professor Henri Bouas-Laurenton the occasion of his 80th birthday

.AngewandteReviews P. Zhao, D. Astruc, and N. Li

1756 www.angewandte.org � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2014, 53, 1756 – 1789

93

http://www.angewandte.org

1. Introduction

Although nanogold represents one of the most remark-able areas of modern nanoscience and nanotechnology,spherical gold nanoparticles (AuNPs) have been known formillenia. Illustratory examples from history are the Lycurguscup[1] and the Faraday publication.[2] Modern milestones fromthe second half of the 20th century are the Turkevitch[3] andSchiffrin–Brust synthetic methods,[4] Schmid�s magic numberof gold atoms in stable colloids,[5] and Haruta�s discovery ofthe efficient oxidation of CO by O2 at low temperatures bysmall (< 5 nm) AuNPs.[6] The outstanding properties ofAuNPs are related to their easy stabilization and handlingthrough thiolate ligands (Giersig and Mulvaney)[7] and thequantum size effect that is involved when the de Brogliewavelength of the valence electrons is on the same order asthe size of the particle itself.[8] The free mobile electrons aretrapped in a quantum box (the particle) and show thecollective oscillation frequency of the plasman resonance,thus giving rise to the well-known plasmon absorption near530 nm for 5–20 nm spherical AuNPs that causes the deep-redcolor and provides a variety of optical applications.[9–11] Theresulting single-electron transitions result in the observedCoulomb blockade and, for example, the generation of up to15 high-resolution quantized double-layer chargings in hex-anethiol-Au38 particles.[12] This Coulomb blockade can lead toapplications as transistors, switches, electrometers, oscillators,and sensors. Finally, the large surface/volume ratio of AuNPsresults in the AuNPs having an extraordinary reactivity thatprovides a large variety of catalytic applications.[13–16]

Scientists already noticed the existence of anisotropicAuNPs at the beginning of the 20th century. In his book thatwas published in 1909, Zsimondy noted that gold particles“are not necessarily spherical when their size is 40 nm (mm) or

below”. He also discovered different colored anisotropic goldparticles. Zsimondy invented the ultramicroscope, whichallowed him to visualize the shapes of gold particles, and hereceived the 1925 Nobel Prize for “his demonstration of theheterogeneous nature of colloidal solutions and for themethods he used”. He observed that gold often crystallizedin a leaflike form with six sides.[17] In a well-known seminalarticle in 1908, Mie theoretically described the absorption andscattering to explain the colors (surface plasmon band) ofgold particles. Although his theory applied only to sphericalAuNPs, Mie attributed the deviations in some cases tononspherical gold particles.[8] In 1912 Gans extended Mie�stheory and showed that aspherical particles absorb at a longerwavelength than spherical particles of comparable size.[18]

Some years later, Svedberg, who discovered that particlescould be separated with an ultracentrifuge, described experi-ments in which X-ray scattering was used to determine size-and shape-dependent properties of gold particles,[19] and hewas awarded the 1926 Nobel Prize for “his work on dispersesystems”. Following Einstein�s description of Brownianmotion as a diffusion process and development of a viscosityrelationship in 1905 for dilute solutions of spherical parti-cles,[20] in 1922 Jefferey extended the hydrodynamic calcu-

Anisotropic gold nanoparticles (AuNPs) have attracted the interest ofscientists for over a century, but research in this field has considerablyaccelerated since 2000 with the synthesis of numerous 1D, 2D, and 3Dshapes as well as hollow AuNP structures. The anisotropy of thesenonspherical, hollow, and nanoshell AuNP structures is the source ofthe plasmon absorption in the visible region as well as in the near-infrared (NIR) region. This NIR absorption is especially sensitive tothe AuNP shape and medium and can be shifted towards the part ofthe NIR region in which living tissue shows minimum absorption. Thishas led to crucial applications in medical diagnostics and therapy(“theranostics”), especially with Au nanoshells, nanorods, hollownanospheres, and nanocubes. In addition, Au nanowires (AuNWs) canbe synthesized with longitudinal dimensions of several tens of micro-meters and can serve as plasmon waveguides for sophisticated opticaldevices. The application of anisotropic AuNPs has rapidly spread tooptical, biomedical, and catalytic areas. In this Review, a briefhistorical survey is given, followed by a summary of the syntheticmodes, variety of shapes, applications, and toxicity issues of this fast-growing class of nanomaterials.

From the Contents

1. Introduction 1757

2. Pioneering Syntheses ofAnisotropic AuNPs 1758

3. Methods and Techniques for theSynthesis of Anisotropic AuNPs 1759

4. The Morphology of AuNPs 1765

5. Optical Plasmonic Properties ofAnisotropic AuNPs: SPR andSERS 1773

6. Applications of AnisotropicAuNPs 1774

7. Toxicology 1781

8. Conclusion and Outlook 1782

[*] N. Li, Dr. P. Zhao, Prof. D. AstrucISM, UMR CNRS 5255, Univ. Bordeaux33405 Talence Cedex (France)E-mail: [email protected]

Dr. P. ZhaoScience and Technology on Surface Physics andChemistry LaboratoryP.O. Box 718-35, Mianyang 621907, Sichuan (China)E-mail: [email protected]

Gold NanoparticlesAngewandte

Chemie

1757Angew. Chem. Int. Ed. 2014, 53, 1756 – 1789 � 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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lations of the viscosity increase to solutions containingellipsoidal particles.[21]

The investigations of anisotropic shapes and morpholo-gies of AuNPs in particular have increased during the lastdecade, most often relying on the development of seed-mediated synthetic methods. In this respect, AuNPs areprobably the class of nanoparticles that has provided thelargest variety of shapes and has been studied the most. Suchsyntheses of anisotropic AuNPs have attracted interestbecause the structural, optical, electronic, magnetic, andcatalytic properties are different from, and most oftensuperior to, those of spherical AuNPs and have potentialapplications. In particular, compared to spherical (nonhollow)AuNPs, the main attractive feature of most anisotropic andhollow AuNPs is probably the appearance of a plasmon bandin the near-infrared (NIR) region, where absorption by tissuesis low. Therefore, the “water window” between 800 nm and1300 nm can be used for medicinal diagnostics and photo-thermal therapy (“theranostics”).[22–25] Other noteworthyproperties of nonspherical AuNPs are the enhancement ofthe SERS effect[26] and the catalytic properties of smallAuNPs (< 5 nm) on textured surfaces.[12–21] In this Review, wehighlight the synthesis, properties, and applications of thevarious shapes of AuNPs, with an emphasis on nonsphericaland hollow AuNPs.

2. Pioneering Syntheses of Anisotropic AuNPs

AuNPs with hexagonal (icosahedral) and pentagonal(decahedral) profiles were synthesized by vapor depositionmethods in 1979[27] and 1981.[28] In 1989, Wiesner and Wokaunreported the first example of rod-shaped AuNPs by adding Auseeds to solutions of HAuCl4.

[29] The Au seeds were formed byreduction of HAuCl4 with phosphorus (as in Faraday�ssynthesis),[2] and then gold nanorods (AuNRs) were grownby reduction of AuIII with H2O2. Modern concepts of seed-mediated synthesis were established by the Murphy researchgroup at the beginning of the 2000s. They reported thesynthesis of AuNRs by the addition of citrate-capped AuNPsto an AuI growth solution generated by the reduction of AuIII

with ascorbic acid in the presence of cetyltrimethylammo-nium bromide (CTAB) and Ag+ (Figure 1).[30] The seed-growth method has become established as the most efficientand popular one to synthesize specific shapes in high

yields.[30,31] Bulk-solution methods have been reported toproduce nanocrystals with multiple shapes, but with a lowyield of a specific shape.[32]

The first physical synthetic method used to make AuNRswas the photochemical reduction of auric acid reported in1995 by Esumi et al.[33] In this method, AuIII ions bound torodlike cationic micelle surfactants to form ion pairs andwhen excited by UV light are reduced to Au0. A two-stepprocess was proposed, involving the aggregation of metalnuclei to form primary particles followed by aggregation of

Li Na was born in Ningxia province, China.She studied chemical engineering with Prof.Shiqiang Yan at Lanzhou University in Lanz-hou, China. She then joined the researchgroup of Prof. Didier Astruc at the Universityof Bordeaux, France, in 2011, for PhD study.Her research interests are the functionaliza-tion and engineering of gold nanoparticlesfor applications in nanomedicine.

Pengxiang Zhao was born near Chengdu,China. He studied chemistry and engineeringwith Prof. Wuyong Chen at Sichuan Univer-sity in Chengdu. He completed his PhD in2012 in the group of Prof. Didier Astruc atthe University of Bordeaux on the applica-tion of gold nanoparticles for docetaxeldelivery. He is currently an independentresearcher position at the Science and Tech-nology on Surface Physics and ChemistryLaboratory at Mianyang, Sichuan, China.His research interests concern gold nano-particles.

Figure 1. Seed-mediated synthesis of AuNRs by Murphy and co-work-ers. From Ref. [30]. Copyright 2001 Wiley-VCH.

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these particles to form rod-shaped particles resulting from thestabilization of a specific crystal face by surfactant micelles.[34]

Another early method to form AuNRs was the electro-chemical reduction method, which was developed by theWang research group in the late 1990s.[35, 36] It was later shownthat CTAB was crucial in this method for the high-yieldingformation of AuNRs. In 2001 the El-Sayed research groupalready noted that CTAB induced the formation of a bilayerstructure on the longitudinal surface of AuNRs, with thetrimethylammonium head groups of the primary layer facingthe AuNR surface.[37]

3. Methods and Techniques for the Synthesis ofAnisotropic AuNPs

A large variety of bottom-up methods and techniquesinvolving templates or capping agents have been used duringthe last decade to synthesize many types of anisotropic orhollow AuNPs. However, the versatile and more-complexseed-mediated method has become dominant, especially forthe synthesis of AuNRs. Two or several of these methods areoften combined (in particular, a template method withanother method) for the synthesis of anisotropic AuNPs.Supramolecular chemistry also provides a means of assem-bling AuNPs. Top-down routes (mostly lithography) are muchrarer, but are sometimes combined with a bottom-uptechnique.

3.1. Simple Chemical Reduction of AuIII

Cetyltrimethylammonium bromide (CTAB) is a fre-quently used surfactant for the structuration of nonsphericalAuNPs, and the role of its purity and mechanism of actionhave been debated.[22–24] Forms of silver, either as AgNO3 orAg nanoplates,[38, 39] are also often used because of the key rolesilver plays in anisotropic growth.[40] For example, theaddition of ascorbic acid to a mixture of CTAB, silverplates, and HAuCl4 reduced orange AuIII to almost colorlessAuI. The rapid addition of NaOH then induced the formationof anisotropic AuNPs, whose color changed from pale blue todark red within one day. The TEM images showed theformation of various shapes, including spheres (40 %), tad-pole-like monopods (25 %), L-shaped, I-shaped, and V-shaped bipods (23 %), T-shaped, Y-shaped, and regular

triangular tripods (9%), and cross-like tetrapods (3 %; fccstructures, no incorporation of silver; Figure 2). NaOH playsa role in the branching of the NPs, as the use of NaBH4 insteadonly yields spherical and rod-shaped AuNPs. The function ofthe silver plates is only to improve the yield, while thepresence of Ag+ is detrimental.[40] This example clearly showsthe use of structuring agents for the formation of anisotropicAuNPs, but also the need for sophistication to improve theyields.[41]

3.2. The Seed-Mediated Method

Compared with the in situ synthesis, the seed-growthmethod enlarges the particles step by step, so that it becomeseasier to control the sizes and shapes of the AuNPs. Thus, thisprocedure is widely used in the most recent size- and shape-controlled AuNPs syntheses.

The seed growth usually takes place over two steps. In thefirst step, small AuNP seeds are prepared. In the second step,the seeds are added to a “growth” solution containing HAuCl4

and the stabilizing (capping) and reducing agents, and thenewly reduced Au0 then grows on the seed surface to formlarge AuNPs. The reducing agents used in the second step arealways mild ones that reduce AuIII to Au0 only in the presenceof Au seeds as catalysts (in the absence of the Au0 catalyst,ascorbic acid only reduces AuIII to AuI in acidic medium).Thus, the newly reduced Au0 can only assemble on the surfaceof the Au seeds, and no nucleation of new particles occurs insolution. Moreover, as a consequence of the use of a mildreducing agent, the second step is much slower than the firstone, and it can be repeated to continue the growth process.

In the course of the seed-growth synthesis of AuNPs, thesize, shape, and surface properties are controlled by theamount and nature of the reducing agent and stabilizer, aswell as their ratio to the Au precursor.

A two-step method was devised by Zsigmondy, whocombined his technique with Faraday�s method, which had

Didier Astruc was born in Versailles andstudied in Rennes, where he completed hisPhD with Prof. R. Dabard. After postdoc-toral research at MIT in Cambridge withProf. R. R. Schrock he took sabbatical leaveat the University of California, Berkeley withProf. K. P. C. Vollhardt. He is a full Professorat the University of Bordeaux anda Member of the Institut Universitaire deFrance. His research interests are inorganicchemistry and nanomaterials, including cat-alysis, sensors, molecular electronics, andnanomedicine.

Figure 2. TEM image of branched gold nanocrystals and the corre-sponding electron diffraction pattern. From Ref. [40]. Copyright 2003American Chemical Society.


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remained ignored for 40 years before Zsimondy took notice.Zsimondy�s two-phase method was published in his book in1909,[42] and it is this two-step method that was much laterrenamed as the seed-growth method.

In the seminal procedure by the Murphy research groupfor the formation of AuNRs, HAuCl4 is reduced to HAuCl2 byascorbic acid in the presence of CTAB and AgNO3, thencitrate-capped spherical AuNPs are added to this HAuCl2

solution.[30] These spherical AuNPs catalyze the reduction ofAuI to Au0 by ascorbic acid. A three-step procedure in theabsence of AgNO3 allows longer AuNRs with aspect ratios(length/width) of up to 25 to be prepared. The AuNRs formedin the first stage serve as seeds for a second growth, and thelatter are in turn used as seeds for the third growth(Figure 3).[41–45] The yield and monodispersity are improvedby addition of nitric acid to the third seeding growthsolution.[46]

Other modifications from the El-Sayed research group,which improved the yield and polydispersity of the AuNRs,were the replacement of sodium citrate by the stronger CTABstabilizer during the formation of the seeds and the use ofAgNO3 to control the aspect ratio of the AuNRs (Figure 4).[47]

In this approach, the seeds are formed upon reduction ofHAuCl4 with NaBH4 at 0 8C in the presence of CTABfollowed by the addition of AgNO3; this seed solution is thenadded to HAuCl2 previously formed in the presence of CTAB.The AuNRs are obtained in 99% yield with aspect ratiosbetween 1.5 and 4.5 by using this method. Higher aspect ratiosup to 10 or 20 are obtained upon addition of a cosurfactant(benzylhexadecylammonium chloride (BDAC)[47] or PluronicF-127[48]) to the original growth solution and changing theAgNO3 concentration. Even higher aspect ratios of up to 70have been obtained by a fourth addition of growth solution.[42]

Optimization studies have clearly shown that many param-eters play a role in influencing the yield, shape, anddispersity.[41–55] In particular, impurities in the various com-mercial CTAB sources greatly affect the yield, dispersity, and

aspect ratio. Traces of iodide, in particular, have a significantaffect, because it binds selectively to the Au(111) facet, thusleading to the AuNRs.[54,55]

Two AuNR growth mechanisms have been pro-posed[45, 56,57] and discussed[22,56–59] (Scheme 1). They involvea growth that is governed either by preferential binding of thehead group of a cationic surfactant to the {100} face of theAuNP seed (rather than the less-favored rod end)[45, 56] or bythe electric field of the double layer between the positivelycharged seed and negatively charged AuCl2

� on the CTABmicelle (Scheme 1a,b).[57] Studies of the role of Ag+ haveshown that single-crystalline CTAB-capped seeds lead tosingle-crystalline AuNRs with {110} faces on the side and{100} faces on the end, whereas multiply twinned crystallinecitrate-capped seeds grow into multiply twinned structures.(The role of Ag+ and the effect of an under depositionpotential (UPD) are discussed in Section 3.8.) Ag depositionon the {110} side of the rod is faster than on the {100} ends, andconsequently seeds grow into rods.[50, 60] Murphy and co-workers have also proposed a hybrid mechanism involvingdiffusion of AuCl2

� on the CTAB micelles to CTAB-cappedseed spheres resulting from electric-field interactions. Sub-sequently, silver ions preferentially deposit onto the {110}facets, on which CTAB is preferentially bound, therebyresulting in particle growth into AuNRs along the [110]direction (Scheme 1c).[60] The critical role of the bromidecounterion of CTAB or NaBr in the formation of AuNRs hasbeen illustrated by the observation that there is a critical[Br�]/[Au3+] ratio around 200 that leads to the maximumaspect ratio of the AuNRs, beyond which Br� is a poison.[61]

3.3. Photochemistry

Photochemistry is also a convenient method to generateanisotropic AuNPs. UV light can reduce HAuCl4 to formAuNRs when a cationic micelle with a rod shape is bound toHAuCl4. The photoreduction to Au0 atoms is followed in thiscase by controlled aggregation.[33,34] The micelle surfactant

Figure 3. Three-step seed-mediated growth approach for making goldand silver nanorods with a controlled aspect ratio. From Ref. [45].Copyright 2005 American Chemical Society.

Figure 4. TEM images of gold NRs with different positions of theplasmon bands. Scale bar = 50 nm. From Ref. [47]. Copyright 2003American Chemical Society.

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stabilizes a specific crystal face, as in the seed-growthprocedure, thereby leading to AuNRs.[34,62–64] The presenceof NaCl increases the AuNR aspect ratio and yield.[34] As inthe seed-growth process, Ag+ also improves the aspect ratioand yield.[63] UV light with a wavelength of 300 nm is optimalfor these properties.[64] The method largely benefits from theimprovement observed in the seed-growth method, namelythe use of sodium borate, AgNO3, ascorbic acid, and CTAB;the advantage here is that the AuNRs are obtained in highyield in a single step,[65, 66] unlike in the seed-growth methoditself. The amount of sodium borate[65] and the temperature[66]

can alter the aspect ratio. The photochemical routehas also been performed in the presence of poly-(vinylpyrrolidone) (PVP) and ethylene glycol,[67] orTiO2 colloids.[68–70] For example, the Zhang researchgroup synthesized platelet-like AuNRs with an asym-metric five-twinned structure as well as, in combina-tion with seed growth, six-star AuNPs. TiO2 servesboth as a photocatalyst and a stabilizer of the AuNPs(Scheme 2).[70] Graphene oxide was also used toassemble Au nanodots to patterned chains.[71]

Although the photochemical method requires a longreaction time on the order of 30 h,[62, 63] this period canbe reduced to 30 min if HAuCl4 is first reduced byascorbic acid, and then exposed to UV irradiation inthe presence of AgNO3.

[72–74] The use of ketyl radicalswith a short triplet lifespan (generated from 4-(2-hydroxyethyloxy)phenyl(2-hydroxy-2-propyl)ketone,known as Irgacure-2959 (I-2959)) results in an espe-cially efficient reaction, and causes the rapid reduc-tion of AuIII to Au0 and formation of AuNRs uponirradiation at 300 nm.[75–77]

3.4. Electrochemistry

The electrochemical method to produce AuNPswas first reported by Svedberg in 1921.[78] In themodern electrochemical technique developed byWang and co-workers, an Au plate anode and a Ptplate cathode were immersed in an electrolyte con-taining CTAB and tetradodecylammonium bromide(TOAB) as a cosurfactant. Electrolytic oxidation ofthe Au anode then formed AuIIIBr4

� bound to theCTAB micelle, which then underwent migration tothe cathode and cathodic reduction to Au0. AuNRswere formed with aspect ratios that were controlledby the presence of Ag+ cations produced by the redoxreaction between AuIII and an Ag plate. The latter wasgradually inserted into the solution. The AuNRs wereseparated from the cathode by ultrasonification.[35,36]

This method produces AuNRs with aspect ratios of 3–7 that are single crystals without stacking faults, twins,or dislocations, as shown by HRTEM and diffractionstudies (Figure 5).[79] Gold nanorods have also beenelectrochemically deposited inside porous mem-branes.[80–82] Although the electrochemical method isone of the pioneering methods for the synthesis ofAuNPs, including anisotropic AuNPs, it remains

actively investigated because of its simplicity, efficiency, andapplicability.[83,84]

3.5. Sonochemistry

Ultrasound has become a useful tool for the synthesis ofvery small nanoparticles, because the effects derived fromacoustic cavitation drives chemical reactions under extremeconditions. This method, however, yields nanoparticles withmultiple shapes and a wide size distribution.[85] This problem

Scheme 1. Mechanisms for the formation of AuNRs. a,c) Reproduced fromRefs. [45] and [60] with permission. Copyright 2005 American Chemical Societyand 2006 American Chemical Society, respectively. b) Reproduced from Ref. [57]with permission. Copyright 2004 Wiley-VCH.


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is circumvented by the use of surfactants, as in other methods,and added alcohols also serve to control the particle shapeand size.[86, 87] For example, in the presence of a-d-glucose, themajor reactions in the sonolysis process of aqueous HAuCl4

follow Equations (1)–(4).[88, 89]

H2O! HC þOHC ð1Þ

sugar! pyrolysis radicals ð2Þ

AuIII þ reducing radicals! Au0 ð3Þ

n Au0 ! AuNP ð4Þ

Han and co-workers have syn-thesized single-crystalline flexibleAu nanobelts with a width of 30–50 nm and a length of severalmicrometers with this method(Figure 6).[90]

3.6. Templates

The synthesis of nonsphericalAuNPs is often driven by the use oftemplates that have a complemen-tary morphology to the AuNPs.[24]

The templates are solid substrates,such as porous membranes,[91,92]

mesoporous silica,[93] Si(100) wafers,[91] pyrolytic graphite,[94]

polymers[92, 95] (including block copolymers),[96] nanoparti-cles,[97, 92] carbon nanotubes,[98] inorganic clusters such asLiMo3Se3,

[99] surfactants organized in micelles,[35,42, 43, 100] orLangmuir–Blodgett films,[101] as well as biomolecules such asplant extracts,[102, 103] microorganisms,[104] polypeptides, andDNA.[105]

The essential role of the surfactant for the growth ofanisotropic AuNPs (AuNRs) was already detailed in Sec-tion 3.2. Mulvaney proposed the electric-field model, accord-ing to which the rods grow because of a higher rate of mass

Scheme 2. TiO2-catalyzed photochemical synthesis of a) Au platelet-like nanorods and b) six-starAuNPs. Reprinted from Ref. [70] with permission. Copyright 2010 American Chemical Society.

Figure 5. HRTEM images recorded from a [110]-oriented Au nanorodand the corresponding positions of the projected atom rows. FromRef. [79]. Copyright 2000 American Chemical Society.

Figure 6. a,b) TEM images, c) HRTEM image, d) SAED pattern, ande) XRD pattern of gold nanobelts synthesized by a sonochemicalmethod. From Ref. [90]. Copyright 2006 Wiley-VCH.

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transfer of gold cations to the tips as a result of theasymmetric double layer around the rod. The CTAB bilayerconfers a positive charge onto the Au rods, and the CTAB alsobinds AuI ions (produced by reduction of AuIII by ascorbicacid), which retards its transfer to the Au rods. The surfacepotential decays more rapidly at the tips because of theircurvature, thereby explaining why the rod tips grow fasterthan the lateral facets.[106] Other models have been pro-posed[57, 106,107] and discussed,[58] in particular in terms of stericand chemical factors to direct preferential interactionsbetween the cationic head group of CTAB and the growthsites.[107]

Templates are frequently also used in combination withphotochemistry, electrochemistry, and sonochemistry for thesynthesis of anisotropic AuNPs. The template structuredirects anisotropic growth by selective adsorption on specificcrystallographic sites of the metal. This has been used incombination with surfactants, for example, with poly(vinyl-pyrolidone) (PVP). PVP also serves as a reductant, forexample, for the synthesis of Au plates.[108,109] The reducingability of PVP is due to its hydroxy termini and is dramaticallyenhanced in the presence of water bound to the PVP. Thus,kinetic control of the AuNP growth depends on the solventand nature of the reductant and yields various morphologiesthat can sometimes be made selectively.[110]

One of the most successful nanomaterials for the synthesisof AuNPs is silica nanospheres, which serve as templatingcores around which Au layers can be coated. This powerfulstrategy was reported by Halas and co-workers, and allows thesize of the Au nanoshell and the thickness of the nanogoldlayer to be controlled at will by changing the reaction timeand the concentration of the plating solution (Figure 7).[111–114]

3.7. Galvanic Replacement

Galvanic replacement is a very simple approach in whichgold cations in the plating bath are spontaneously (i.e. ina thermodynamically and kinetically favorable reaction)reduced by a metal without external current sources.[115–130]

The driving force is the difference in the redox potentialbetween the reducing metal and the Au3+/Au system. Thismethod was proposed and exploited by Crooks and co-workers to prepare AuNPs encapsulated in dendrimers bymetal exchange between dendrimer-encapsulated CuNPs andAuIII from HAuCl4.

[115, 122, 129] Au@Pt dendrimer-encapsulated

nanoparticles have also recently been fabricated in thisway.[129] The driving force for exchange is the lower redoxpotential of CuII/Cu0 (E8= 0.340 V versus NHE) compared toAuCl4

�/Au0 (E8= 0.99 V versus NHE).The reducing Ag metal (E8Ag/Ag+ = 0.80 V versus NHE;

E8Ag/AgCl = 0.22 V versus NHE) in the form of an Ag nano-structure has been used extensively as a sacrificial template, inparticular by the Xia research group[116, 118, 121,123, 124, 125] tofabricate hollow Au nanostructures. Gold nanocages(AuNCs) have been synthesized in this way starting fromAg nanocubes and an aqueous HAuCl4 solution. Thesereactions proceed in two steps: 1) formation of seamlesshollow structures with the walls made of Au-Ag alloys bygalvanic replacement of Ag and AuIII by Ag-Au alloying and2) formation of hollow structures with porous walls bydealloying.[123]

Aluminum foil is also often used as the metal source,because it is inexpensive and has a very low oxidationpotential [E8(Al3+/Al=�1.67 V versus SHE] and can thusreduce many transition-metal cations through an exergonicreaction [Eq. (5)]:

AlþAuIII ! AlIII þAu0 ð5Þ

This reaction is marred, however, by the thin layer ofalumina Al2O3 on the aluminum metal surface. The use of themetal chloride (AuCl3 or HAuCl4) in a high concentration[131]

together with prior removal of the aluminum oxide withNaOH[132] can circumvent this difficulty. In the presence ofchloride anions, oxidized aluminum cations form solubletetrachloroaluminate salts that do not prevent the depositionof AuNPs. Fluoride forms stronger bonds than chloride, andNaF and NH4F have also been used to dissolve the aluminalayer to allow the galvanic displacement through AlIII

dissolution [Eq. (6)].

Al2O3 þ 6 Hþ þ 12 F� ! 2 AlF63� þ 3 H2O½133� ð6Þ

This galvanic technique does not require the presence oftemplate, surfactant, or stabilizer and is conducted at roomtemperature. The use of Al foil, NaF, and HAuCl4 for thegalvanic replacement of Al by AuIII results in Au dendrites.[133]

3.8. The Effect of Ag+ Salts and Underpotential Deposition

A crucial finding by Murphy and co-workers was thefavorable role of AgNO3 in the controlled formation of longAuNRs.[41] By varying the parameters and using the seed-growth procedure it was possible to direct the aspect ratio,optimize the yield (up to 50%), and obtain long AuNRs(Figure 8).[60, 134,135] Nikoobahkt and El-Sayed furtherimproved the yield of the AuNRs up to 99 % by usingCTAB[31] instead of the citrate-capped seeds used by Murphyand co-workers. The seed-mediated growth was much slowerin the presence of CTAB. However, along with AuNRformation, the longitudinal surface plasmon band (SPB) isred-shifted in the absence of AgNO3 (increase in the aspectratio, that is, AuNR growth at the tips), whereas in the

Figure 7. a) Formation of a nanoshell around a silica nanoparticlecore, and b) the TEM image of an Au nanoshell. From Ref. [111].Copyright 2002 American Chemical Society.


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presence of AgNO3 it is blue-shifted after 2 minutes. Thus, thelength and aspect ratio quickly increases during this shorttime, then slowly decreases.[135] AgNO3 immediately formsAgBr in the presence of CTAB. It was proposed that Ag+ isnot reduced at acidic pH values, (typically pH 3) because theascorbic acid reductant is too weak, as confirmed by the lackof the AgNP SPB at 400 nm (AgNPs only form at a basicpH value, typically pH 8). Consequently, Ag+ forms ion pairs[AgBr] that decrease the charge density on the Br� ion andthe repulsion between head groups on the AuNR surface, thusinducing CTAB elongation.[31] It was alternatively argued thatthe adsorption of [AgBr] on the Au nanocrystal facets slowsdown the reduction of the gold ion and induces the growth ofsingle-crystalline AuNR.[56]

An underpotential deposition of Ag onto the AuNR hasbeen invoked to explain the dramatic role of AgNO3 on thegrowth of the AuNRs.[50] Underpotential deposition is thedeposition of a metal adlayer onto a metal surface (Au) belowthe Nerst reduction potential (up to 0.5 to 0.9 V) of the metalions (AgNO3/Ag), as a result of strong bonding interactionsbetween the two metals in the adsorbed layer.[10, 139] It appearsthat Ag+ is essentially not reduced, although CIP analysis hasshown the presence of Ag at up to 4.5%.[60] However, it is theAg+ adsorption on AuNR (in the form of AgBr) thatconsiderably slows down the growth of AuNRs. This ratedecrease is selective and less efficient on the tips because ofpoorer coverage, which results in the formation of AuNRs.

The role of Ag+ is not only crucial for the formation ofAuNRs, but also for other shapes of AuNPs, as recently shownby several research groups. High-index concave cubic Aunanocrystals with {720} surfaces have indeed been synthesizedby Mirkin and co-workers by the reduction of HAuCl4 withascorbic acid in the presence of a chloride-containingsurfactant and small amounts of AgNO3.

[137] Ag+ has alsobeen used for the synthesis of {730}-faceted bipyramids[50,138]

and high-index AuNRs.[31, 139–142]

3.9. Supramolecular Arrangements

Supramolecular chemistry[143, 144] is another generalmethod for assembling spherical[16] or nonspherical AuNPs(in particular AuNRs[59]) into new nonspherical AuNPs in theform of liquid crystals, supracrystals, or supported orderedarrays.[145–148]

Various examples will be described in the following. Largealigned structures of AuNRs were obtained upon dryinga drop of AuNR solution on a copper TEM grid in air with thegrid immersed halfway.[149] AuNRs pack together upon dryinga rod–sphere mixture on a silicon wafer in a water vaporatmosphere.[150] AuNRs linearly align in a head-to-tail fashionafter centrifugation, but a 2D parallel assembly is obtainedafter three rounds of centrifugation.[151] Liquid-crystallinestructures of aligned AuNRs spontaneously form in a side-onarrangement with high aspect ratios in concentrated solu-tions.[152]

Pileni has examined the ordering of transition-metalnanoparticles over long distances in 3D superlattices calledsupracrystals.[145, 153–157] In particular, it has been shown thatthis ordering of alkanethiolate-AuNPs into supracrystalsdepends on the solvent[153] and on the addition of water,[154]

with their final morphology determined through eithera layer-by-layer growth or a process of nucleation insolution.[153] Gold supracrystals can also grow from suspen-sions of gold nanocrystals, with the building process takingplace in solution and at the air–liquid interface. These growthprocesses determine the crystallinity and mechanical proper-ties of the supracrystals.[157]

Anisotropic AuNP arrangements can also be formed byusing bridging thiolate ligands. Feldheim and co-workers usedphenylacetylene oligomers to synthesize 2D and 3D crystal-line arrangements of AuNPs (e.g. dimers and trimers). Theoligomers play the role of “molecular wires” between theAuNPs. In this way, well-defined, rigid arrays with a variety ofgeometries could be produced.[158]

Examples of end-to-end AuNR assemblies include the useof biotin disulfide (in combination with streptavidin;Figure 9),[159] thioalkyl carboxylic acids (hydrogen bond-ing),[160, 161] alkanedithiols (thiolate coordination),[162] thio-lated DNA (hybridization),[163] thiolated alkynes and azides(click reaction),[164] and polymers such as polystyrene.[165,166]

Mann and co-workers showed that DNA hybridizationcould also be used to assemble AuNRs side-by-side by firstsubstituting CTAB with thiolated oligonucleotides.[167] Otherresearch groups also described such arrangements(Figure 10).[168–171] Another way to achieve the side-by-sideassembly of AuNRs is by appropriate choice of the thiolateligands (e.g. 1,2-dipalmitoyl-sn-glycero-3-phophothioetha-nol)[172] or mercaptopropylsilane[173]) followed by solventevaporation.

Polymer engineering (see also Section3.6)[108–114, 165,166, 174–179] is a well-developed strategy to assembleAuNPs. Besides the previously discussed use of PVP, otherpolymers such as poly(N-isopropylacrylamide) and its acrylicacid derivative,[174, 175] poly(viny alcohol),[176–178] and poly(styr-ene-b-methylacrylate) allow fabrication of anisotropicarrangements of AuNPs.[179]

Figure 8. Increasing the amount of silver ions leads to gold nanorodsof higher aspect ratios, which is consistent with the red-shifting LSPR.From Ref. [59]. Copyright 2009 Wiley-VCH.

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3.10. Top-Down Syntheses: Lithography Methods

The most common lithography technique used to produceAuNPs is electron-beam lithography (EBL).[180,181] First,a substrate is coated with an electron-sensitive resist. Theelectron beam dissociates this coated substrate into frag-ments, which are removed with a developing agent. Thenanoscale structure remaining is suitable for the deposition ofAuNPs. Another lithography technique is focused ion beam(FIB) lithography.[180–182] A gallium ion beam sputters parts ofa film to form the desired nanostructure shape. Theselithography techniques have produced AuNRs[180–183] and Aunanodisks,[184] although a drawback is that AuNPs smaller

than 10 nm as well as larger particles are usually notaccessible. Ebbesen and co-workers have combined ion-beam and electron-beam techniques[185–187] to synthesizearrays of Au microholes,[185] grooves, and nanowire circuits.[186]

Colloidal masks commonly used in lithography[169] have led tothe production of, for example, hexagonal arrays of Autriangles[189] and Au nanorings.[190] A modern lithographymethod, on-wire lithography (OWL), has been reported bythe Mirkin research group.[191, 192] OWL is a template-basedelectrochemical process for forming gapped cyclindricalstructures on a solid support. The size of the gaps andsegment length can be controlled on a length scale of under100 nm (Figure 11). This method allows the composition and

distances between adjacent particles to be tailored down to2 nm.[193–195] 1D arrays of Au nanostructures as small as 35 nmin diameter, which allow control of the segment length andspacing down to about 6 and 1 nm, respectively, weresynthesized in this way.[196] Such nanostructures can becombined with organic and biological molecules to createsystems with emergent and highly functional properties.[194]

4. The Morphology of AuNPs

4.1. Platonic AuNPs[123, 178,179]

AuNPs with the morphology of the five platonic solids—the tetrahedron (four triangles),[197] hexahedron (cube, sixsquares),[137,198–200] octahedron (eight triangles),[201] dodecahe-dron (twelve pentagons),[202] and icosahedron (twenty trian-gles)[203–210]—and their aqueous synthesis is often based onseed growth, as shown by the Murphy research group.[211]

They are characterized by low-index facets ({111} fortetrahedron, octahedron, dodecahedron, and icosahedronand {100} for the cube). Yang and co-workers used a modifiedpolyol process with PVP to form AuNPs in high yield with

Figure 9. Principle of the formation of gold nanorods by surfacefunctionalization with biotin disulfide as well as the correspondingTEM images. Scale bars: a) 100 nm, b) 20 nm, c) 100 nm, andd) 500 nm. From Ref. [159]. Copyright 2003 American ChemicalSociety.

Figure 10. TEM images of the aligned Au nanorods. From Ref. [171].Copyright American Chemical Society.

Figure 11. Synthetic strategy for preparing nanostructure arrays withOWL. From Ref. [196]. Copyright 2011 American Chemical Society.


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distinct highly uniform tetrahedra, cube, octahedra, andicosahedra (dubbed platonic nanocrystals) with sizes of 100–300 nm. Solutions of HAuCl4 and PVP in ethylene glycol wereinjected simultaneously in boiling ethylene glycol, which alsoserved as the reductant. The shape was controlled by the PVP/HAuCl4 ratio (4.3:1 to 8.6:1), with the AuNP shapes beinghighly sensitive to the concentration of the HAuCl4.

[197] Hanand co-workers carried out the synthesis of rhombic dodec-ahedral AuNPs from an aqueous solution of HAuCl4 withoutthe use of any seeds, surfactants, or foreign metal ions but onlywith DMF added as both the co-solvent and reductant at 90–95 8C for 15 h. Purification was carried out by centrifugationand washing with ethanol. It was suggested that reactiontemperatures lower than the boiling point of DMF (156 8C)results in slower, kinetically controlled reductions that areresponsible for the observed shapes formed.[201] Rhombicdodecahedral AuNPs (together with gold bipyramids) werealso obtained by Mirkin and co-workers[210] by an Ag-assisted,seed-mediated growth process (Figure 12).[204] Dodecahedral

AuNPs were transformed into other nonplatonic shapes suchas rhombic cuboctahedron and then truncated octahedron inthe presence of PVP at a low water content. At high watercontent, the dodecahedral AuNPs were transformed intorhombic cuboctahedra, then to truncated cubes, then cuboc-tahedra, and truncated octahedra.[211] Song and co-workershave used the popular polyol process, specifically 1,5-penta-nediol at reflux, to successfully and quantitatively producea variety of shaped AuNPs, including cubes, in the range ofabout 100 nm by incremental change in the AgNO3 concen-tration. Smaller cubes and octahedral were also produced byusing large amounts of PVP.[199]

4.2. One-Dimensional AuNPs: Nanorods,[212–221]

Nanowires,[222–233] Nanotubes,[234–243] and Nanobelts[244–247]

Nanorods are the most extensively investigated one-dimensional anisotropic AuNPs to date. In Section 3, theelectrochemical[35] and seed-growth methods leading to theformation of AuNRs were detailed, in particular the seminalstudies by the Murphy[45] and El-Sayed[100] research groups, aswell as several other synthetic techniques. For example, the

seed-mediated growth leads to either single-crystalline orpentahedrally twinned AuNR structures.

Various other remarkable one-dimensional nanogoldstructures have also been synthesized, including nanowires,nanobelts, and nanotubes. When the aspect ratio of AuNRsincreases, these AuNRs are called Au nanowires, thus there isa continuum between these two categories of AuNPs. AuNRscan also be assembled in line (Figures 13 and 14)[176–178,212] orinto other hybrid nanostructures such as nanotubes,[213] inparticular by using polymer films as hosts.[214] Various aspectsof AuNR materials, including their optical properties and

Figure 12. SEM image of AuNPs in the form of A) rhombic dodecahe-dra and B) bipyramids. Scale bars: 500 nm (main images) and 100 nm(insets). From Ref. [210]. Copyright 2011 American Chemical Society.

Figure 13. Formation of hot spots by end-to-end self-assembly of goldNRs in chains. From Ref. [212]. Copyright 2011 American ChemicalSociety.

Figure 14. a) STEM images of the self-assembled chains of AuNRsfrom Figure 13. Scale bar = 40 nm. b) Variation of the extinctionproperties of NRs during the course of their self-assembly into chains(LSPR shifts from 754 to 812 nm). From Ref. [212]. Copyright 2011American Chemical Society.

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application properties, have been detailed in reviews by theresearch groups of Murphy,[45, 22, 215,216] El-Sayed,[59, 101] and Liz-Marzan and Mulvaney.[217]

The main interest in AuNRs arises because of theirtremendous utility and multifunctionality for the diagnosisand treatment of cancer. They are indeed used as drug-delivery vehicles and as contrast agents for near-IR photo-thermal tumor ablation (see Section 6).[218–221]

Gold nanowires (AuNWs) are synthesized by the tip-selective growth of AuNRs.[222] AuNRs stabilized by CTABand pentahedrally twinned are, for example, used for suchprocessess.[223, 224] This method produces crystalline AuNWsthat are 12–15 mm long with a diameter of (90� 10) nm.AuNWs can also be prepared by UV irradiation (> 350 nm),photoreduction, and thermal reduction (at 70 8C) of HAuCl4

in the bulk phase of the block copolymer made from PEG20-PPE70-PEG20 (PPO = poly(propylene oxide) and PluronicP123.[225] AuNWs have potential applications as nanoscaleoptical waveguides in the visible and near-IR regions.[226–228]

AuNWs are indeed an ideal platform to produce surfaceplasmon waves by direct illumination of one end of thenanostructure. They can thus be used as tools for fundamentalstudies of subwavelength plasmon-based optics of wavepropagation. This strategy was pioneered by Halas and co-workers, who used Ag- and AuNWs with longitudinaldimensions of more than 10 mm. The addition of an adjacentnanowire, substrate, or other symmetry-breaking defectenables direct coupling with the guided waves in a nanowire.Networks of plasmonic AuNWs can serve as the basis foroptical devices such as interferometric logic gates, which canlead to nanorouters and multiplexes, light modulators, anda complete set of Boolean logic functions.[228]

Bimetallic AuPtNWs are useful electrochemical sensorsfor glucose with increased selectivity, sensibility, and repeat-ability compared to monometallic nanowires.[229] CuAuNWshave been intensively studied because of their widespreadapplications.[230] Interestingly, the method of fabrication ofAuCuNWs can also lead to the formation of AuCu nanotubes(AuCuNTs). Therefore, CuNWs were used as templates, andthe AuCuNWs are formed as intermediates that ultimatelylead to the AuCuNTs (Scheme 3).[231]

AuNRs and AuNWs have also served as seeds for thefabrication of higher-order AuNRs and AuNWs containingperiodic starfruit-like morphologies by Vigderman andZubarev.[232] Nanowires are required for applications such asultrasensitive and multiplex DNA detection through SERSand other biomedical SERS-based techniques.[233]

Both AuNWs and Au nanotubes (AuNTs) can beprepared by electroless deposition onto the pore walls ofporous polymer membranes, as shown by the seminal study byWirtz and Martin.[234] In such membranes, the pores act asa template for the nanostructuration. A commercially avail-able example of a support membrane is a polycarbonate filterwith cyclindrical nanopores. Long Au deposition times leadsto the preparation of AuNWs, while short deposition timesgive AuNTs. The AuNWs and AuNTs synthesized in this waycan be used as nanoelectrodes, molecular filters, and chemicalswitches.[234] AuNTs are also sensitive refractive index report-ers.[235] Finally, AuNTs have also been designed for specific

catalytic applications (see Section 6.1). 4-(Dimethylamino)-pyridine is a powerful auxiliary reagent for this electrolessdeposition method (Figure 15).[236] Indeed, AuNTs are cur-rently synthesized by the galvanic replacement reaction,[235,237]

for example, by using an anodized aluminum oxide tem-plate[238, 239] and a polymer NT as a sacrificial core to producehollow AuNTs that have exquisite sensitivity to the refractiveindex.[235] Thiol-functionalized nanoporous films can also actas a scaffold for the development of such highly ordered Auarrays.[240] Conical AuNT/pores can be advantageous to avoidunwanted plugging and are ideally suited to detect protein-type bioanalytes.[241] Inorganic nanostructures that serve astemplates for the formation of AuNTs include goethite(FeOOH) rods.[242] Finally, density functional theory can beof tremendous help when designing discrete AuNTs such asAu32 units with a zigzag structure.[243]

Among the 1D AuNPs, Au nanobelts (AuNBs; or Aunanoribbons) have attracted interest, because they mayrepresent a good system for examining dimensionally con-fined transport phenomena and for fabricating functionalnanodevices. Han and co-workers synthesized single-crystal-line AuNBs by using a combination of ultrasound irradiationand a-d-glucose as a directing agent under ambient con-ditions (Figure 16). The sugar is pyrolized to provide radicalsthat reduce AuIII to Au0.[90] Gemini surfactants have also beenused as a template in an aqueous phase by using dimethylenebis(tetradecylammonium bromide) (14-2-14) as a cappingagent and template. A two-step seed-growth method (to avoidsecondary nucleation) was used, whereby the first seed-growth step yielded AuNRs of high aspect ratio; then AuNBs

Scheme 3. Mechanism for the formation of Cu-Au alloy nanotubes.Reprinted from Ref. [231] with permission. Copyright 2012 AmericanChemical Society.


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that were several micrometers long and 5 nm thick weregrown in the second step.[244]

Au nanoarrays of single-crystalline AuNBs with long-range identical crystallographic orientation have been syn-thesized by directional solid-state transformation of an Fe-Aueutectoid followed by a precise electrochemical treatment(Figure 17).[245] Nanostructured reactive precursors have beenemployed as effective sacrificial templates for the controlledsynthesis of 1D inorganic nanostructures with desired com-positions. For example, porous AuNBs were fabricated frommetal–surfactant complexes of precursor NBs formed byHAuCl4 and a bolaform surfactant containing two quaternaryammonium head groups.[246] Plasmonic effects were studied innanostructures for the transport of optical information, andtunable plasmon resonance was indeed disclosed in AuNBswith cross-sectional dimensions smaller than 100 nm andnarrow transverse plasmon modes.[247]

4.3. Two-Dimensional AuNPs: Gold Nanoplates[248–267]

The synthesis of gold nanoplates with specific shapes(stars, pentagons, squares/rectangles, dimpled nanoplates,[248]

hexagons, and truncated triangles) of well-defined particle

sizes have been extensively exploited for their specificproperties and features. One of the simplest and versatilemethods to produce gold nanoplates is the polymer templatemethod, whereby the polymers have an extraordinary effectas stabilizers, templates, and reductants. In 2004, Lee and co-workers used bulk polymeric phases of PEO20PPO70PEO20

(PEO = poly(ethylene oxide), PPO = poly(propylene oxide))as both the reductant and stabilizer, with the large (10 mm inwidth and 100 nm in thickness) gold nanosheets beingobtained by reduction of HAuCl4 in THF.[225] In anotherexample, Radhakrishnan and co-workers generated polygo-nal gold nanoplates in situ in a poly(vinyl alcohol) matrixthrough thermal treatment.[249] Such a procedure occurs inhigh yield, does not involve the need for a reducing agent, andhas been widely utilized in the synthesis of large single-crystalline gold nanoplates.[250, 251] In some cases the polymersacted only as stabilizers, such as in the formation ofunprecedented starlike gold nanoplates through the reductionof HAuCl4 by l-ascorbic acid in the presence of poly(N-vinyl-2-pyrrolidone) as reported by Nakamoto and co-workers.[252]

On the other hand, Hojo and co-workers indicated that themorphology of polyhedral nanoplates was controlled withHAuCl4 and polyvinylpyrrolidone (PVP) through a polyolprocess when using ethylene glycol as both the solvent andreducing agent.[253]

In addition to the polymer process previously discussed,a wet-chemical route has also been proposed and exploited inthe last decade. It was demonstrated that the morphologycould be finely adjusted through control of the reactant ratioand the reaction conditions. In 2004, Wang and co-workersalso reported a mild large-scale synthesis of micrometer-scaleAu nanoplates. In this process, HAuCl4 is reduced by ortho-

Figure 15. a) Equilibria between DMAP, elemental Au, and protons onAu surfaces. b) SEM images of free-standing NTs. From Ref. [236].Copyright 2010 American Chemical Society.

Figure 16. a,b) SEM images and c,d) high-magnification SEM imagesof gold nanobelts. From Ref. [90]. Copyright 2006 Wiley-VCH.

Figure 17. SEM images of Au nanobelts. From Ref. [245]. Copyright2008 American Chemical Society.

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phenylenediamine in aqueous medium to form hexagonalsingle-crystalline Au nanoplates with preferential growthalong the Au(111) plane. This result suggests that the molarratio of ortho-phenylenediamine to gold is key to producingAu nanoplates.[254] Huang and co-workers carried out thesynthesis of trianglular and hexagonal gold nanoplates inaqueous solution by thermal reduction of HAuCl4 withtrisodium citrate in the presence of CTAB surfactant in just5–40 min. The size of the gold nanoplates was varied from assmall as 10 nm in width to several hundreds of nanometers. A[CTAB]/[HAuCl4] ratio of 6:1 in the reaction solution wasfavorable for the formation of gold nanoplates (Figure 18).[255]

A shape transformation from triangular to hexagonal nano-plates was evident on selective etching of Au triangularnanoplates, growing of Au nanodisks, then ripening ofhexagonal nanoplates, which corresponded to the change ofthe medium upon alternate addition of HAuCl4 and ascorbicacid.[256]

Dong and co-workers introduced a mild and relatively“green” one-pot biomimetic method for the fabrication ofgold nanoplates. The reactions were carried out at 25 8C inaqueous solution containing HAuCl4 and aspartate as thereductant for 12 h. The hexagonal and truncated triangularnanoplates with a thickness of less than 30 nm were obtainedafter evaporation of the solvent.[257] This use of a biologicalreductant was investigated extensively over the last decade.For example, the use of brown seaweed Sargassum,[258] tannicacid,[259] or serum albumin protein led to the formation ofsingle-crystalline gold nanoplates,[260] whereas glycine wasused in the facile synthesis of concave gold nanoplates.[261] Theadvantage of this method is that it is environmentally friendly,and it has been applied to the synthesis of other shapedAuNPs.

Gold nanoplates exhibit a wide range of unique electricaland optical properties, for example, a significant surface

enhanced Roman scattering (SERS),[262] tip-enhanced Ramanscattering (TERS),[263] and a shape- and size-dependentsurface plasmon absorbance in the visible to infraredregion. These properties result in potential applications assensors and probes.[263, 264]

A particular interesting morphology is triangular nano-prisms that exhibit three congruent edge lengths in the rangeof 40 nm to 1 mm and a defined thickness ranging from 5 to50 nm. These triangular nanoprisms have plasmonic featuresin the visible and IR regions, can be prepared in high yield,and can be readily functionalized with a variety of sulfur-containing adsorbates as well as other functional materi-als.[265–267]

4.4. 3-Dimensional AuNPs4.4.1. Gold Nanotadpoles[268–271]

Gold nanotadpoles are a class of anisotropic 3D goldnanostructures with tadpole-like appearance. These interest-ing nanostructures with special optical and electrical proper-ties have unique potential applications in second-ordernonlinear optics, nanoelectronics, and other fields. Thesuccessful synthesis of gold nanotadpoles was reported bythe Tian research group in 2004. They used a simple chemicalprocedure in which the tadpole-shaped gold nanoparticleswere synthesized in aqueous solution by the reduction ofchloroauric acid with trisodium citrate in the presence ofsodium dodecylsulfonate as a capping agent. These three-dimensional and crystallized structures were characterized byTEM, AFM, and HRTEM methods (Figure 19).[268] Soonafterwards, tadpole-shaped AuNPs were synthesized in high

Figure 18. a) TEM image of gold nanoplates. b,c) TEM images of goldnanoplates arranged into chainlike structures. Scale bar= 200 nm.d) TEM image of a single triangular gold nanoplate and e) thecorresponding electron diffraction pattern. Scale bar = 50 nm. f) TEMimage of a single quasihexagonal gold nanoplate and g) the corre-sponding electron diffraction pattern. Scale bar =50 nm. FromRef. [255]. Copyright 2006 American Chemical Society.

Figure 19. A) TEM and B) AFM images of tadpole-shaped AuNPs.C,D) HRTEM images of the C) head and D) tail of a gold nanotadpole.Insets: the corresponding Fourier transform patterns. From Ref. [268].Copyright 2004 American Chemical Society.


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yield by a temperature-reducing seeding approach, withoutany additional capping agent or surfactant.[269] An aggrega-tion-based growth process was proposed as the formationmechanism. Very recently, Au nanotadpoles were synthesizedthrough the normal seed-mediated process in the presence ofAg+ ions and CTAB at room temperature.[270] A hybridnanostructure consisting of Au heads and Pd tails and themechanism of formation of this morphology were demon-strated by Xia and co-workers.[271] It was expected that thesePd-Au tadpoles would combine the properties of both the Pdnanorods and AuNPs.

4.4.2. Gold Nanodumbbells (AuNDs)[272–277]

The seed-mediated growth of gold nanodumbbells(AuNDs) was described and particularly well investigatedby the Liz-Marz�n research group.[272,273] It was reported thatthe presence of tiny amounts of iodide modified the growth ofgold nanorods in such a way that tip growth was greatlyenhanced, thereby resulting in the formation of well-defineddumbbell morphologies (Figure 20).

Gold-containing hybrid nanodumbbells are of a greatinterest because of their ability to carry multiple functionsthat can be simultaneously utilized. The Au/Ag core/shellnanodumbbells have recently been synthesized either throughthe deposition of silver onto the surface of the AuNDs,[274] orby galvanic replacement and reagent reduction.[275] Anotherhybrid morphology is that of gold-tipped metal nanorods(nanodumbbells), such as CdSe-Au nanodumbbells,[276] Thenucleation and growth mechanism of the formation of CoPt3/Au, FePt/Au, and Pt/Au nanodumbbells were systemicallystudied by Prakapenka and co-workers. The authors wereable to propose a general strategy for the synthesis ofdumbbells with precise control over the size distributionand yield.[277]

4.4.3. Branched AuNPs: Nanopods and Nanostars[278–291]

Branched gold nanostructures, including monopods,bipods, tripods, tetrapods, hexapods,[278] and multipods such

as nanoflowers, nanostars, and urchins[279] are highly desiredbecause of their sharp edges and the correspondingly highlocalization of any surface plasmon modes. There are greatexpectations for such branched AuNPs as potential candi-dates in nanocircuits and nanodevices, and for in vivoapplication as a result of their high tissue penetration inthat spectral range. So far, branched AuNPs have indeed beenutilized in biosensing,[280] imaging,[281] targeting,[282] and photo-thermal therapy.[283]

The synthesis of branched gold nanocrystals in aqueoussolution was first reported by Carroll and co-workers in2003.[40] They demonstrated the use of triangular Ag plateletsas seeds for the synthesis of Au monopods, bipods, tripods,and tratrapods through the reduction of AuIII with ascorbicacid in the presence of CTAB. Sau and Murphy introduceda seed-mediated synthesis whereby the dimension andnumber of branches were varied under various combinationsof the [seed]/[Au3+] ratio.[211] Subsequently, Hao et al.reported the synthesis of new “branched” gold nanocrystalsin high yield (over 90 %) by a wet-chemical route duringwhich HAuCl4 was reduced by sodium citrate in a solution ofbis-(p-sulfonatophenyl)phenylphosphine dipotassium dihy-drate (BSPP) and H2O2 at room temperature.[284] Manyother routes were subsequently used to synthesize branchedAuNPs.[279,285–291]

The branched AuNPs are generally not as highly mono-disperse as other shapes. It was expected that the branchednanoparticles would have complicated localized surfaceplasmon resonance (LSPR) spectral features that would belost in ensemble measurements. To test this hypothesis,scattering spectra were measured on single Au nanostars,and the result showed that the spectra consisted of multiplesharp peaks in the visible and NIR region.[289] The LSPRspectra of highly branched AuNPs have been explored bysimulating the simpler structural subunits. The finite-differ-ence time-domain (FDTD) method was used to calculate thenear- and far-field properties of a gold nanostar, whereby thenanostar was modeled as a solid core with protruding prolatetips. This study showed that the resulting LSPR energies canbe thought of as a hybridization of the core and tip plasmons(Figure 21).[290] This hybridization greatly increases the over-all excitation cross-section and field enhancement of thenanostar tips. This antenna effect of the nanostar core may beresponsible for the relatively bright and narrow scatteringspectra of nanostars in the single particle measurements.[291]

4.4.4. Gold Nanodendrites[292–295]

The Au dendrites possess a hierarchical tree-type archi-tecture with trunks, branches, and leaf components. Goldnanodendrites with hyperbranched architectures haveattracted much attention because of their importance inunderstanding the fascinating fractal growth phenomena andtheir potential applications in functional devices, plasmonics,biosensing, and catalysis.[292–295] The most important syntheticmethod for the preparation of Au dendrites is electrochemicaldeposition because of its ease of control and simple operation,and because it generates highly pure and uniform deposits.Hung and co-workers, obtained hyperbranched Au dendrites

Figure 20. TEM micrographs of Au nanorods: a) initial AuNRs,b) grown in the absence of KI, c–g) grown in the presence of KI andwith the amount of KI decreasing from (c) to (g). h) Electrontomography 3D reconstruction of a single Au dumbbell from thesample shown in (g). From Ref. [273]. Copyright 2008 Wiley-VCH.

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on a glassy carbon electrode by electrodeposition witha square-wave potential from a solution of HAuCl4 containingcysteine as the blocking molecule.[292]

Huang et al. reported the first shape-controlled synthesisof Au nanostructures in the presence of supramolecularcomplexes formed from dodecyltrimethylammonium bro-mide (DTAB) and b-cyclodextrin (b-CD). Well-definedplanar Au nanodendrites were formed by the reduction ofchloroauric acid in aqueous DTAB/b-CD solutions(Figure 22).[293] Another example of surfactant/reductant

combination has been reported for which the three-dimen-sional dendritic gold nanostructures were prepared by anultrafast one-step homogeneous solution method by reducingHAuCl4 in the presence of decane-1,10-bis(methylpyrrolidi-nium bromide) ([mpy-C10-mpy]Br2) as the capping agent and

l-ascorbic acid (AA) as the reducing agent.[294] DendriticAuNPs exhibited significant catalytic activities, and the goodSERS sensitivity for the detection of biomolecules alsoindicated their potential applications in biosensing and nano-devices.

4.5. Au Nanoshells[296–308]

Core/shell nanomaterials containing a supporting corematerial and a thin Au nanoshell in the form of dielectricSiO2@Au particles have been designed by Radloff and Halas.Such Au nanoshells exhibit a strong plasmon resonance, andthe SERS effect sensitively depends on the core radius andshell thickness.[297] The authors provided a seminal systematicapproach for “nanoengineering” the optical resonance wave-length of metal NPs. This SPB wavelength could indeed be“tuned” across a large region of the visible and infraredspectrum in particular in the crucial near-infrared regionbetween 700–1100 nm, for biomedical applications, by varia-tion of the relative size of the inner and outer shell layer (seeSection 6). Gold nanoshells are among the most importantAuNPs and find considerable usage in both therapy anddiagnostics (concept of theranostic).[298] Other core@shellnanomaterials with a metal or metal oxide core and Aunanoshells are also known.[296] The scattering spectra of singlegold nanoshells were also measured by dark-field microscopycombined with high-resolution scanning electron and atomicforce microscopy,[299] and it has been demonstrated that thegold nanoshells show the same fluorescence enhancements asdye molecules.[300–302] The fabrication of supported hemishellstructures known as Au nanocups was also reported by theHalas research group.[303] Briefly, a 35 nm thick Au layer wasdeposited by electron-beam evaporation onto silica NPs(120 nm diameter), thereby forming an Au film on top of thesilica NPs. The Au nanocap generates second-harmonic light,whose intensity increases as the angle between the incidentfundamental beam and the nanocup symmetry axis isincreased (Figure 23). These plasmon structures providea promising approach for the design and fabrication ofstable, synthetic second-order nonlinear optical materials.

SiO2@Au NPs were also applied to optical imaging,[304]

biomedical detection,[305] and photothermal cancer therapeu-tic ability,[306] and may enable a new class of infrared materials,components, and devices to be developed.

Moreover, Fe3O4@Au core/shell NPs modified with anti-bodies and fluorescent dyes have been reported to act ascontrast probes for the multimodal imaging of tumors. Thisfinding illustrates the great potential of Fe3O4@Au NPs toimprove the accuracy of tumor diagnosis.[307] Very recently,magnetic Co@Au core/shell NPs with a pure Co core, anintermediate Au shell, and a compact outer cobalt oxide shellwere reported.[308]

Figure 21. Principle of the plasmon hybridization of the LSPR of a goldnanostar. From Ref. [290]. Copyright 2007 American Chemical Society.

Figure 22. SEM images of Au nanodendrites grown in mixed DTAB/b-CD solution. From Ref. [293]. Copyright 2009 American ChemicalSociety.


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4.6. Hollow AuNPs4.6.1. Hollow Gold Nanospheres (HAuNSs)[309–319]

The investigation of HAuNSs was pioneered in 1997 bythe Halas research group.[309] They described the properties ofAu-coated dielectric nanoparticles, or gold nanoshells, inwhich the configuration of a dielectric core coated witha metal nanoshell occurs naturally during the growth of Au/Au2S nanoparticles. It was found that gold nanoshells possessquite remarkable optical properties that differ dramaticallyfrom those of solid AuNPs. During the growth of the core/shell cluster, the plasmon-related absorption peak undergoesvery large shifts in its wavelength, from 650 to 900 nm. Suchstructures potentially exhibit tremendous importance foroptical applications related to the absorbance of IR light.The plasmon resonant optical properties[310, 311] and SERSeffects[312] of nanoparticles consisting of core/shell structureswere analyzed, and it was shown that they have a tunableplasmon resonance that depends on the ratio of the coreradius to the total radius.

One of the most versatile approaches for the preparationof coated and hollow spheres is the layer-by-layer (LbL)assembly method.[111, 313] Polyelectrolyte-modified polystyrene(PS) nanospheres were widely introduced as templates for theconstruction of HAuNS morphologies by the size-controllableLbL technique. The PS core was subsequently treated byeither calcination, causing the removal of the core, ordissolution of the core into a specific solvent (such as,THF).[314, 315] Wan and co-workers reported a facile and

effective approach to fabricate HAuNSs with tunable cavitysizes.[316] These HAuNSs were fabricated by using Co nano-particles (CoNPs) as sacrificial templates and varying thestoichiometric ratio between the HAuCl4 starting materialand the reductants. The formation of these hollow nano-structures is attributed to two subsequent reduction reactions:the initial reduction of HAuCl4 by CoNPs, followed byreduction with NaBH4. This strategy allows the convenientone-pot synthesis of homogeneous HAuNSs.

Recently, biomacromolecules have been investigated asprecursor materials for the synthesis of nanoparticles. Rosiand co-workers first reported that, in the presence ofinorganic salts and reducing agents, properly designedpeptide conjugates can orchestrate a one-pot reaction inwhich the synthesis and assembly of nanoparticles intocomplex superstructures occurs simultaneously. Hexanoicacid-AAAYSSGAPPMPPF (C6-AA-PEPAu) conjugatesdirect the formation of well-defined HAuNS superstructures(diameter = 136.5� 2.6 nm) upon incubation in water for 24 h(Figure 24).[317] Remarkably, the C12-PEPAu conjugate, which

has a slightly different composition, directs the dramaticformation of double-helical nanoparticle superstructures.[318]

The impact of further modification of the peptide sequenceon the resultant nanoparticle assembly was explored with thepeptide sequence BP-Ax-PEP Au (C12H9CO-Ax-AYSS-GAPPMPPF; x = 0–3; BP = biphenyl). The studies showed

Figure 23. Images and spectra of nanocups. a) SEM images fromabove (left) and tilted (right). The yellow curves highlight the geo-metries of the nanocups. Scale bar = 100 nm. b) Theoretical extinctionspectra of these nanocups. The dashed red line indicates the wave-length of the incident light in SHG experiments. c) Surface-chargedistribution on a nanocup (08) and the magnetic field on its symmetryplane one-quarter cycle later showing the magnetic dipole mode. FromRef. [303]. Copyright 2011 American Chemical Society.

Figure 24. a–c) TEM images, X-Y computational slices, X-Y computa-tional slices assembly (i–viii), and d) the 3D surface rendering of thehollow spherical gold nanoparticle superstructures. e) Synthesis of theAuNP superstructures. From Ref. [317]. Copyright 2010 AmericanChemical Society.

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that the small modifications to the peptide sequence, in thiscase the addition of a single alanine residue, can havea significant impact on the diameter of the resulting sphericalsuperstructure (29.4–270 nm). These investigations revealedthe versatility of this bio-based method and the rich structuraldiversity that occurs when this method is employed.[319]

4.6.2. Gold Nanocages and Nanoframes[320–328]

Au nanocages (AuNCs), a novel class of remarkablenanostructures possessing hollow interiors and porous walls,were pioneered by the Xia research group.[320] AuNCs areattractive for colorimetric sensing and biomedical applica-tions. Galvanic replacement is a facile and general synthesismethod for the preparation of hollow metal structures. Thetypical synthesis of gold nanocages can be described asfollows: The controlled addition of HAuCl4 solution toa boiling suspension of Ag nanocubes (as both template andreducing agent) leads to galvanic replacement because of theelectrochemical potential difference between Au and Ag (thereduction potential of AuCl4

�/Au (0.99 V versus the standardhydrogen electrode, SHE) is more positive than that of AgCl/Ag (0.22 V versus SHE)). The redox reaction takes placeaccording to Equation (7), with the consumption of Ag atomsand the deposition of Au0 confined to the Ag nanocubesurface. When more HAuCl4 is added, the formation of thehollow, porous cagelike Au nanostructure is observed. Themorphology was confirmed by Xia and co-workers by SEMand TEM.[123, 320]

3 AgðsÞ þHAuCl4 ! AuðsÞ þ 3 AgClðsÞ þHClðaqÞ ð7Þ

The controlled selective removal (or dealloying) of Agfrom the Au/Ag alloy nanoboxes was achieved with a wetaqueous etchant Fe(NO3)3. Ag was selectively dissolved fromAu/Ag-alloyed nanoboxes or nanocages by galvanic replace-ment [Eq. (8)], without the deposition of solid Fe.

AgðsÞ þ FeðNO3Þ3 ! AgNO3ðaqÞ þ FeðNO3Þ2ðaqÞ ð8Þ

Nanoboxes derived from 50 nm Ag nanocubes wereconverted into nanocages and then cubic nanoframes byincreasing the amount of the etchant Fe(NO3)3 in thedealloying process (Figure 25). The structural change wasaccompanied by the SPR peaks continuously shifting from thevisible region to 1200 nm.[321] These nanoframes have sensi-tivity factors that are several times higher than those of goldnanospheres, gold nanocubes, and gold nanorods, as well asthose of comparable-sized AuNCs.[322]

AuNCs and Au nanoframes were investigated in cataly-sis[323] and biosensing in view of their controllable LSPRproperties that depend on the size and, most importantly, thethickness of the walls.[324–328]

5. Optical Plasmonic Properties of AnisotropicAuNPs: SPR and SERS

5.1. SPR Properties of Anisotropic AuNPs

The rates of absorption and scattering, as well as theposition of the plasmon band (SPR peak), of AuNPs werefound to depend on their shape, size, and structures.[322] Someanisotropic AuNPs have unique SPR properties that aredifferent from those of spherical AuNPs. For example, theAuNRs (also the AuNDs and AuNTs) exhibit two plasmonbands: a strong longitudinal band in the near-infrared regionand a weak transverse band, similar to that of sphericalAuNPs, in the visible region. The band in the IR region, wheretissue absorption is minimal, is very useful for potentialin vivo applications in nanomedicine.[235, 329] Moreover, thelocation and intensity of the SPR peaks of AuNRs areremarkably more sensitive to the local refractive index in thevicinity of the nanorods and can be altered by the binding ofbiomolecular targets to the surface of the AuNR, which formsthe basis of their utility as attractive biosensors. Additionally,the nanorods have an inherently higher sensitivity to the localdielectric environment than similarly sized spherical nano-

Figure 25. A) Principle of the formation of an AuNC from an Agnanocube, and then an Au nanoframe. 1) Formation of Au/Ag alloynanocage, 2) selective removal of the Ag atoms from the nanobox withan aqueous etchant, 3) complete removal of Ag from the nanocage asmore etchant is added. B–E) Corresponding TEM and SEM images(insets) of the Ag nanocube, Au nanobox, Au nanocage, and Aunanoframes, respectively. From Ref. [321]. Copyright 2007 AmericanChemical Society.


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particles, thus making AuNRs excellent colorimetricprobes.[330] The plasmon bands of other intricate-shapeAuNPs have recently been explored, and the well-definedplasmon band in the ensemble spectra is observed in everycase.[247, 278, 284,291, 288, 320] For example, gold nanostars typicallyshow a plasmon band of the core and multiple plasmon bandscorresponding to the tips and core–tip interactions.[284] Thehollow AuNPs (AuNCs and other Au nanoframes) have thehighest sensitivity factors, and their plasmon bands aretunable throughout the visible and into the near-infraredregions. The relative intensity of the scattering and absorptioncross-sections of the hollow-structured AuNPs can be tunedby varying their size, and this feature makes them attractivefor colorimetric sensing and biomedical applications.[320]

Although silica@Au nanoshells are spherical and presenta single broad plasmon absorption, the fine-tuning at will ofthe position of this SPB differentiates them from standardspherical AuNPs and allows their efficient use in vivo forcancer therapy and imaging (see Section 6).[22,114]

5.2. SERS Properties of Anisotropic AuNPs

The SERS effect originates from the dramatic amplifica-tion of electromagnetic fields in the NP ensembles. Consid-erable enhancement occurs at the AuNP surface, because theintensity of the Raman signals depends on the fourth power ofthe local electric field, which is very high at the AuNP surfacebecause of the plasmon resonance. This enhancement alsooriginates from electromagnetic coupling between adsorbedmolecules and the AuNP surface as a result of charge transferbetween the adsorbed molecules and the AuNP surface.Amplified electromagnetic fields at AuNP junctions contrib-ute to SERS, because the selective enhancement of SERS iscontrolled by polarization-dependent resonance bands. Inaddition to the elastically scattered light by the AuNPsthemselves, which can be imaged using a dark-field opticalmicroscope, the AuNP surface provokes an inelastic SERSeffect as a result of adsorbed molecules generating a Ramanspectrum, which enables their identification. The two mainstrategies for SERS detection are direct identification ofRaman-active adsorbed molecules and indirect detection ofmolecules that are incorporated into a biolabel.[330, 331]

The Raman scattering signal of molecules located onnonspherical AuNPs is distinctly enhanced by contributionsfrom the strong absorptions in the near IR regime and theextremely high electric field intensities at their tips or hollowstructure.[332–335] Thus, controlling the size, shape, and struc-ture of anisotropic AuNPs is critical to enhance the sensitivityfor effective molecular detection.[238, 336] For example, El-Sayed and co-workers showed that oral cancer cells can alignAuNRs that have been conjugated with anti-epidermalgrowth factor receptor antibodies on the cell surface, therebyleading to a SERS fingerprint specific to the cancer cell.[337]

The Halas research group has discriminated between acidiccancer cells and healthy cells by monitoring changes in theRaman spectrum induced by pH changes of carboxy groups ina mercaptobenzoic acid layer on HAuNSs that were active inthe NIR region.[338]

5.3. Fluorescence Enhancement

The interaction between AuNPs and a fluorophore resultsfrom a change in the electromagnetic field and the intensity ofthe photonic mode near the fluorophore. For AuNP–fluoro-phore distances less than 4 nm, the fluorescence is stronglyquenched. At larger distances, the fluorescence intensity isincreased, including by coupling with far-field scattering. Forexample, the quantum yield of indocyanine green (ICG),a near-infrared fluorophore, was increased by up to 80% nearthe surface of an Au nanoshell. Such conjugates have beenused for enhancing sensitivities in fluorescence imagingin vitro and in vivo.[114, 301,302]

6. Applications of Anisotropic AuNPs

6.1. Catalytic Applications of Anisotropic AuNPs

The catalytic activity and selectivity of metal NPs (MNPs)is dependent primarily on the size and shape; therefore,nanoengineering is crucial in tailoring NP catalysts. Asa consequence of the presence of sharp edges and corners,the number of active surface sites in anisotropic AuNPs isvery high compared to spherical AuNPs. The shape of an NPis composed of a particular crystallographic plane, whichultimately determines the number of active surface sitespresent in that NP. For example, with 5 nm tetrahedral PtNPs,which have only {1,1,1} facets, 35% of the surface atoms arelocated at corners or edges, whereas this proportion is only6% for cubes, with {1,0,0} facets. With such PtNPs, theaverage rate constants were found to increase exponentiallyas the percentage of surface atoms at the corners and edgesincreased when surface coordination was involved in the rate-limiting step of the reaction.[344] The {1,1,0} facets found indodecahedral nanocrystals have the highest energy among thelow-index facets. The synthesis of metal nanocrystals withhigh-energy facets is, thus, challenging in terms of catalyticapplications, because these facets endow crystals with highactivity.

Catalysis of carbon monoxide oxidation by dioxygen atlow temperature by small (< 5 nm) AuNPs on titanium oxidewas pioneered by Haruta et al. in the late 1980s.[339] This studywas a breakthrough in catalysis science that opened up a widearea of AuNP-catalyzed oxidation reactions.[5, 13–15, 339–343] Forexample, oxide-supported Au/carbon catalysts were found tohave high catalytic activity in the selective oxidation ofcyclohexene and cyclooctene.[340] It is widely accepted thatCO molecules are preferentially adsorbed at edges and stepson the surface of nonspherical or hemispheical AuNPs, ratherthan on the facets.[341,342] Very recently, it was shown that theperimeter interfaces around AuNPs are the sites for COoxidation (Figure 26).[343]

Therefore, investigations in catalysis have recentlyfocused on anisotropic AuNPs such as gold nanotubes,nanodendritic gold, gold nanopyramids, and polygonalgold.[344, 345] Gold nanotubes were found to be very efficientcatalysts for CO oxidation at room temperature.[346,347] Forexample, gold nanotubes deposited within the pores of

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polycarbonate membranes played the role of catalysts andnanoreactors, respectively, for CO oxidation. The catalyticefficiency of these nanotubes was found to be higher thansimple supported AuNPs.[346] An et al. reported the oxidationof CO at room temperature by using single-walled helicalgold nanotubes as catalysts. The high catalytic activity of the(5,3) nanotube for CO oxidation may be due to the presenceof under-coordinated Au sites in the helical geometry. On themicroscopic level, the high activity may be attributed to theelectronic resonance between the d state of the Au atom atthe reaction site and the antibonding 2p* state of CO and O2,and the concomitant partial charge transfer.[347]

Huang et al. reported the synthesis of dendritic AuNPswith the cationic surfactant decane-1,10-bis(methylpyrrolidi-nium bromide) ([mpy-C10-mpy]Br2). Widely exposed activesurface provided active sites for selective adsorption to allowthe efficient reduction of p-nitroaniline.[294] Very recently,Losic and co-workers highlighted the catalytic properties ofgold nanotubes on porous anodic aluminum oxide. Thesystem showed excellent catalytic activity for the reductionof 4-nitrophenol (4-AP) to 4-aminophenol (4-NP).[239]

Some hybrid bimetallic anisotropic AuNPs also exhibithigh activities in various catalytic reactions.[348, 349, 350] Forexample, Au-ZnO nanopyramids (hexagonal pyramid-likestructure) demonstrated a higher photocatalytic efficiencythan pure ZnO nanocrystals in the degradation of rhodami-ne B.[348] Bimetallic Au-Pt nanowires prepared by the electro-deposition method were used as electrocatalysts for the real-time nonenzymatic impedancimetric detection of glucose.[229]

Cui et al. prepared Au/Ag-Mo NRs by deposition of AuNPsonto Ag-Mo NRs (Figure 27). This hybrid catalyst was a veryefficient heterogeneous catalyst for the tandem reaction ofalcohols and nitrobenzenes to generate N-alkyl amines andimines.[349]

6.2. Sensors and Molecular Recognition by Anisotropic AuNPs6.2.1. Detection of Toxic Ions

It is well known that heavy metal ions are widelydistributed in biological systems and the environment, andplay important roles in many biological and environmentalprocesses. Thus, the analytical determination of toxic metals isan important issue in both environmental monitoring andclinical research.[330] AuNRs currently are the most widelyused nonspherical AuNPs for detecting heavy metal ions. Thisis due to the extinction coefficient of AuNRs of around1010

m�1 cm�1, which results in the variation of the longitudinal

plasmon absorption (wavelength shift or intensity degrada-tion) that is a highly sensitive probe for sensing applica-tions.[351]

For example, AuNRs with various functionalized ligandson the surface led to a characteristic change in the longi-tudinal plasmon absorption on coordination to differentmetal ions. Cysteine (Cys) modified AuNRs have been usedas colorimetric probes in the titration of Cu2+ ions. The strongcoordination of Cu2+ ions with cysteine results in a stable Cys-Cu-Cys complex and induces the aggregation of the AuNRsalong with a rapid color change from blue-green to darkgray.[330] Dithiothreitol (DTT) modified AuNRs were used asa SPR sensor of Hg2+ ions. In this case, the DTT was stronglyadsorbed on the surface of the AuNRs through SH groups andinduced the aggregation of AuNRs. The induced aggregationof AuNRs was inhibited in the presence of Hg2+ ions, with theaggregation level dependent on the concentration of Hg2+

ions. The degree of aggregation could be determined by thechange in the intensity of the longitudinal plasmon absorptionin the UV/Vis spectrum (Figure 28).[351] The detection of some

Figure 26. Schematic view of an AuNP under reaction conditions forthe oxidation of CO (1 vol% CO in air (100 Pa) at room temperature).An AuNP with {111} and {100} facets has a polygonal interface withthe TiO2 support. Possible catalytically active sites are highlighted ingreen. From Ref. [343]. Copyright 2012 Wiley-VCH.

Figure 27. a) SEM image of Au/Ag-Mo nanorods, b) TEM image of Au/Ag-Mo nanorods, c) TEM image of an Au/Ag-Mo nanorod, andd) HRTEM image of an Au/Ag-Mo nanorod. From Ref. [349]. Copyright2012 Royal Society of Chemistry.


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other metals such as CrVI and PbII was recently reported byusing a similar method.[352, 353]

Besides the alteration of the longitudinal plasmonabsorption, fluorescence is also a very effective method forion detection. For example, Chen et al. reported a fluores-cence method for the detection of Hg2+ ions in a homogeneousmedium, with AuNRs used as a fluorescence quencher. Underoptimum conditions, the method exhibits a dynamic responseranging from 10 pmolL�1 to 5 nmolL�1, with a detection limitof 2.4 pmolL�1.[354]

In conclusion, the strong affinity between anisotropicAuNPs and heavy metal cations alters the position of theplasmon band of AuNRs or the fluorescence property oftargeted ions. This method allows heavy metal cations to bedetected in aqueous solutions with ultrahigh sensitivity andexcellent selectivity without sample pretreatment.

6.2.2. Biosensors and Bioprobes

The SPR and SERS properties of nonspherical AuNPshave been widely used for biosensing.[355] Up to now, Aunanorods (including bimetallic Au@Ag nanorods), nanopyr-amids, nanotubes, nanocages, nanowires, and nanostars havebeen reported as biosensors and bioprobes.[356–358] The typicalroutes to biosensors are illustrated in Equation (9). Thenonspherical AuNPs functionalized with specific molecules(small molecules, DNA, antibodies, and biotin) recognizedparticular nano-objects (protein, DNA, drugs, and streptavi-din), which caused the change in the plasmon absorption orthe SERS intensity of the AuNPs.

nonspherical AuNP þspecial functionalization

biosensing

SPR, SERS, etc:��!special object

ð9Þ

AuNRs also gained the most interest of all the various-shaped nonspherical AuNPs for applications as biosensorsand bioprobes. For example, AuNRs modified with double-

stranded (DS-) DNA exhibited temperature-dependentassembly and disassembly. Modified AuNRs assembled atlow temperature and disassembled at high temperature, withthe reversible plasmon band observed during the process.[359]

Bimetallic Au/Ag core/shell nanoparticles show a higherSERS activity than monometallic AuNRs, which results in10 times lower detection limit.[356]

Besides AuNRs, other shaped AuNPs also have advan-tages for use as biosensors. For example, Yoo et al. presenteda SERS sensor based on a patterned Au nanowire (NW) ona film for multiplex detection of pathogen DNA through anexonuclease III assisted recycling reaction of target DNA.Multiple probe DNAs are added to the target DNA solution,and among them, only the complementary probe DNA isselectively digested by exonuclease III, thereby resulting ina decrease in its concentration. The digestion process isrepeated by recycling of the target DNAs (Figure 29). Thedecrease in the complementary probe DNA concentration isdetected by SERS, and the detection limit is only 100 fm.[233]

The locally enhanced fields at the sharp ends and tips ofAu nanostars were exploited to amplify SERS and allowmolecular detection at the zeptomolar level. Dondapati et al.reported Au nanostars functionalized with biotinylatedbovine serum albumin (BSA) as a label-free biosensor forstreptavidin recognition, and the results showed that theconcentrations of streptavidin as low as 100 pm were detectedby a plasmon shift of 2.3 nm.[280]

AuNRs and AuNCs were found to act as SPR- and SERS-based probes for the detection of thrombin at concentrationsof 10 am and 1 fm, respectively.[357]

Castellana et al. recently reported a lipid-capped AuNRbiosensor for the capture and label-free detection of a mem-brane-active drug (amphotericin B) by mass spectrometry(MS). In this case, the signal for amphotericin B appeared inthe mass spectrum after incubation.[358] This MS methodshould become a very important technique for biosensors andbioprobes in the future.

Fluorescent enhancement of Au nanoshell/fluorophoreconjugates is a powerfull sensing technique that is used inbiomedical fluorescence imaging.[144]

6.2.3. Molecular Recognition

Based on the same principles of biosensors describedabove and in Equation (9), anisotropic AuNPs are also usedfor molecular recognition. The introduction of a thiolateligand is a key feature for application to molecular recog-nition.[361, 362] For example, functionalized AuNRs and Aunanoplates have been used for toxin recognition and glucoserecognition, respectively.[259, 363] Mandal and co-workers inves-tigated anisotropic AuNPs for the recognition of organicsolvents. Cyclam-stabilized AuNPs (mixture of spherical andtriangular) were “dip-coated” onto the wall of a quartzcuvette to form a thin film. The Au thin film showedcharacteristic changes in the plasmon band in various organicsolvents, thus indicating the system to be an excellentrefractive index sensor.[364]

Figure 28. The absorption spectra of AuNRs (1), AuNRs-DTT (2), andthe AuNRs-DTT-Hg2+ (3–7) system. Hg2+ concentrations: 1 (3), 5 (4),10 (5), 20 (6), and 50 � 10�9 molL�1 (7). From Ref. [351]. Copyright2012 Elsevier.

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6.2.4. Nanoelectrodes

Nonspherical AuNPs have also been used in electro-chemistry applications. Very recently, for example, Au nano-tubes were investigated as nanoelectrodes. 3D Au nano-electrodes were prepared by controlled chemical etching oflong Au nanotubes. The cyclic voltammogram of 3D Aunanoelectrodes showed they had a much higher sensitivity(more than twice) than the embedded Au nanoelectrodes andcould be used in many applications such as moleculardetection.[365]

6.3. Biomedical Applications: Diagnostics and Therapy

Spherical Au NPs, AuNRs, HAuNSs, AuNCs, and Aunanostars are the most remarkable AuNPs for biomedicalapplications because: 1) they have long body circulationtimes; 2) they selective accumulate at sites of interest throughthe enhanced permeability and retention (EPR) effect or bysurface modification with specific coatings; 3) they havea large absorption in the near-infrared window for photo-thermal therapy; 4) their simple functionalization (e.g. withPEG) and structural features allows their use as nanocarriersfor drugs, DNA, or RNA.[320, 366–385, 386] The concept of “thera-nostic” AuNP nanocomposites has emerged for AuNPs thatcombine functionalities of both contrast agent and therapeu-tic actuators within a single nanoparticle. Au nanoshells werethe first Au NPs to be used as efficient theranostic agents thatcombine imaging and phototherapy functions.[114]

6.3.1. Contrast Agents in Diagnostics

The development of new techniques to diagnose cancerearly is contributing to an increase in cancer survival rates.For example, the resolution of conventional imaging tech-

niques have been improved and new imaging modalities havebeen developed.[320] AuNPs are photoresistant and stable, thusoffering long-time operation for optical imaging. Plasmonicnanoparticles, such as spherical Au nanoshells,[114] AuNPs,[387]

AuNRs, Au nanocages, and Au nanostars are efficientcontrast agents in optical imaging as a result of their uniqueinteraction process with light particles (i.e., the excitation ofthe SPR by light). The most important in vivo diagnostictechniques include light scattering imaging, two-photonfluorescence imaging, and photothermal/photoacoustic imag-ing.[371]

For example, the Au nanoshells developed by Halas andco-workers that scatter light in the NIR physiological “waterwindow” have been used as contrast agents for dark-fieldscattering,[22, 114,304] photoacoustic imaging,[114, 325] and opticalcoherence tomography (OCT).[114, 306] With a core radius of60 nm and a shell thickness of 10–12 nm, Au nanoshells canboth absorb and scatter light at 800 nm, and thus serve as bothimaging and therapeutic (theranostic) agents.[304] Lee and co-workers compared three different AuNP shapes (cubic cages,rods, and quasispherical), each possessing at least onedimension in the 40–50 nm range. Each NP was covalentlyfunctionalized with an antibody (anti-thrombin) and used aspart of a sandwich assay in conjunction with an Au SPR chipmodified with a DNA–aptamer probe specific to thrombin.

AuNPs strongly scatter light at their plasmon wavelengths.The scattering cross-sections are 105–106 times stronger thanthat of the emission from a fluorescent dye molecule. AuNRsthat strongly scatter in the near-infrared region are capable ofdetecting cancer cells under excitation at spectral wave-lengths where biological tissues absorb only slightly(Figure 30).[367] Moreover, nucleus targeting and imaginghave also been achieved by conjugating the nanorods to thenuclear localization signal (NLS) peptides for potentialin vivo imaging.[368] Oldenburg et al. demonstrated thatAuNRs less than 50 nm in length are good contrast agents

Figure 29. Principle of the identification of pathogenic fungal DNAs by a patterned nanowire-on-film SERS sensor coupled with an exonuclease IIIassisted target recycling reaction. From Ref. [233]. Copyright 2011 Wiley-VCH.


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with little back scattering, thus rendering them appropriatefor the highly scattering tissue phantom.[369] The sensitivity iscomparable to the absorption-based in vivo transmissionimaging.[370] Currently, dark-field imaging based on thelight-scattering properties of nonspherical AuNPs (shells,spheres, rods, and cages) is widely used for cancer imagingthrough functionalized nanoparticle–receptor binding to cell-surface biomarkers.[371,372]

Nonspherical AuNPs, especially AuNRs, exhibitenhanced two-photon luminescence (TPL), thereby makingthem detectable at single-particle levels under femtosecondNIR laser excitation. In comparison to confocal fluorescencemicroscopy, TPL has the advantages of higher spatialresolution and a reduced background signal. For example,the nanorod-enabled TPL intensity was three times strongerthan that of two-photon autofluorescence,[374] and TPLimaging of AuNRs is 100 times stronger than the emissionof a single fluorescein isothiocyanate molecule.[375] However,deleterious photothermal effects are induced by plasmonexcitation upon continuous scanning with high-intensitypulsed laser light. Despite these problems, TPL has beenused recently for cancer imaging in vivo. For example, Heet al. reported the detection of circulating tumor cells in vivoby using the TPL technique.[376] In this experiment, CTC-mimetic leukemia cells were injected into the blood stream oflive mice, followed by injection of folate-conjugated AuNRsto preferentially label the circulating cancer cells in vivo. TPLimaging with an intravital flow cytometer detected singlecancer cells in the vasculature of the mouse ear.

Photothermal (PT) and photoacoustic (PA) imaging arebased on the laser-induced heating of materials, with theformer relying on the direct detection of heat and the latter onthe detection of acoustic waves generated by the thermalexpansion of air surrounding the materials. Compared tofluorescence-based approaches, PT imaging has the advan-tages of a larger detection volume and a high stability of thephotothermal signal.[371] The PT imaging technique hasusually been employed in photothermal therapy, and thusthis technique will also be discussed in the following section.

Furthermore, PA imaging is used much more often than PTimaging in biomedicine. This is because the PA techniquecombines the high contrast of optical imaging with the deeptissue penetration of ultrasound imaging. Numerous applica-tions have been shown in recent years. One of these key areasis in tumor imaging. For example, Agarwal et al. used PTimaging to detect prostate cancer by using AuNRs conjugatedwith anti-HER2.[377] This technique was also used by Li et al.to perform multiplexed imaging of different cancer cellreceptors by using AuNRs of varying aspect ratios and withvarious target molecules.[378] Another key area is in vivoimaging. For example, Xia and co-workers used PA to imagethe cerebral cortex of a rat before and after three successiveadministrations of PEGylated AuNCs. An enhancement ofthe brain vasculature by up to 81 % was observed (Fig-ure 31A,B). A difference image (Figure 31C) confirms the

enhancement achieved by administration of the Au nanocage.A photograph of the open skull (Figure 31D) reveals that theanatomical features of the vasculature match well with thoserevealed by the PA technique. Moreover, when comparedwith Au nanoshells, the AuNCs appear to be more effectivecontrast enhancement agents for PA, which is likely related totheir larger absorption cross-section and more compactsize.[379]

6.3.2. Photothermal Cancer Therapy

Thermal therapy involves the destruction of cancer tissuesby heating. Various energy sources have been applied,including radio frequencies, high-intensity focused ultra-

Figure 30. Cancer diagnostics using AuNR-enhanced light scattering.Optical dark-field microscopy of normal HaCaT cells and cancerousHSC and HOC cells incubated with anti-EGFR antibody conjugatedgold nanospheres (top panels, left to right). Bottom, as above, butwith gold nanorods. Anti-EGFR-conjugated gold nanoparticles specifi-cally bound to cancer cells, thereby resulting in strong scatteringunder dark-field microscopy and thus enabling detection of malignantcells. From Ref. [367]. Copyright 2006 American Chemical Society

Figure 31. Photoacoustic tomogram (PAT) of a rat’s cerebral cortexA) before and B) 2 h after the final injection of PEGylated AuNCs. C) Adifferential image. D) An open-skull photograph of the rat’s cerebralcortex, revealing features of the vasculatur. From Ref. [379]. Copyright2007 American Chemical Society.

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sound, microwaves, and lasers. The heat energy can bedelivered by external or internal means, through interstitial,intraluminal, or intracavitary approaches. However, becauseof absorption by normal tissues, the amount of energydelivered to the treatment volume is limited, which reducesthe potency of the thermal effect. To improve the efficacy andtumor selectivity, light-absorbing materials (known as photo-thermal contrast agents) are introduced into tumor cells tomediate the photothermal effect. A temperature increase of30–35 8C provokes cell death. Various Au nanostructures,including nanoshells,[388,389] nanorods, nanocages, and nano-stars that absorb NIR light (wavelength 700–850 nm), havebeen shown to be effective in photothermal therapy.[366]

The first use of anisotropic AuNPs in targeted photo-thermal therapy was conducted by the Halas research groupby using silica@Au nanoshells functionalized with antibodiessuch as anti-HER2. The antibodies direct the AuNPs towardthe cancer cells because they conjugate with surface cellmarkers that are overexpressed by cancer cells. These anti-bodies were linked to orthopyridyl disulfide-PEG-n-hydro-succinimide (OPSS-PEG-NHS) that was bound to the Ausurface through strong Au�S bonds. The advantage of thePEG linker is that it provides an enhanced permeability andretention (EPR) effect involving the new blood vesselsformed at the tumor site. This photothermal therapy wasfirst demonstrated in mice with subcutaneous tumors of 1 cmsize. Analysis showed that phothermal treatment resulted intissue damage over a similar sized area as that exposed tolaser irradiation. Magnetic resonance thermal imaging(MRTI) revealed an aveage temperature increase of 37 8Cafter 5 min irradiation, which is sufficient to induce irrever-sible tissue damage. Nanoshell-free samples showed anaverage increase of 9 8C, which was considered to be safefor cell viability.[113] Further experiments determined animalsurvival times of over 90 days.[22] Theranostic experimentswere conducted with the same antibody and Au nanoshellswith a core radius of 60 nm and a shell 10 nm thick (plasmonabsorption at 800 nm). The cells were imaged with a dark-field microcope, and irradiated with a NIR laser at 820 nm(0.008 Wcm�2, 7 mn). Only the cancer cells show a distinctenhancement in the dark-field scattering image and a darkcircular area of cell death corresponding to the beam spotupon laser irradiation.[304] Au nanoshells have also been usedto target tumor hypoxia, regions with reduced blood flow thatare resitant to NP accumulation, by combining mild hyper-thermia and radiation therapy.[22] Au nanoshells have alsobeen examined in vivo for their ability to enhance opticalcoherence tomography (OCT) and to induce photothermalcell death.[306] Further use of theranostics by the Halasresearch group successfully involved multimodal imagingand therapy, that is, with two diagnostic capabilities, MRI andNIR fluorescence, in addition to photothermal therapy. Thenanoensembles were prepared by encapsulating Au nano-shells in a silica epilayer doped with 10 nm Fe3O4 nano-particles and indocyanine green (ICG), functionalized withstreptavidin, and conjugated with thiolated PEG. Theseensembles showed very good results in vitro by targetingbreast cancer cells and also in vivo in breast cancer xeno-grafts.[390]

El-Sayed and co-workers pioneered strategies for theapplication of AuNRs in photothermal therapy. Conjugationof AuNRs to anti-EGFR antibodies enabled selective photo-thermal therapy as a result of preferential AuNR binding tohuman oral cancer cells.[367] In more-recent studies, theylinked macrolide to PEG-functionalized AuNRs, whichpreferentially delivered AuNRs into inflamed tumor tissuesvia tumor-associated macrophage cells (TAMs).[221]

AuNCs with large absorption cross-sections also showa large photothermal effect. The absorbed photons areconverted into phonons (lattice vibrations), which in turnproduce a localized temperature increase. Xia and co-workersdemonstrated the photothermal destruction of breast cancercells in vitro through the use of immuno-Au nanocages.AuNCs with an edge length of 45 nm were selected because oftheir predicted large absorption cross-section. SK-BR-3 cellswere treated with these immuno-AuNCs, then irradiated witha laser with a wavelength of 810 nm and a power density of1.5 Wcm�2 for 5 min. The treated cells were stained withcalcein-AM and ethidium homodimer-1 so that live cellsfluoresced green and dead cells fluoresced red. This analysisrevealed a well-defined zone of cellular death consistent withthe size of the laser spot.[380]

Au nanostars were also investigated for phototherapyapplications. They were successfully conjugated with anti-HER2 nanobodies and demonstrated specific interaction withHER2t and SKOV3 cells. The FACS data and the dark-fieldimages clearly revealed that the Au nanostars conjugated withanti-HER2 specifically bound to the cells, while almost nobinding was observed for the controls. Furthermore, theconjugate resulted in specific photothermal destruction oftumor cells in vitro. Exposing the cells to either only NIR lightor nanoparticles did not affect cell viability. Nonspecific NPsconjugated with anti-PSA nanobodies did not result in anycell death upon exposure to laser irradiation, thus demon-strating the high specificity of these anti-HER2-conjugatedAu nanostars.[283]

Hybrid nanomaterials composed of two unique compo-nents not only retain the beneficial features of both, but alsoshow synergistic properties. Hybrid AuNCs were also inves-tigated in photothermal therapy. Single-wall carbon nano-tubes (SWCNTs) were functionalized and attached to AuNCsthrough a thiol group (Figure 32). The as-prepared AuNC-decorated SWCNTs were then modified with RNA aptamerA9, which is specific to human prostate cancer cells. Thephotothermal response for the hybrid nanomaterial is muchhigher than for single nanomaterials.[243]

In conclusion, the in vitro and in vivo studies describedhave proved remarkably successful, yet tumors that aretreated are those that are easily accessible to NIR light andonly a few centimeters under the skin surface. It has beensuggested that techniques to deliver NIR light into deepertissues should exploit fiber optic probes, and such a challengeremains crucial.

6.3.3. Drug and Gene Delivery

The search for nonviral drug or gene vectors is indispen-sible because of the risk of cytotoxicity of and immunologic


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responses to conventional virus-mediated drug or genedelivery.[382–384] Nonspherical AuNPs have recently beenused as nanocarriers for efficient drug or gene deliverysystems.[385, 390] Lee et al. reported the use of cationic phos-pholipid functionalized AuNRs as plasmonic carriers thatsimultaneously exhibit carrier capabilities, demonstrateimproved colloidal stability, maintain plasmonic properties,and show no cytotoxicity under physiological conditions. Thein vivo studies demonstrated that these functionalized ANRsare stable under physiological conditions, thus retaining theirunique plasmonic properties. Furthermore, the positivelycharged surface of AuNRs adsorbs cargos such as DNAoligonucleotides, RNA oligonucleotides, and siRNA.[387]

Halas and co-workers described an SiO2@Au nanoshellthat released single-stranded DNA from its surface whenilluminated with plasmon-resonant light. This system allowedexamination of DNA dehybridization induced by excitationof localized surface plasmons on the NPs (Figure 33).[391] Inanother study, the light-triggered release of the fluorescentmolecule DAPI (4’,6-diamidino-2-phenylindole) inside livingcells was investigated from a host–guest complex with DNAbound to SiO2@Au nanoshells.[392] Diagnostic and therapeuticdrug delivery based on SiO2@Au nanoshells was also inves-tigated recently for the treatment of ovarian cancer[393] andthe diagnosis of breast cancer.[394]

With their hollow structures, AuNCs serve as “pockets”that are appropriate for drug release. For example, PEG-coated AuNCs have been used as nanocarriers for doxorubi-cin and triggered drug release under irradiation with NIRlight. This drug delivery system was considered to be a dual-modality cancer therapy that combined both photothermal

therapy and chemotherapy. An in vivo study of this deliverysystem indicated greater antitumor activity than eitherdoxorubicin or AuNCs alone.[366] Moreover, the surface ofAuNCs was functionalized with thermally responsive poly-mers to control the release through NIR laser irradiation orhigh-intensity focused ultrasound. Another reported con-trolled-release system used a phase-change material (PCM)loaded in the hollow interiors of AuNCs to achieve thecontrolled release. An increase in temperature uncaps thepores and releases the guest molecules from the AuNCs. Therelease is controlled by varying the power or duration of theultrasound treatment.[395, 396] Very recently, Wan and co-work-ers reported a bioresponsive controlled-release AuNCsystem. The AuNC was selected as a support and an ATPmolecule was used as the target (Figure 34). AuNCs were

functionalized with two kinds of thiol-modified single-stranded oligonucleotides (SH-DNAs) by means of Au-thiolate bonding on the surface of the AuNCs. The bases ofthe two immobilized SH-DNAs were partly complementaryto that of the two ends of the ATP aptamer. Mixing thesurface-modified AuNCs with the ATP aptamers resulted inhybridization of the ATP aptamers with the two immobilizedSH-DNAs. This effected assembly of the ATP aptamers onthe surface of the AuNCs, thereby capping the pores. Therelease of the guest molecule from the aptamer-AuNCs could

Figure 32. Synthesis protocol for the formation of hybrid nanomaterialsand the principle for the imaging and destruction of cancers. FromRef. [366]. Copyright 2012 Royal Society of Chemistry.

Figure 33. Principle of light-controlled release of ssDNA from Aunanoshells. From Ref. [391]. Copyright 2009 Elsevier.

Figure 34. Principle of the aptamer–target interaction for the biores-ponsive controlled-release of AuNCs. From Ref. [397]. Copyright 2012Royal Society of Chemistry.

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be triggered by the addition of ATP molecules, therebyopening the pores and releasing the cargo molecules.[397]

7. Toxicology

A number of in vitro studies have shown that AuNP coresare, in general, nontoxic for cells. These findings are incontrast with other nanoparticles such as carbon nanotubes,asbestos, and metal oxides, which have been shown to causedrastic damage to cells. On the other hand, although it hasbeen extensively demonstrated that anisotropic AuNPs havean enormous potential in theranostics, the in vivo toxicity ofthese AuNPs nedd to be established before drug adminis-tration can be allowed. Therefore, in vitro and in vivotoxicology studies have been undertaken to examine therisk of damage on cells, tissues, and organs of animals. Most ofthese studies have been conducted on AuNPs that wereconsidered to be spherical[398] and only a few studies haveconcerned AuNRs that are the prototype of anisotropicAuNPs with biomedical applications. The toxicity of AuNPshas been the subject of excellent reviews.[371, 399] Thus, werestrct the discussion to a few general aspects.

The first problem is the distinction between the toxicity ofthe AuNP core and that of the coating stabilizer, because it isnot possible to study the AuNP core without a stabilizer.In vitro studies have shown that the toxicity of AuNRs is dueto the CTAB ligands, not the core. Indeed, Murphy, Wyatt,and co-workers have shown that AuNPs that were coated withpolyacrylic acid or poly(allylamine) hydrochloride resulted inalmost no death of HT29 cells.[400] It is generally consideredthat AuNP cores larger than 5 nm behave as bulk gold interms of reactivity, whereas AuNPs smaller than 2 nm arespecifically reactive. AuNPs larger than 5 nm are indeedinactive in catalytic reactions, such as CO oxidation by O2,while oxide-supported AuNPs smaller than 2 nm are highlyactive.[12–16] This rule of thumb should be considered withcaution, especially concerning anisotropic AuNPs, for whichthe smaller dimension is often much smaller than the largestdimension (AuNRs, AuNTs, HAuNSs, and AuNCs). The“large” AuNPs, that is, with sizes between 5 nm and 100 nm,show a plasmon band that reflects a quantum behavior thatprobably has an effect on their reactivity. Such particles aremore reactive than bulk gold because of the large surface and,more specifically, because of the presence of edges, corners,and numerous structural defects (consider Au dendrites, forexample). On the other hand, small AuNPs that are supposedto be highly reactive when they are naked can be wellprotected, for example, by biocompatible PEGylated thiolateligands.

The second important problem is that of the oxidationstate of gold. We know that AgNPs are very toxic, because oftheir relative ease of oxidation to Ag+ salts, which have beengenerally recognized as intrinsically toxic.[401] Of course, Au0 ismuch more difficult to oxidize than Ag0, but the oxidizabilityof Au0 depends on the AuNP size, shape, and surroundingligands. For example, with the most common citrate andthiolate ligands, the Au�O and Au�S bonds on the AuNP coresurface are polarized (Aud+�Od� and Aud+�Sd�, respectively).

Moreover, cationic AuI and AuIII atoms have been generallyproposed to be responsible for the activity in the oxidation ofsubstrates in aerobic AuNP-catalyzed oxidation reac-tions.[12–16,402] Redox reactions are intrinsic to all biologicalorganisms and are facilitated by cytochromes; cytochro-me P450, in particular, is a strong oxidation catalyst. There-fore, the potential oxidation of Au atoms to toxic AuI or AuIII

ions at the surface of AuNP core that could subsequently beleached should not be underestimated. Again, these potentialproblems and risks are more acute with anisotropic AuNPsthan with isotropic ones because of their highly exposedAuNP surface areas and defects. Although from in vitrostudies it appears so far that the AuNP cores of isotropicAuNPs larger than 5 nm are biologically inert,[399, 371, 402] morestudies are needed with anisotropic AuNPs and in vivostudies.

The third problem is the dichotomy between the in vitroand in vivo studies in terms of results and number of studies.A large number of in vitro studies have been carried out usingTEM, microscopy techniques, and ICP-MS, and they areinteresting from a fundamental point of view and bringmechanistic information (for example, how AuNPs peneratecells as a function of size, coating type, and nature of the cell,as well as how some ionic capping agents such as CTAB orcationic ligands are toxic).[399, 371] However, there are very fewin vivo studies and there is no correlation with the in vitroresults. In vitro studies by Chan and co-workers indicated thatthe optimum size for cell penetration is 40–50 nm because thisis the maximized antibody–receptor interaction for receptor-mediated endocytosis.[403] In vitro studies involve a largevariety of parameters that, as underligned by Murphy and co-workers,[399, 371] do not provide a precise overall picture oftoxicity. Xia and co-workers have distinguished AuNPs thatentered cells from others by using a I2/KI mixture thatselectively solvates surface-cell AuNPs that do not inducetoxicity.[404] The aspect of AuNP aggregation has also beenaddressed.[405]

Some in vivo studies have addressed the pharmacokinet-ics of AuNPs. Toxicity studies of citrate-capped AuNPs inmice by Chen et al. showed that small (3–5 nm) and largeAuNPs (30 and 100 nm) were not toxic, whereas medium-sized AuNPs (8, 12, 17, and 37 nm) provoked severe sickness,loss of weight, change in fur color, and shorter life spans. Thesystemic toxicity was due to injury of the liver, spleen, andlungs.[406] On the other hand, 13 nm, citrate-caped AuNPswere shown by Lasagna-Reeves et al. not to cause any acuteside effects.[407] Small 10 nm AuNPs were found by ICP-MSanalysis in the liver, spleen, testis, lung, blood, and brain 24 hafter intravenous injection, whereas larger AuNPs (up to250 nm) were found only in the spleen and kidneys.[408] Forclearance through the kidneys, the NPs must pass the cross-filtration glomeruli barrier (6–8 nm hydrodynamic diameter)and must, therefore, be smaller than 5.5 nm. Indeed, smallerAuNPs were shown to be excreted in the urine, whereas18 nm AuNPs accumulated in the liver and spleen.[409,410]

Agglomeration of small (2 nm) AuNPs to larger aggregates,however, can also prevent renal clearance.[411] As an exampleof the coating influence, it was shown that glutathione-coatedsmall (2 nm) AuNPs underwent renal clearance more effi-


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ciently (because of low binding to serum proteins) thancitrate-coated AuNPs, but larger gluthathione AuNPs (13 nm)did not pass the glomeruli barrier.[411] Studies have also beenconducted on the environmental and ecological impact ofCTAB-capped AuNRs in model estuarine systems (contain-ing sediments, microbiol films, plants, clams, snails, and fish),and it was found that biofilms were the main route of entryinto the food chain.[412]

8. Conclusion and Outlook

A gold rush at the end of the 20th century resulted fromthe recognition of the excellent catalytic properties of verysmall AuNPs (< 5 nm) and of the potential provided by thequantum dot and optical properties of larger AuNPs(> 3 nm). Emphasis was on the size rather than on theshape. Although anisotropic AuNPs have attracted theattention of scientists since the very beginning of the 20thcentury, increased focus on their investigation only occurredat the beginning of the 21st century with the discovery ofmyriads of shapes including platonic, 1D, 2D, 3D, and hollowstructures. This multiplicity of crystallization modes hasquestioned the influence of many parameters on the growthmechanisms. Whereas the key role of some stabilizers such asCTAB, Ag+, and halide ions has been rationalized, the large-scale reproducible production of AuNPs of specific shapesremains a crucial challenge.

The advantage of and great interest in anisotropic AuNPscompared to classic spherical AuNPs are not only their betterdefinition as precise nanocrystals, but also their very impor-tant optical and catalytic properties.[344] Whereas the plasmonband is unique in the visible region for homogeneousspherical AuNPs, nonspherical AuNPs show a second plas-mon absorption that can be shifted to the near-infrared regionbetween 800 nm and 1300 nm. In this region the absorption bytissues is low, and thus allows phototherapy applications.Important factors for the wide application of anisotropicAuNPs are the scale of production, reproducibility, andtoxicity. So far, only the toxic CTAB stabilizer can lead to thegeneration of such 1D structures. The discovery of alternative,nontoxic stabilizers is another challenging issue. It is remark-able that the preparation of Au nanoshells, AuNCs, and someother anisotropic AuNPs that absorb light in the NIR “waterwindow” and are the subject of clinical anticancer “thera-nostic” applications do not suffer from the toxicity problemfound with CTAB.

The catalytic performance of anisotropic AuNPs is relatedto the presence of edges, corners, steps, and other defects,which are considerably more numerous than in sphericalAuNPs.[413,414] It can be predicted that this field will expandgiven the well-established role of AuNPs in catalysis. Precisestudies at the interface between AuNPs and solid oxidesupports should result in a better definition of the oxidationstates of surface Au atoms, which are key intermediates inoxidation reactions. This issue is not only important forcatalysis, but also for understanding the risk of the oxidationof surface Au atoms in vivo and possible subsequent toxicity.It is, thus, also essential for the future applications of

nonspherical and hollow AuNPs as well as SiO2@Au nano-shells in nanomedicine.[415]

Another aspect is the new bottom-up emergence of Aunanowires that reach longitudinal dimensions of several tensof micrometers for applications as plasmon waveguides andnetworks for optical devices, such as interferometric logicgates, which are promising for future information process-ing.[228, 416]

Financial support from the University Bordeaux, ChinaScholarship Council (CSC, PhD grants to L.N. and P.Z.),Science and Technology on Surface Physics and ChemistryLaboratory (Mianyang), CNRS, IUF (D.A.), NanosolutionEuropean consortium, and L�Or�al are gratefully acknowl-edged.

Received: January 17, 2013Revised: March 26, 2013Published online: January 13, 2014

[1] I. Freestone, N. Meeks, M. Sax, C. Higgit, Gold Bull. 1976, 9,134 – 139.

[2] M. Faraday, Philos. Trans. R. Soc. London 1857, 147, 145 – 181.[3] J. Turkevich, P. C. Stevenon, J. Hillier, Discuss. Faraday Soc.

1951, 11, 55 – 75.[4] M. Brust, M. Walker, D. Bethell, D. J. Schiffrin, R. Whyman, J.

Chem. Soc. Chem. Commun. 1994, 801 – 802.[5] G. Schmid, Chem. Rev. 1992, 92, 1709 – 1727.[6] M. Haruta, Nature 2005, 437, 1098 – 1099.[7] M. Giersig, P. Mulvaney, Langmuir 1993, 9, 3408 – 3413.[8] A. P. Alivisatos, Science 1996, 271, 933 – 937.[9] G. Mie, Ann. Phys. 1908, 25, 377 – 445.

[10] U. Kreibig, M. Vollmer, Optical Properties of Metal Clusters,Springer, Berlin, 1995.

[11] P. Mulvaney, Langmuir 1996, 12, 788 – 800.[12] B. M. Quinn, P. Liljeroth, V. Ruiz, T. Llaksonen, K. Kontturi, J.

Am. Chem. Soc. 2003, 125, 6644 – 6645.[13] A. Corma, P. Serna, Science 2006, 313, 332 – 334.[14] N. Dimitratos, J. A. Lopez-Sanchez, G. J. Hutchings, Chem. Sci.

2012, 3, 20 – 44.[15] Gold Nanoparticles for Physics, Chemistry, Biology (Eds.: C.

Louis, O. Pluchery), Imperial College, London, 2012.[16] M. C. Daniel, D. Astruc, Chem. Rev. 2004, 104, 293 – 346.[17] R. Szymondy, The Chemistry of Colloids, Wiley, New York,

1917.[18] R. Gans, Ann. Phys. 1912, 37, 881 – 900.[19] T. Svedberg, The Formation of Colloids, Von Nostrand

Reinhold, New York, 1921.[20] A. Einstein, Ann. Phys. 1905, 17, 549 – 560.[21] G. B. Jeffery, Proc. R. Soc. London Ser. A 1922, 102, 161 – 179.[22] S. Lal, S. E. Clare, N. J. Halas, Acc. Chem. Res. 2008, 41, 1842 –

1851.[23] C. J. Murphy, A. M. Gole, J. W. Stone, P. N. Sisco, A. M.

Alkilany, E. C. Goldsmith, S. C. Baxter, Acc. Chem. Res.2008, 41, 1721 – 1730.

[24] C. Burda, X. Chen, M. A. El-Sayed, Chem. Rev. 2005, 105,1025 – 1102.

[25] Y. Yin, A. P. Alivisatos, Nature 2005, 437, 664 – 670.[26] K. L. Kelly, E. Coronado, L. L. Zhao, G. C. Shatz, J. Phys.

Chem. B 2003, 107, 668 – 677.[27] C. Y. Yang, K. Heinemann, M. J. Yacaman, H. Poppa, Thin

Solid Films 1979, 58, 163 – 168.[28] A. Renou, M. Gillet, Surf. Sci. 1981, 106, 27 – 34.[29] J. Wiesner, A. Wokaun, Chem. Phys. Lett. 1989, 157, 569 – 582.

.AngewandteReviews



119

http://dx.doi.org/10.1039/df9511100055

http://dx.doi.org/10.1039/df9511100055

http://dx.doi.org/10.1039/c39940000801

http://dx.doi.org/10.1039/c39940000801

http://dx.doi.org/10.1021/cr00016a002

http://dx.doi.org/10.1038/4371098a

http://dx.doi.org/10.1021/la00036a014

http://dx.doi.org/10.1126/science.271.5251.933


http://dx.doi.org/10.1021/ja0349305



http://dx.doi.org/10.1039/c1sc00524c

http://dx.doi.org/10.1039/c1sc00524c

http://dx.doi.org/10.1021/cr030698+

http://dx.doi.org/10.1098/rspa.1922.0078

http://dx.doi.org/10.1021/ar800150g

http://dx.doi.org/10.1021/ar800150g





http://dx.doi.org/10.1038/nature04165

http://dx.doi.org/10.1021/jp026731y


http://dx.doi.org/10.1016/0040-6090(79)90231-1

http://dx.doi.org/10.1016/0040-6090(79)90231-1

http://dx.doi.org/10.1016/0039-6028(81)90177-1

http://dx.doi.org/10.1016/S0009-2614(89)87413-5


[30] N. R. Jana, L. Gearheart, C. J. Murphy, Adv. Mater. 2001, 13,1389 – 1393.

[31] B. Nikoobakht, M. A. El-Sayed, Chem. Mater. 2003, 15, 1957 –1965.

[32] C. J. Murphy, Science 2002, 298, 2139 – 2141.[33] K. Esumi, K. Esumi, K. Matsuhisa, K. Torigoe, Langmuir 1995,

11, 3285 – 3287.[34] E. Leontidis, K. Kleitou, T. Kiprianidou-Leodidou, V. Bekiari,

P. Lianos, Langmuir 2002, 18, 3659 – 3668.[35] Y. Yu, S. S. Chang, C. L. Lee, C. R. C. Wang, J. Phys. Chem. B

1997, 101, 6661 – 6664.[36] S. S. Chang, C. W. Shih, C. D. Chen, W. C. Lai, C. R. C. Wang,

Langmuir 1999, 15, 701 – 709.[37] B. Nikoobakht, M. A. El Sayed, Langmuir 2001, 17, 6368 –

6374.[38] S. Chen, D. L. Caroll, Nano Lett. 2002, 2, 1003 – 1007.[39] S. Chen, Z. Fan, D. L. Caroll, J. Phys. Chem. 2002, 106, 10777 –

10781.[40] S. Chen, Z. L. Wang, J. Ballato, S. H. Foulger, D. L. Caroll, J.

Am. Chem. Soc. 2003, 125, 16186 – 16187.[41] N. R. Jana, G. L. Gearheart, C. J. Murphy, J. Phys. Chem. B

2001, 105, 4065 – 4067.[42] V. Sharma, K. Park, M. Srinivararao, Mater. Sci. Eng. R 2009,

65, 1 – 38.[43] B. D. Busbee, S. O. Obare, C. J. Murphy, Adv. Mater. 2003, 15,

414 – 416.[44] A. Gole, C. J. Murphy, Chem. Mater. 2004, 16, 3633 – 3640.[45] C. J. Murphy, T. K. Sau, A. M. Gole, C. J. Orendorff, J. Gao, L.

Gou, S. E. Hunjadi, T. Li, J. Phys. Chem. B 2005, 109, 13857 –13870.

[46] H. Y. Wu, H. C. Chu, T. J. Kuo, C. L. Kuo, M. H. Huang, Chem.Mater. 2005, 17, 6447 – 6451.

[47] B. Nikoobakht, M. A. El-Sayed, Chem. Mater. 2003, 15, 1957 –1962.

[48] M. Iqbal, Y. Chung, G. Tae, J. Mater. Chem. 2007, 17, 335 – 338.[49] H. M. Chen, H. C. Peng, R. S. Liu, K. Asakura, C. L. Lee, J. F.

Lee, S. F. Hu, J. Phys. Chem. B 2005, 109, 19553 – 19555.[50] M. Liu, P. Guyot-Sionnest, J. Phys. Chem. B 2005, 109, 22192 –

22200.[51] X. C. Jiang, A. Brioude, M. P. Pileni, Colloids Surf. A 2006, 277,

201 – 206.[52] X. C. Jiang, M. P. Pileni, Colloids Surf. A 2007, 295, 228 – 232.[53] E. Carb�-Argibay, B. Rodriguez-Gonzales, J. Pacifico, I.

Pastoriza-Santos, J. Perez-Juste, L. M. Liz-Marzan, Angew.Chem. 2007, 119, 9141 – 9145; Angew. Chem. Int. Ed. 2007, 46,8983 – 8987.

[54] D. K. Smith, B. A. Korgel, Langmuir 2008, 24, 644 – 649.[55] J. E. Millstone, W. Ei, M. R. Jones, H. Yoo, C. A. Mirkin, Nano

Lett. 2008, 8, 2526 – 2529.[56] C. J. Johnson, E. Dujardin, S. A. Davis, C. J. Murphy, S. Mann,

J. Mater. Chem. 2002, 12, 1765 – 1770.[57] J. P�rez-Juste, L. M. Liz-Marzan, S. Carnie, D. Y. C. Chan, P.

Mulvaney, Adv. Funct. Mater. 2004, 14, 571 – 579.[58] M. Grzelczak, J. P�rez-Juste, P. Mulvaney, L. M. Liz-Marzan,

Chem. Soc. Rev. 2008, 37, 1783 – 1791.[59] X. Huang, S. Neretina, M. A. El-Sayed, Adv. Mater. 2009, 21,

4880 – 4910.[60] C. J. Orendorff, C. J. Murphy, J. Phys. Chem. B 2006, 110, 3990 –

3994.[61] S. Si, C. Leduc, M. H. Delville, B. Lounis, ChemPhysChem

2012, 13, 193 – 202.[62] F. Kim, H. Song, P. Yang, J. Am. Chem. Soc. 2002, 124, 14316 –

14317.[63] O. R. Miranda, T. S. Ahmadi, J. Phys. Chem. B 2005, 109,

15724 – 15734.[64] O. R. Miranda, N. R. Dollahon, T. S. Ahmadi, Cryst. Growth

Des. 2006, 6, 2747 – 2753.

[65] N. R. Jana, Small 2005, 1, 875 – 882.[66] P. Zijlstra, C. Bullen, J. W. M. Chon, M. Gu, J. Phys. Chem. B

2006, 110, 19315 – 19318.[67] S. Eustis, H. Y. Hsu, M. A. El-Sayed, J. Phys. Chem. B 2005,

109, 4811 – 4815.[68] C. Y. Wang, C. Y. Liu, X. Zhang, J. Chen, J. Colloid Interface

Sci. 1997, 191, 464 – 470.[69] C. Y. Wang, C. Y. Liu, X. Zheng, J. Chen, T. Shen, Colloids Surf.

A 1998, 131, 271 – 280.[70] X. Huang, X. Qi, Y. Huang, S. Li, C. Xue, C. L. Gan, F. Boey, H.

Zhang, ACS Nano 2010, 4, 6196 – 6202.[71] X. Huang, X. Z. Zhou, S. X. Wu, Y. Y. Wei, X. Y. Qi, J. Zhang,

F. Boey, H. Zhang, Small 2010, 6, 513 – 516.[72] K. Nishioka, Y. Niidome, S. Yamada, Langmuir 2007, 23,

10353 – 10356.[73] Y. Niidome, K. Nishioka, H. Kawasaki, S. Yamada, Chem.

Commun. 2003, 2376 – 2377.[74] See Ref. [64].[75] L. K. McGilvray, R. M. Decan, D. Wang, C. J. Scaiano, J. Am.

Chem. Soc. 2006, 128, 15980 – 15981.[76] L. M. Marin, L. K. McGilvray, C. J. Scaiano, J. Am. Chem. Soc.

2008, 130, 16572 – 16584.[77] M. Ahmed, R. Narain, Langmuir 2010, 26, 18392 – 18399.[78] T. Svedberg, The Formation of Colloid, Von Nostrand Rein-

hold, New York, 1921.[79] Z. L. Wang, R. P. Gao, B. Nikoobakht, M. A. El-Sayed, J. Phys.

Chem. B 2000, 104, 5417 – 5420.[80] C. R. Martin, Science 1994, 266, 1961 – 1966.[81] C. R. Martin, Acc. Chem. Res. 1995, 28, 61 – 68.[82] J. C. Hulteen, C. R. Martin, J. Mater. Chem. 1997, 7, 1075 – 1087.[83] W. Ye, J. Yan, F. Zhou, J. Phys. Chem. 2010, 114, 15617 – 15624.[84] A. Taleb, C. Mangeney, V. Ivanova, Nanotechnology 2011, 22,

205301.[85] T. Gao, T. H. Wang, Chem. Mater. 2005, 17, 887 – 892.[86] K. Barbour, M. Ashokkumar, F. Grieser, R. A. Caruso, F.

Grieser, J. Phys. Chem. B 1999, 103, 9231 – 9236.[87] X. F. Qiu, J. J. Zhu, H. Y. Chen, J. Cryst. Growth 2003, 257,

378 – 383.[88] K. Okitsu, Y. Mizukoshi, H. Bandow, A. T. Yamamoto, Y.

Nagata, Y. Madea, J. Phys. Chem. B 1997, 101, 5470 – 5472.[89] J. Belloni, M. Mostafavi, H. Remita, J. L. Marignier, M. O.

Delcourt, New J. Chem. 1998, 22, 1239 – 1255; J. Belloni, M.Mostafavi, H. Remita, J. L. Marignier, M. O. Delcourt, New J.Chem. 1998, 22, 1257 – 1265.

[90] J. Zhang, J. Du, B. Han, Z. Liu, T. Jiang, Z. Zhang, Angew.Chem. 2006, 118, 1134 – 1137; Angew. Chem. Int. Ed. 2006, 45,1116 – 1119.

[91] J. Henzie, E. S. Kwak, T. W. Odom, Nano Lett. 2005, 5, 1199 –1202.

[92] M. Tr�guer-Delapierre, J. Majimel, S. Mornet, S. Ravaine, GoldBull. 2008, 41, 195 – 207.

[93] G. L�, R. Zhao, G. Gian, Y. Qi, X. Wang, J. Suo, Catal. Lett.2004, 97, 115 – 118.

[94] R. M. Penner, J. Phys. Chem. B 2002, 106, 3339 – 3353.[95] V. M. Cepak, C. R. Martin, J. Phys. Chem. B 1998, 102, 9985 –

9990.[96] M. Antonietti, A. Th�nemann, E. Wenz, Colloid Polym. Sci.

1996, 274, 795 – 801.[97] S. E. Skrabalak, J. Chen, L. Au, X. Lu, X. Li, Y. Xia, Adv. Mater.

2007, 19, 3177 – 3184.[98] Y. Zhang, H. Dai, Appl. Phys. Lett. 2000, 77, 3015 – 3017.[99] J. H. Song, Y. Wu, B. Messer, H. Kind, P. Yang, J. Am. Chem.

Soc. 2001, 123, 10397 – 10398.[100] M. A. El-Sayed, Acc. Chem. Res. 2001, 34, 257 – 264.[101] M. E. Meyre, M. Tr�guier-Delapierre, C. Faure, Langmuir 2008,

24, 4289 – 4294.


Chemie


120

http://dx.doi.org/10.1002/1521-4095(200109)13:18%3C1389::AID-ADMA1389%3E3.0.CO;2-F

http://dx.doi.org/10.1002/1521-4095(200109)13:18%3C1389::AID-ADMA1389%3E3.0.CO;2-F






http://dx.doi.org/10.1021/la011368s

http://dx.doi.org/10.1021/jp971656q

http://dx.doi.org/10.1021/jp971656q

http://dx.doi.org/10.1021/la980929l

http://dx.doi.org/10.1021/la010530o

http://dx.doi.org/10.1021/la010530o

http://dx.doi.org/10.1021/nl025674h

http://dx.doi.org/10.1021/ja038927x




http://dx.doi.org/10.1016/j.mser.2009.02.002


http://dx.doi.org/10.1002/adma.200390095


http://dx.doi.org/10.1021/cm0492336



http://dx.doi.org/10.1021/cm051455w

http://dx.doi.org/10.1021/cm051455w



http://dx.doi.org/10.1039/b610761c

http://dx.doi.org/10.1021/jp053657l

http://dx.doi.org/10.1021/jp054808n









http://dx.doi.org/10.1021/la703625a

http://dx.doi.org/10.1021/nl8016253


http://dx.doi.org/10.1039/b200953f

http://dx.doi.org/10.1002/adfm.200305068






http://dx.doi.org/10.1002/cphc.201100710

http://dx.doi.org/10.1002/cphc.201100710

http://dx.doi.org/10.1021/ja028110o




http://dx.doi.org/10.1021/cg060455l

http://dx.doi.org/10.1021/cg060455l

http://dx.doi.org/10.1002/smll.200500014





http://dx.doi.org/10.1006/jcis.1997.4976

http://dx.doi.org/10.1006/jcis.1997.4976

http://dx.doi.org/10.1016/S0927-7757(97)00086-1

http://dx.doi.org/10.1016/S0927-7757(97)00086-1

http://dx.doi.org/10.1021/nn101803m






http://dx.doi.org/10.1021/ja066522h




http://dx.doi.org/10.1021/la103339g



http://dx.doi.org/10.1126/science.266.5193.1961


http://dx.doi.org/10.1039/a700027h

http://dx.doi.org/10.1088/0957-4484/22/20/205301

http://dx.doi.org/10.1088/0957-4484/22/20/205301


http://dx.doi.org/10.1021/jp990811t

http://dx.doi.org/10.1016/S0022-0248(03)01467-2

http://dx.doi.org/10.1016/S0022-0248(03)01467-2

http://dx.doi.org/10.1021/jp970415f

http://dx.doi.org/10.1039/a801445k







http://dx.doi.org/10.1007/BF03216597

http://dx.doi.org/10.1007/BF03216597

http://dx.doi.org/10.1021/jp013219o



http://dx.doi.org/10.1007/BF00654676

http://dx.doi.org/10.1007/BF00654676



http://dx.doi.org/10.1063/1.1324731



http://dx.doi.org/10.1021/ar960016n


[102] J. L. Gardea-Torresdey, J. G. Parsons, E. Gomez, J. Peralta-Videa, H. E. Troiani, P. Santiago, M. J. Yacaman, Nano Lett.2002, 2, 397 – 401.

[103] S. P. Chandran, M. Chaudhary, R. Pasricha, A. Ahmad, M.Sastry, Biotechnol. Prog. 2006, 22, 577 – 583.

[104] S. He, Y. Zhang, Z. Guo, N. Gu, Biotechnol. Prog. 2008, 24,476 – 480.

[105] S. Brown, M. Sarikaya, E. Johnson, J. Mol. Biol. 2000, 299, 725 –735.

[106] C. Lofton, W. Sigmund, Adv. Funct. Mater. 2005, 15, 1197 –1208.

[107] J. Gao, C. M. Bender, C. J. Murphy, Langmuir 2003, 19, 9065 –9070.

[108] C. S. Ah, Y. J. Yun, H. J. Park, W. J. Kim, D. H. Ha, W. S. Yun,Chem. Mater. 2005, 17, 5558 – 5561.

[109] Y. Xiong, I. Washio, J. Chen, H. Cai, Z. Y. Li, Y. Xia, Langmuir2006, 22, 8563 – 8570.

[110] J. Zhang, H. Liu, Z. Wang, N. Ming, Adv. Funct. Mater. 2007, 17,3295 – 3303.

[111] T. Pham, B. Jackson, N. J. Halas, T. R. Lee, Langmuir 2002, 18,4915 – 4920.

[112] J. L. West, N. J. Halas, Annu. Rev. Biomed. Eng. 2003, 5, 285 –292.

[113] L. R. Hirsch, R. J. Stafford, J. A. Bankson, S. R. Sershen, B.Rivera, R. E. Price, J. D. Hazle, N. J. Halas, J. L. West, Proc.Natl. Acad. Sci. USA 2003, 100, 13549 – 13554.

[114] Theranostics applications: R. Bardhan, S. Lal, A. Joshi, N. J.Halas, Acc. Chem. Res. 2011, 44, 936 – 946.

[115] M. Zhao, R. M. Crooks, Chem. Mater. 1999, 11, 3379 – 3385.[116] M. F. Mrozek, Y. Xia, M. J. Waever, Anal. Chem. 2001, 73,

5953 – 5960.[117] S. R. Brankovic, J. X. Wang, R. R. Adzic, Surf. Sci. 2001, 474,

L171 – L179.[118] Y. Sun, B. Mayers, Y. Xia, Nano Lett. 2002, 2, 481 – 485.[119] Y. Sun, Y. Xia, Anal. Chem. 2002, 74, 5297 – 5305.[120] G. S. M�traux, Y. Cao, R. Jin, C. A. Mirkin, Nature 2003, 425,

487 – 490.[121] Y. Sun, B. Mayers, Y. Xia, Adv. Mater. 2004, 16, 264 – 268.[122] H. Lang, S. Maldonado, K. J. Stevenson, B. D. Chandler, J. Am.

Chem. Soc. 2004, 126, 12949 – 12956.[123] Y. Sun, Y. Xia, J. Am. Chem. Soc. 2004, 126, 3892 – 3910.[124] J. Chen, B. Wiley, J. McLellan, Y. Xiong, Z. Y. Li, Y. Xia, Nano

Lett. 2005, 5, 2058 – 2062.[125] L. Au, X. Lu, Y. Xia, Adv. Mater. 2008, 20, 2517 – 2522.[126] V. Bansal, A. P. O�Mullane, S. K. Bhargava, Electrochem.

Commun. 2009, 11, 1639 – 1642.[127] C. M. Cobley, Y. Xia, Mater. Sci. Eng. 2010, 70, 44 – 62.[128] Y. S. Shon, G. B. Dawson, M. Porter, M. W. Murray, Langmuir

2002, 18, 3880 – 3885.[129] D. F. Yancey, E. V. Carino, R. M. Crooks, J. Am. Chem. Soc.

2010, 132, 10988 – 10989.[130] S. Pande, M. G. Weir, B. A. Zaccheo, R. M. Crooks, New J.

Chem. 2011, 35, 2054 – 2060.[131] Q. Xu, G. Meng, X. Wu, Q. Wei, M. Kong, X. Zhu, Z. Chu,

Chem. Mater. 2009, 21, 2397 – 2402.[132] C. Zuo, P. W. Jagodzinsski, J. Phys. Chem. B 2005, 109, 1788 –

1793.[133] W. Ye, Y. Chen, F. Zhou, C. Wang, Y. Li, J. Mater. Chem. 2012,

22, 18327 – 18243.[134] See Ref. [30].[135] T. K. Sau, C. J. Murphy, Langmuir 2004, 20, 6414 – 6420.[136] L. B. Rogers, D. P. Krause, J. C. Griess, D. B. Ehrlinger, J.

Electrochem. Soc. 1949, 95, 33 – 46.[137] J. Zhang, M. R. Langille, M. L. Personick, K. Zhang, S. Li, C. A.

Mirkin, J. Am. Chem. Soc. 2010, 132, 14012 – 14014.[138] T. Ming, W. Feng, Q. Tang, F. Wang, L. Sun, J. Wang, C. Yan, J.

Am. Chem. Soc. 2009, 131, 16350 – 16351.

[139] J. Li, L. Wang, L. Liu, L. Guo, X. Han, Z. Zhang, Chem.Commun. 2010, 46, 5109 – 5111.

[140] X. Kou, W. Ni, C. K. Tsung, K. Chan, H. Q. Lin, G. D. Stucky,Small 2007, 3, 2103 – 2113.

[141] E. Carb�-Argibay, B. Rodriguez-Gonzalez, S. Gomez-Graa, A.Guerrero-Martinez, I. Pastoriza-Santos, J. Perez-Juste, L. M.Liz-Marzan, Angew. Chem. 2010, 122, 9587 – 9590; Angew.Chem. Int. Ed. 2010, 49, 9397 – 9400.

[142] H. Katz-Boon, C. Rossouw, M. Weyland, A. M. Funston, A. M.Mulvaney, J. Etheridge, Nano Lett. 2011, 11, 273 – 278.

[143] J. M. Lehn, Supramolecular Chemistry. Concepts and Perspec-tives, VCH, Weinheim, 1995.

[144] L. Isaac, D. N. Chin, N. Bowden, Y. Xia, G. M. Whitesides inSupramolecular Technology (Ed.: D. N. Reinhout), Wiley, NewYork, 1999, pp. 1 – 46.

[145] M. P. Pileni, Acc. Chem. Res. 2007, 40, 685 – 693.[146] D. Nykypanchuk, M. M. Maye, D. van der Lelie, O. Gang,

Nature 2008, 451, 549 – 552.[147] D. V. Talapin, E. V. Shevchenko, M. I. Bodnarchuk, X. Ye, J.

Chen, C. B. Murray, Nature 2009, 461, 964 – 967.[148] W. Cheng, M. J. Campolongo, J. J. Cha, S. J. Tan, C. C. Umbach,

D. A. Muller, D. Luo, Nat. Mater. 2009, 8, 519 – 525.[149] B. Nikoobakht, Z. L. Wang, M. A. El-Sayed, J. Phys. Chem. B

2000, 104, 8635 – 8640.[150] Z. C. Xu, C. M. Chen, C. W. Xiao, T. Z. Yang, S. T. Chen, H. L.

Li, H. J. Gao, Chem. Phys. Lett. 2006, 432, 222 – 225.[151] G. Kawamura, Y. Yang, M. I. Nogamia, Appl. Phys. Lett. 2007,

90, 261908.[152] R. Jana, L. A. Gearheart, S. O. Obare, C. J. Johnson, K. J.

Edler, S. Mann, C. J. Murphy, J. Mater. Chem. 2002, 12, 2909 –2912.

[153] N. Goubet, J. Richardi, P. A. Albouy, M. P. Pileni, J. Phys.Chem. Lett. 2011, 2, 417 – 422.

[154] C. Salzemann, W. Zhai, N. Goubet, M. P. Pileni, J. Phys. Chem.Lett. 2010, 1, 149 – 154.

[155] P. Yang, I. Arfaoui, T. Cren, N. Goubet, M. P. Pileni, Nano Lett.2012, 12, 2051 – 2055.

[156] P. Yang, I. Arfaoui, T. Cren, N. Goubet, M. P. Pileni, Phys. Rev.B 2012, 86, 075409.

[157] N. Goubet, H. Portales, C. Yan, I. Arfaoui, P. A. Albouy, A.Mermet, M. P. Pileni, J. Am. Chem. Soc. 2012, 134, 3714 – 3719.

[158] L. C. Brousseau III, J. P. Novak, S. M. Marinakos, D. L. Feld-heim, Adv. Mater. 1999, 11, 447 – 449.

[159] K. S. Caswell, J. N. Wilson, U. H. F. Bunz, C. J. Murphy, J. Am.Chem. Soc. 2003, 125, 13914 – 13915.

[160] S. Zhang, X. Kou, Z. Yang, Q. Shi, G. D. Stucky, L. Sun, J.Wang, C. Yan, Chem. Commun. 2007, 1816 – 1818.

[161] N. Varghese, S. R. C. Vivekchand, A. Govindaraj, C. N. R. Rao,Chem. Phys. Lett. 2008, 450, 340 – 344.

[162] S. T. Shibu Joseph, B. I. Ipe, P. Pramod, K. G. Thomas, J. Phys.Chem. B 2006, 110, 150 – 157.

[163] B. Pan, L. Ao, F. Gao, H. Tian, R. He, D. Cui, Nanotechnology2005, 16, 1776 – 1780.

[164] R. Voggu, P. Suguna, S. Chandrasekaran, C. N. R. Rao, Chem.Phys. Lett. 2007, 443, 118 – 121.

[165] P. Khanal, E. R. Zubaev, Angew. Chem. 2007, 119, 2245 – 2248;Angew. Chem. Int. Ed. 2007, 46, 2195 – 2198.

[166] Z. H. Nie, D. Fava, M. Rubinstein, E. Kumacheva, J. Am.Chem. Soc. 2008, 130, 3683 – 3689.

[167] E. Dujardin, L. B. Hsin, C. R. C. Wang, S. Mann, Chem.Commun. 2001, 1264 – 1265.

[168] C. J. Orendorff, P. L. Hankins, C. J. Murphy, Langmuir 2005, 21,2022 – 2026.

[169] A. Gole, C. J. Murphy, Langmuir 2005, 21, 10756 – 10762.[170] B. Pan, C. Cui, C. Ozkan, P. Xu, T. Huang, Q. Li, H. Chen, F.

Liu, F. Gao, R. He, J. Phys. Chem. 2007, 111, 12572 – 12576.

.AngewandteReviews



121

http://dx.doi.org/10.1021/nl015673+

http://dx.doi.org/10.1021/nl015673+

http://dx.doi.org/10.1021/bp0501423



http://dx.doi.org/10.1006/jmbi.2000.3682

http://dx.doi.org/10.1006/jmbi.2000.3682



http://dx.doi.org/10.1021/la034919i

http://dx.doi.org/10.1021/la034919i

http://dx.doi.org/10.1021/cm051225h

http://dx.doi.org/10.1021/la061323x

http://dx.doi.org/10.1021/la061323x



http://dx.doi.org/10.1021/la015561y

http://dx.doi.org/10.1021/la015561y

http://dx.doi.org/10.1146/annurev.bioeng.5.011303.120723

http://dx.doi.org/10.1146/annurev.bioeng.5.011303.120723

http://dx.doi.org/10.1073/pnas.2232479100



http://dx.doi.org/10.1021/cm990435p

http://dx.doi.org/10.1021/ac0106391


http://dx.doi.org/10.1021/nl025531v





http://dx.doi.org/10.1021/ja039734c

http://dx.doi.org/10.1021/nl051652u

http://dx.doi.org/10.1021/nl051652u


http://dx.doi.org/10.1016/j.elecom.2009.06.018

http://dx.doi.org/10.1016/j.elecom.2009.06.018


http://dx.doi.org/10.1021/la025586c

http://dx.doi.org/10.1021/la025586c

http://dx.doi.org/10.1021/ja104677z


http://dx.doi.org/10.1039/c1nj20083f

http://dx.doi.org/10.1039/c1nj20083f

http://dx.doi.org/10.1021/cm803458b



http://dx.doi.org/10.1039/c2jm32170j


http://dx.doi.org/10.1021/la049463z

http://dx.doi.org/10.1149/1.2776732

http://dx.doi.org/10.1149/1.2776732

http://dx.doi.org/10.1021/ja106394k



http://dx.doi.org/10.1039/c0cc00138d

http://dx.doi.org/10.1039/c0cc00138d





http://dx.doi.org/10.1021/nl103726k

http://dx.doi.org/10.1021/ar6000582



http://dx.doi.org/10.1038/nmat2440

http://dx.doi.org/10.1021/jp001287p


http://dx.doi.org/10.1016/j.cplett.2006.10.056

http://dx.doi.org/10.1063/1.2752026

http://dx.doi.org/10.1063/1.2752026



http://dx.doi.org/10.1021/jz200004f

http://dx.doi.org/10.1021/jz200004f

http://dx.doi.org/10.1021/jz900109r

http://dx.doi.org/10.1021/jz900109r



http://dx.doi.org/10.1021/ja207941p

http://dx.doi.org/10.1002/(SICI)1521-4095(199904)11:6%3C447::AID-ADMA447%3E3.0.CO;2-I

http://dx.doi.org/10.1021/ja037969i

http://dx.doi.org/10.1021/ja037969i

http://dx.doi.org/10.1039/b618818d




http://dx.doi.org/10.1088/0957-4484/16/9/061

http://dx.doi.org/10.1088/0957-4484/16/9/061







http://dx.doi.org/10.1039/b102319p

http://dx.doi.org/10.1039/b102319p





[171] T. S. Sreeprasad, A. K. Samal, T. Pradeep, Langmuir 2008, 24,4589 – 4599.

[172] H. Nakashima, K. Furukawa, Y. Kashimura, K. Tirimitsu,Chem. Commun. 2007, 1080 – 1082.

[173] K. Mitamura, T. Imae, N. Saito, O. Takai, J. Phys. Chem. B 2007,111, 8891 – 8898.

[174] M. Das, N. Sanson, D. Fava, E. Kumacheva, Langmuir 2007, 23,196 – 201.

[175] M. Karg, I. Pastoriza-Santos, J. Perez-Juste, T. Hellweg, L. M.Liz-Marzan, Small 2007, 3, 1222 – 1229.

[176] C. J. Murphy, C. J. Orendorff, Adv. Mater. 2005, 17, 2173 – 2177.[177] J. P�rez-Juste, B. Rodriguez-Gonz�les, P. Mulvaney, L. M. Liz-

Marz�n, Adv. Funct. Mater. 2005, 15, 1065 – 1071.[178] P. Zijlstra, J. W. M. Chon, M. Gu, Opt. Express 2007, 15, 12151 –

12160.[179] R. Deshmukh, Y. Liu, R. J. Composto, Nano Lett. 2007, 7,

3662 – 3668.[180] L. Billot, M. Lamy de La Chapelle, A. S. Grimault, A. Vial, D.

Bachiesi, J. L. Bijeon, P. M. Adam, P. Royer, Chem. Phys. Lett.2006, 422, 303 – 307.

[181] E. J. Smythe, E. Cubukcu, F. Capasso, Opt. Express 2007, 15,7439 – 7447.

[182] P. Babu Dayala, F. Koyama, Appl. Phys. Lett. 2007, 91, 111107.[183] P. K. Jain, W. Huang, M. A. El-Sayed, Nano Lett. 2007, 7, 2080 –

2088.[184] A. N. Grigorenko, N. W. Roberts, M. R. Dickinson, Y. Zhang,

Nat. Photonics 2008, 2, 365 – 370.[185] E. Devaux, T. W. Ebbesen, J. C. Weeber, A. Dereux, Appl.

Phys. Lett. 2003, 83, 4936 – 4938.[186] W. L. Barnes, A. Dereux, T. W. Ebbesen, Nature 2003, 424,

824 – 830.[187] S. I. Bozhevolnyi, V. S. Volkov, E. Devaux, J. Y. Laluet, T. W.

Ebbesen, Nature 2006, 440, 508 – 511.[188] S. M. Yang, S. G. Yang, D. G. Choi, S. Kim, H. K. Yu, Small

2006, 2, 458 – 475.[189] B. J. Y. Tan, C. H. Sow, T. S. Koh, K. C. Chin, A. T. S. Wee, C. K.

Hong, J. Phys. Chem. B 2005, 109, 11100 – 11109.[190] D. Jia, A. Goonewardene, Appl. Phys. Lett. 2006, 88, 053105.[191] L. Qin, S. Park, L. Huang, C. A. Mirkin, Science 2005, 309, 113 –

115.[192] L. Qin, S. Zou, C. Xue, A. Atkinson, G. C. Schatz, C. A. Mirkin,

Proc. Natl. Acad. Sci. USA 2006, 103, 13300 – 13303.[193] M. J. Branholzer, L. D. Qin, C. A. Mirkin, Small 2009, 5, 2537 –

2540.[194] A. B. Braunschweig, A. L. Schmucker, W. D. Wei, C. A. Mirkin,

Chem. Phys. Lett. 2010, 486, 89 – 98.[195] M. J. Banholzer, K. D. Osberg, S. Li, B. F. Mangelson, G. C.

Schatz, C. A. Mirkin, ACS Nano 2010, 4, 5446 – 5452.[196] K. D. Osberg, A. L. Schmucker, A. J. Senesi, C. A. Mirkin,

Nano Lett. 2011, 11, 820 – 824.[197] F. Kim, S. Connor, H. Song, T. Kuykendall, P. Yang, Angew.

Chem. 2004, 116, 3759 – 3763; Angew. Chem. Int. Ed. 2004, 43,3673 – 3677.

[198] Y. Sun, Y. Xia, Science 2002, 298, 2176 – 2179.[199] D. Seo, J. C. Park, H. Song, J. Am. Chem. Soc. 2006, 128, 14863 –

14870.[200] E. Boisselier, A. K. Diallo, L. Salmon, C. Ornelas, J. Ruiz, D.

Astruc, J. Am. Chem. Soc. 2010, 132, 2729 – 2742.[201] C. Li, K. L. Shuford, Q. H. Park, W. Cai, Y. Li, E. J. Lee, S. O.

Cho, Angew. Chem. 2007, 119, 3328 – 3332; Angew. Chem. Int.Ed. 2007, 46, 3264 – 3268.

[202] J. G. Heong, M. Kim, Y. W. Lee, W. Choi, W. T. Oh, Q. H. Park,S. W. Han, J. Am. Chem. Soc. 2009, 131, 1672 – 1673.

[203] K. Kwon, K. Y. Lee, Y. W. Lee, M. Kim, J. Heo, S. Ahn, S. W.Han, J. Phys. Chem. C 2007, 111, 1161 – 1165.

[204] J. F. Parker, C. A. Fields-Zinna, R. W. Murray, Acc. Chem. Res.2010, 43, 1289 – 1296.

[205] M. Yavuz, W. Li, Y. Xia, Chem. Eur. J. 2009, 15, 13181 – 13187.[206] M. Zhou, S. Chen, S. Zhao, J. Phys. Chem. Lett. 2006, 110,

4510 – 4513.[207] O. Guliamov, A. I. Frenkel, L. D. Menard, R. G. Nuzzo, L.

Kronik, J. Am. Chem. Soc. 2007, 129, 10978 – 10979.[208] Y. Li, H. Cheng, T. Yao, Z. Sun, W. Yan, Y. Jiang, Y. Xie, Y. Sun,

Y. Huang, S. Liu, J. Zhang, Y. Xie, T. Hu, L. Yang, Z. Wu, S.Wei, J. Am. Chem. Soc. 2012, 134, 17997 – 18003.

[209] M. R. Langille, J. Zhang, M. Personick, S. Li, C. A. Mirkin,Science 2012, 337, 954 – 957.

[210] M. L. Personick, M. R. Langille, J. Zhang, N. Harris, G. C.Schatz, C. A. Mirkin, J. Am. Chem. Soc. 2011, 133, 6170 – 6173.

[211] T. K. Sau, C. J. Murphy, J. Am. Chem. Soc. 2004, 126, 8648 –8649.

[212] B. M. I. van der Zande, L. Pages, R. A. M. Hikmet, A. vanBlaaderen, J. Phys. Chem. B 1999, 103, 5761 – 5767.

[213] M. A. Correa-Duarte, J. Perez-Juste, A. Sanchez-Iglesias, M.Giersig, L. M. Liz-Marzan, Angew. Chem. 2005, 117, 4449 –4452; Angew. Chem. Int. Ed. 2005, 44, 4375 – 4378.

[214] C. J. Murphy, L. B. Thompson, D. J. Chernak, J. A. Yang, S. T.Sivapalan, S. P. Boulos, J. Y. Huang, A. M. Alkimlany, P. N.Sisco, Curr. Opin. Colloid Interface Sci. 2011, 16, 128 – 134.

[215] J. A. Yang, S. E. Lohse, S. P. Boulos, C. J. Murphy, J. Cluster Sci.2012, 23, 799 – 809.

[216] J. Perez-Juste, I. Pastoriza-Santos, L. M. Liz-Marzan, P. Mulva-ney, Coord. Chem. Rev. 2005, 249, 1870 – 1901.

[217] A. Lee, G. F. S. Andrade, A. Ahmed, M. L. Souza, N. Coombs,E. Tumarkin, K. Liu, R. Gordon, A. G. Brolo, E. Kumacheva, J.Am. Chem. Soc. 2011, 133, 7563 – 7570.

[218] J. V. Jokerst, Z. Miao, C. Zavaleta, Z. Cheng, S. S. Gambhir,Small 2011, 7, 625 – 633.

[219] B. Y. S. Kim, J. T. Rutka, W. C. W. Chan, N. Engl. J. Med. 2010,363, 2434 – 2443.

[220] A. Bajaj, O. R. Mirnda, I. B. Kim, R. L. Phillips, D. J. Jerry,U. H. F. Bunz, V. M. Rotello, Proc. Natl. Acad. Sci. USA 2009,106, 10912 – 10916.

[221] E. C. Dreaden, S. C. Mwakwari, L. A. Austin, M. J. Kieffer,A. K. Oyelere, M. A. El-Sayed, Small 2012, 8, 2819 – 2822.

[222] A. Paul, D. Solis, K. Bao, W. S. Chang, S. Nauert, L. Vidgerman,E. R. Zubarev, P. Nordlander, S. Link, ACS Nano 2012, 6,8105 – 8113.

[223] B. P. Khanal, E. R. Zubarev, J. Am. Chem. Soc. 2008, 130,12634 – 12635.

[224] K. Critchley, B. P. Khanal, M. L. Gorzny, L. Vigderman, S. D.Evans, E. R. Zubarev, N. A. Kotov, Adv. Mater. 2010, 22, 2338 –2342.

[225] J. U. Kim, S. H. Cha, K. Shin, J. Y. Jho, J. C. Lee, Adv. Mater.2004, 16, 459 – 464.

[226] S. Nah, L. Li, R. Liu, J. Ha, S. B. Lee, J. T. Fourkas, J. Phys.Chem. C 2010, 114, 7774 – 7779.

[227] P. Kusar, C. Gruber, A. Hohenau, J. R. Krenn, Nano Lett. 2012,12, 661 – 665.

[228] S. Lal, J. H. Hafner, N. J. Halas, S. Link, P. Norlander, Acc.Chem. Res. 2012, 45, 1887 – 1895.

[229] C. C. Mayorga-Martinez, M. Guix, R. E. Madrid, A. MerkoÅi,Chem. Commun. 2012, 48, 1686 – 1688.

[230] A. K. Sra, T. D. Ewers, R. E. Schaak, Chem. Mater. 2005, 17,758 – 766.

[231] Z. Jiang, Q. Zhang, C. Zong, B. J. Liu, B. Ren, Z. Xie, L. Zheng,J. Mater. Chem. 2012, 22, 18192 – 18197.

[232] L. Vigderman, E. R. Zubarev, Langmuir 2012, 28, 9034 – 9040.[233] S. M. Yoo, T. Kang, H. Kang, H. Lee, M. Kang, S. Y. Lee, B.

Kim, Small 2011, 7, 3371 – 3376.[234] M. Wirtz, C. R. Martin, Adv. Mater. 2003, 15, 455 – 458.[235] C. R. Bridges, P. M. DiCarmine, D. S. Seferos, Chem. Mater.

2012, 24, 963 – 965.


Chemie


122



http://dx.doi.org/10.1039/b609162h

http://dx.doi.org/10.1021/jp072524s

http://dx.doi.org/10.1021/jp072524s






http://dx.doi.org/10.1364/OE.15.012151

http://dx.doi.org/10.1364/OE.15.012151

http://dx.doi.org/10.1021/nl071908r




http://dx.doi.org/10.1364/OE.15.007439

http://dx.doi.org/10.1364/OE.15.007439

http://dx.doi.org/10.1063/1.2783281

http://dx.doi.org/10.1021/nl071008a


http://dx.doi.org/10.1038/nphoton.2008.78

http://dx.doi.org/10.1063/1.1634379

http://dx.doi.org/10.1063/1.1634379







http://dx.doi.org/10.1063/1.2168938





http://dx.doi.org/10.1021/nn101231u














http://dx.doi.org/10.1021/ar100048c

http://dx.doi.org/10.1021/ar100048c

http://dx.doi.org/10.1002/chem.200901440




http://dx.doi.org/10.1021/ja201826r

http://dx.doi.org/10.1021/ja047846d






http://dx.doi.org/10.1016/j.cocis.2011.01.001

http://dx.doi.org/10.1007/s10876-012-0474-y

http://dx.doi.org/10.1007/s10876-012-0474-y




http://dx.doi.org/10.1056/NEJMra0912273

http://dx.doi.org/10.1056/NEJMra0912273




http://dx.doi.org/10.1021/nn3027112








http://dx.doi.org/10.1021/jp100387k

http://dx.doi.org/10.1021/jp100387k

http://dx.doi.org/10.1021/nl203452d

http://dx.doi.org/10.1021/nl203452d

http://dx.doi.org/10.1021/ar300133j

http://dx.doi.org/10.1021/ar300133j




http://dx.doi.org/10.1039/c2jm33863g




http://dx.doi.org/10.1021/cm203184d

http://dx.doi.org/10.1021/cm203184d


[236] F. Muench, U. Kunz, C. Neetzel, S. Lauterbach, H. J. Kleebe, W.Ensinger, Langmuir 2011, 27, 430 – 435.

[237] Y. Sun, B. Mayers, T. Herricks, Y. Xia, Nano Lett. 2003, 3, 955 –960.

[238] N. R. Sieb, N. C. Wu, E. Majidi, R. Kukreja, N. R. Branda, B. D.Gates, ACS Nano 2009, 3, 1365 – 1372.

[239] Y. Yu, K. Kant, J. G. Shapter, J. Addai-Mensah, D. Losic,Microporous Mesoporous Mater. 2012, 153, 131 – 136.

[240] J. H. Ryu, S. Park, B. Kim, A. Klaikherd, T. O. Russell, S.Thayumanavan, J. Am. Chem. Soc. 2009, 131, 9870 – 9871.

[241] Z. Siwy, L. Trofin, P. Kohli, L. A. Baker, C. Trautmann, C. R.Martin, J. Am. Chem. Soc. 2005, 127, 5000 – 5001.

[242] M. Spuch-Calvar, J. Pacifico, J. P�rez-Juste, L. M. Liz-Marzan,Langmuir 2008, 24, 9675 – 9681.

[243] F. Tielens, J. Andr�s, J. Phys. Chem. 2007, 111, 10342 – 10346.[244] M. S. Bakshi, F. Possmayer, N. O. Petersen, J. Phys. Chem. C

2008, 112, 8259 – 8265.[245] Y. Chen, S. Milenkovic, A. W. Hassel, Nano Lett. 2008, 8, 737 –

742.[246] L. Li, Z. Wang, T. Huang, J. Xie, L. Qi, Langmuir 2010, 26,

12330 – 12335.[247] L. J. E. Anderson, C. M. Payne, Y. R. Zhen, P. Nordlander,

Nano Lett. 2011, 11, 5034 – 5037.[248] Y. Kuroda, Y. Sakamoto, K. Kuroda, J. Am. Chem. Soc. 2012,

134, 8684 – 8692.[249] S. Porel, S. Singh, T. P. Radhakrishnan, Chem. Commun. 2005,

2387 – 2389.[250] X. Sun, S. Dong, E. Wang, Langmuir 2005, 21, 4710 – 4712.[251] B. Lim, P. H. C. Camargo, Y. Xia, Langmuir 2008, 24, 10437 –

10442.[252] M. Yamamoto, Y. Kashiwagi, T. Sakata, H. Mori, M. Naka-

moto, Chem. Mater. 2005, 17, 5391 – 5393.[253] J. H. Lee, K. Kamada, N. Enomoto, J. Hojo, Cryst. Growth Des.

2008, 8, 2638 – 2645.[254] X. Sun, S. Dong, E. Wang, Angew. Chem. 2004, 116, 6520 –

6523; Angew. Chem. Int. Ed. 2004, 43, 6360 – 6363.[255] H. C. Chu, C. H. Kuo, M. H. Huang, Inorg. Chem. 2006, 45,

808 – 813.[256] S. Hong, K. L. Shuford, S. Park, Chem. Mater. 2011, 23, 2011 –

2013.[257] Y. Shao, Y. Jin, S. Dong, Chem. Commun. 2004, 1104 – 1105.[258] B. Liu, J. Xie, J. Y. Lee, Y. P. Ting, J. P. Chen, J. Phys. Chem. B

2005, 109, 15256 – 15263.[259] Y. Zhang, G. Chang, S. Liu, W. Lu, J. Tian, X. Sun, Biosens.

Bioelectron. 2011, 28, 344 – 348.[260] J. Xie, J. Y. Lee, D. I. C. Wang, J. Phys. Chem. C 2007, 111,

10226 – 10232.[261] L. Wang, X. Wu, X. Li, L. Wang, M. Pei, X. Tao, Chem.

Commun. 2010, 46, 8422 – 8423.[262] G. Lin, W. Lu, W. Cui, L. Jiang, Cryst. Growth Des. 2010, 10,

1118 – 1123.[263] P. Pienpinijtham, X. X. Han, T. Suzuki, C. Thanmmacharoen, S.

Ekgasit, Y. Ozaki, Phys. Chem. Chem. Phys. 2012, 14, 9636 –9641.

[264] T. Deckert-Gaudig, V. Deckert, Small 2009, 5, 432 – 436.[265] J. E. Millstone, S. J. Hurst, G. S. M�traux, J. I. Cutler, C. A.

Mirkin, Small 2009, 5, 646 – 664.[266] M. R. Jones, R. J. Macfarlane, A. E. Prigodich, P. C. Patel, C. A.

Mirkin, J. Am. Chem. Soc. 2011, 133, 18865 – 18869.[267] M. J. Banholzer, N. Harris, J. Millstone, G. C. Schatz, C. A.

Mirkin, J. Phys. Chem. C 2010, 114, 7521 – 7526.[268] J. Hu, Y. Zhang, B. Liu, J. Liu, H. Zhou, Y. Xu, Y. Jiang, Z.

Yang, Z. Tian, J. Am. Chem. Soc. 2004, 126, 9470 – 9471.[269] L. Huang, M. Wang, Y. Zhang, Z. Guo, J. Sun, N. Gu, J. Phys.

Chem. C 2007, 111, 16154 – 16160.[270] F. Li, T. Tian, H. Cui, Luminescence 2013, 28, 7 – 15.

[271] P. H. C. Camargo, Y. Xiong, L. Ji, J. M. Zuo, Y. Xia, J. Am.Chem. Soc. 2007, 129, 15452 – 15453.

[272] M. Grzelczak, A. Sanchez-Iglesias, H. H. Mezerji, S. Bals, J.Perez-Juste, L. M. Liz-Marzan, Nano Lett. 2012, 12, 4380 –4384.

[273] M. Grzelczak, A. S�nchez-Iglesias, B. Rodr�guez-Gonz�lez, R.Alvarez-Puebla, J. P�rez-Juste, L. Liz-Marz�n, Adv. Funct.Mater. 2008, 18, 3780 – 3786.

[274] M. Fernanda Cardinal, B. Rodriguez-Gonzalez, R. A. Alvarez-Puebla, J. Perez-Juste, L. M. Liz-Marzan, J. Phys. Chem. C2010, 114, 10417 – 10423.

[275] W. Xie, L. Su, P. Donfack, A. Shen, X. Zhou, M. Sackmann, A.Materny, J. Hu, Chem. Commun. 2009, 5263 – 5265.

[276] E. Shaviv, U. Banin, ACS Nano 2010, 4, 1529 – 1538.[277] G. Krylova, L. J. Giovanetti, F. G. Requejo, N. M. Dimitrijevic,

A. Prakapenka, E. V. Shevchenko, J. Am. Chem. Soc. 2012, 134,4384 – 4392.

[278] D. Y. Kim, T. Yu, E. C. Cho, Y. Ma, O. O. Park, Y. Xia, Angew.Chem. 2011, 123, 6452 – 6455; Angew. Chem. Int. Ed. 2011, 50,6328 – 6331.

[279] L. Lu, K. Ai, Y. Ozaki, Langmuir 2008, 24, 1058 – 1063.[280] S. K. Dondapati, T. K. Sau, C. Hrelescu, T. A. Klar, F. D.

Stefani, J. Feldmann, ACS Nano 2010, 4, 6318 – 6322.[281] H. Yuan, C. G. Khoury, H. Hwang, C. M. Wilson, G. A. Grant,

T. Vo-Dinh, Nanotechnology 2012, 23, 075102.[282] J. Xie, Q. Zhang, J. Y. Lee, D. I. C. Wang, ACS Nano 2008, 2,

2473 – 2480.[283] B. Van de Broek, N. Devoogdt, A. D�Hollander, H. L. Gijs, K,

Jan, L. Lagae, S. Muyldermans, G. Maes, G. Borghs, ACS Nano2011, 5, 4319 – 4328.

[284] E. Hao, R. C. Bailey, G. C. Schatz, J. T. Hupp, S. Li, Nano Lett.2004, 4, 327 – 330.

[285] Z. Li, W. Li, P. H. C. Camargo, Y. Xia, Angew. Chem. 2008, 120,9799 – 9802; Angew. Chem. Int. Ed. 2008, 47, 9653 – 9656.

[286] H. L. Wu, C. H. Chen, M. H. Huang, Chem. Mater. 2009, 21,110 – 114.

[287] S. Guo, L. Wang, E. Wang, Chem. Commun. 2007, 3163 – 3165.[288] S. Barbosa, A. Agrawal, L. Rodriguez-Lorenzo, I. Pastoriza-

Santos, R. A. Alvarez-Puebla, A. Kornowski, H. Weller, L. M.Liz-Marzan, Langmuir 2010, 26, 14943 – 14950.

[289] C. L. Nehl, H. Liao, J. H. Hanfner, Nano Lett. 2006, 6, 683 – 688.[290] F. Hao, C. L. Nehl, J. H. Hafner, P. Nordlander, Nano Lett.

2007, 7, 729 – 732.[291] C. L. Nehl, J. H. Hafner, J. Mater. Chem. 2008, 18, 2415 – 2419.[292] T. H. Lin, C. W. Lin, H. H. Liu, J. T. Sheu, W. H. Hung, Chem.

Commun. 2011, 47, 2044 – 2046.[293] T. Huang, F. Meng, L. Qi, Langmuir 2010, 26, 7582 – 7589.[294] D. Huang, X. Bai, L. Zheng, J. Phys. Chem. C 2011, 115, 14641 –

14647.[295] D. Huang, Y. Qi, X. Bai, L. Shi, G. Jia, D. Zhang, L. Zheng, ACS

Appl. Mater. Interfaces 2012, 4, 4665 – 4671.[296] L. R. Hirsch, A. M. Gobin, A. R. Lowery, F. Tam, R. A.

Drezek, N. J. Halas, J. L. West, Ann. Biomed. Eng. 2006, 34,15 – 22.

[297] C. Radloff, N. J. Halas, Nano Lett. 2004, 4, 1323 – 1327.[298] S. J. Oldenburg, J. B. Jackson, S. L. Westcott, N. J. Halas, Appl.

Phys. Lett. 1999, 75, 2897 – 2899.[299] C. L. Nehl, N. K. Grady, G. P. Goodrich, F. Tam, N. J. Halas,

J. H. Hafner, Nano Lett. 2004, 4, 2355 – 2359.[300] F. Tam, G. P. Goodrich, B. R. Johnson, N. J. Halas, Nano Lett.

2007, 7, 496 – 501.[301] R. Bardhan, N. K. Grady, J. R. Cole, A. Joshi, N. J. Halas, ACS

Nano 2009, 3, 744 – 752.[302] R. Bardhan, N. K. Grady, N. J. Halas, Small 2008, 4, 1716 – 1722.[303] Y. Zhang, N. K. Grady, C. Ayala-Orozco, N. J. Halas, Nano Lett.

2011, 11, 5519 – 5523.

.AngewandteReviews



123

http://dx.doi.org/10.1021/la104015a

http://dx.doi.org/10.1021/nl034312m

http://dx.doi.org/10.1021/nl034312m

http://dx.doi.org/10.1021/nn900099t

http://dx.doi.org/10.1016/j.micromeso.2011.12.011




http://dx.doi.org/10.1021/jp801306x

http://dx.doi.org/10.1021/jp801306x





http://dx.doi.org/10.1021/nl203085t









http://dx.doi.org/10.1021/cg0702075





http://dx.doi.org/10.1021/ic051758s

http://dx.doi.org/10.1021/ic051758s

http://dx.doi.org/10.1021/cm103273c

http://dx.doi.org/10.1021/cm103273c




http://dx.doi.org/10.1016/j.bios.2011.07.041




http://dx.doi.org/10.1039/c0cc03810e




http://dx.doi.org/10.1039/c2cp40330g

http://dx.doi.org/10.1039/c2cp40330g




http://dx.doi.org/10.1021/jp911889a


http://dx.doi.org/10.1021/jp072969g

http://dx.doi.org/10.1021/jp072969g

http://dx.doi.org/10.1002/bio.1380










http://dx.doi.org/10.1021/nn901778k







http://dx.doi.org/10.1021/la702886q

http://dx.doi.org/10.1021/nn100760f

http://dx.doi.org/10.1088/0957-4484/23/7/075102

http://dx.doi.org/10.1021/nn800442q









http://dx.doi.org/10.1021/cm802257e

http://dx.doi.org/10.1021/cm802257e


http://dx.doi.org/10.1021/la102559e

http://dx.doi.org/10.1021/nl052409y

http://dx.doi.org/10.1021/nl062969c

http://dx.doi.org/10.1021/nl062969c




http://dx.doi.org/10.1021/la904393n



http://dx.doi.org/10.1021/am301040b

http://dx.doi.org/10.1021/am301040b

http://dx.doi.org/10.1007/s10439-005-9001-8

http://dx.doi.org/10.1007/s10439-005-9001-8

http://dx.doi.org/10.1021/nl049597x

http://dx.doi.org/10.1063/1.125183

http://dx.doi.org/10.1063/1.125183










[304] C. Loo, A. Lowery, N. Halas, J. West, R. Drezek, Nano Lett.2005, 5, 709 – 711.

[305] L. R. Hirsch, J. B. Jackson, A. Lee, N. J. Halas, J. L. West, Anal.Chem. 2003, 75, 2377 – 2381.

[306] A. M. Gobin, M. H. Lee, N. J. Halas, W. D. James, R. A.Drezek, J. L. West, Nano Lett. 2007, 7, 1929 – 1934.

[307] T. Zhou, B. Wu, D. Xing, J. Mater. Chem. 2012, 22, 470 – 477.[308] D. Llamosa P�rez, A. Espinosa, L. Mart�nez, E. Rom�n, C.

Ballesteros, A. Mayoral, M. Garc�a-Hern�ndez, Y. Huttel, J.Phys. Chem. C 2013, 117, 3101 – 3108.

[309] R. D. Averitt, D. Sarkar, N. J. Halas, Phys. Rev. Lett. 1997, 78,4217 – 4220.

[310] R. D. Averitt, S. L. Westcott, N. J. Halas, J. Opt. Soc. Am. B1999, 16, 1824 – 1832.

[311] E. Prodan, C. Radloff, N. J. Halas, P. Nordlander, Science 2003,302, 419 – 422.

[312] S. J. Oldenburg, S. L. Westcott, R. D. Averitt, N. J. Halas, J.Chem. Phys. 1999, 111, 4729 – 4735.

[313] F. Caruso, M. Spasova, V. SalgueiriÇo-Maceira, L. M. Liz-Marz�n, Adv. Mater. 2001, 13, 1090 – 1094.

[314] Z. Liang, A. Susha, F. Caruso, Chem. Mater. 2003, 15, 3176 –3183.

[315] X. Feng, C. Mao, G. Yang, W. Hou, J. Zhu, Langmuir 2006, 22,4384 – 4389.

[316] H. Liang, L. Wan, Chun. Bai, L. Jiang, J. Phys. Chem. B 2005,109, 7795 – 7800.

[317] C. Song, G. Zhao, P. Zhang, N. L. Rosi, J. Am. Chem. Soc. 2010,132, 14033 – 14035.

[318] C. L. Chen, P. J. Zhang, N. L. Rosi, J. Am. Chem. Soc. 2008, 130,13555 – 13557.

[319] L. Hwang, G. Zhao, P. Zhang, N. L. Rosi, Small 2011, 7, 1939 –1942.

[320] S. E. Skrabalak, J. Chen, Y. Sun, X. Lu, L. Au, C. M. Cobley, Y.Xia, Acc. Chem. Res. 2008, 41, 1587 – 1595.

[321] X. Lu, L. Au, J. McLellan, Z. Li, M. Marquez, Y. Xia, NanoLett. 2007, 7, 1764 – 1769.

[322] M. A. Mahmoud, M. A. El-Sayed, J. Am. Chem. Soc. 2010, 132,12704 – 12710.

[323] M. A. Mahmoud, M. A. El-Sayed, Nano Lett. 2011, 11, 946 –953.

[324] S. A. Khan, R. Kanchanapally, Z. Fan, L. Beqa, A. K. Singh, D.Senapati, P. C. Ray, Chem. Commun. 2012, 48, 6711 – 6713.

[325] Y. Wang, X. Xie, X. Wang, G. Ku, K. L. Gill, D. P. O�Neal, G.Stocia, L. V. Wang, Nano Lett. 2004, 4, 1689 – 1692.

[326] C. M. Cobley, D. J. Campbell, Y. Xia, Adv. Mater. 2008, 20, 748 –752.

[327] W. Wang, T. Yan, S. Cui, J. Wan, Chem. Commun. 2012, 48,10228 – 10230.

[328] B. Khlebtsov, E. Panfilova, V. Khanadeev, O. Bibikova, G.Terentyuk, A. Lvanov, V. Rumyantseva, I. Shilov, A. Ryabova,V. Loshchenov, A. G. Khlebtsov, ACS Nano 2011, 5, 7077 –7089.

[329] J. M. Liu, H. F. Wang, X. P. Yan, Analyst 2011, 136, 3904 – 3910.[330] C. J. Murphy, A. M. Gole, S. E. Hunyadi, J. W. Stone, P. N.

Sisco, A. Akilany, B. E. Kinard, P. Hankins, Chem. Commun.2008, 544 – 557.

[331] R. Wilson, Chem. Soc. Rev. 2008, 37, 2028 – 2045.[332] L. Xu, H. Kuang, L. Wang, C. Xu, J. Mater. Chem. 2011, 21,

16759 – 16782.[333] L. Rodr�guez-Lorenzo, R. A. �lvarez-Puebla, F. J. Garc�a

de Abajo, L. M. Liz-Marz�n, J. Phys. Chem. C 2010, 114,7336 – 7340.

[334] C. Hrelescu, T. K. Sau, A. L. Rogach, F. Jackel, J. Feldmann,Appl. Phys. Lett. 2009, 94, 153113.

[335] E. Nalbant Esenturk, W. Hight, J. Raman Spectrosc. 2009, 40,86 – 91.

[336] H. Ko, S. Singamaneni, V. V. Tsukruk, Small 2008, 4, 1576 –1599.

[337] X. H. Huang, I. H. El-Sayed, W. Qian, M. A. El-Sayed, NanoLett. 2007, 7, 217 – 228.

[338] S. W. Bishnoi, C. J. Rozell, C. S. Levin, M. K. Gheith, B. R.Johnson, D. H. Johnson, N. J. Halas, Nano Lett. 2006, 6, 1687 –1692.

[339] M. Haruta, N. Yamada, T. Kobayashi, S. Iijima, J. Catal. 1989,115, 301 – 309.

[340] M. D. Hughes, Y. J. Xu, P. Jenkins, P. McMorn, P. Landon, D. I.Enache, A. F. Carley, G. A. Attard, G. J. Hutchings, F. King,E. H. Stitt, P. Johnston, K. Griffin, C. J. Kiely, Nature 2005, 437,1132 – 1135.

[341] G. C. Bond, C. Louis, D. Thompson, Catalysis by Gold, ImperialPress, London, 2006.

[342] Nanoparticles and Catalysis (Ed.: D. Astruc), Wiley-VCH,Weinheim, Chapters 12 – 15, 2008.

[343] Y. Kuwauchi, H. Yoshida, T. Akita, M. Haruta, S. Takeda,Angew. Chem. 2012, 124, 7849 – 7853; Angew. Chem. Int. Ed.2012, 51, 7729 – 7733.

[344] R. Narayanan, M. A. El-Sayed, J. Phys. Chem. B 2005, 109,12663.

[345] M. H. Rashid, T. K. Mandal, Adv. Funct. Mater. 2008, 18, 2261 –2271.

[346] M. A. Sanchez-Castillo, C. Couto, W. B. Kim, J. A. Dumesic,Angew. Chem. 2004, 116, 1160 – 1162; Angew. Chem. Int. Ed.2004, 43, 1140 – 1142.

[347] W. An, Y. Pei, X. C. Zeng, Nano Lett. 2008, 8, 195 – 202.[348] P. Li, Z. Wei, T. Wu, Q. Peng, Y. Li, J. Am. Chem. Soc. 2011, 133,

5660 – 5663.[349] X. Cui, C. Zhang, F. Shi, Y. Deng, Chem. Commun. 2012, 48,

9391 – 9393.[350] M. Stratakis, H. Garcia, Chem. Rev. 2012, 112, 4469 – 4506.[351] N. Bi, Y. Chen, H. Qi, X. Zheng, Y. Chen, X. Liao, H. Zhang, Y.

Tian, Sens. Actuators B 2012, 166 – 167, 766 – 771.[352] F. M. Li, J. M. Liua, X. X. Wang, L. P. Lin, W. L. Cai, X. Lin,

Y. N. Zeng, Z. M. Li, S. Q. Lin, Sens. Actuators B 2011, 155,817 – 822.

[353] C. V. Durgadasa, V. Nair Lakshmib, C. P. Sharmaa, K. Sreeni-vasan, Sens. Actuators B 2011, 156, 791 – 797.

[354] G. Chen, Y. Jin, L. Wang, J. Deng, C. Zhang, Chem. Commun.2011, 47, 12500 – 12502.

[355] E. C. Dreaden, M. A. El-Sayed, Acc. Chem. Res. 2012, 45,1854 – 1865.

[356] L. Wu, Z. Wang, S. Zong, Z. Huang, P. Zhang, Y. Cui, Biosens.Bioelectron. 2012, 38, 94 – 99.

[357] M. J. Kwon, J. Lee, A. W. Wark, H. J. Lee, Anal. Chem. 2012,84, 1702 – 1707.

[358] E. T. Castellana, R. C. Gamez, D. H. Russell, J. Am. Chem. Soc.2011, 133, 4182 – 4185.

[359] Z. Li, Z. Zhu, W. Liu, Y. Zhou, B. Han, Y. Gao, Z. Tang, J. Am.Chem. Soc. 2012, 134, 3322 – 3325.

[360] P. Y. Chung, T. H. Lin, G. Schultz, C. Batich, P. Jiang, Appl.Phys. Lett. 2010, 96, 261108.

[361] A. Labande, J. Ruiz, D. Astruc, J. Am. Chem. Soc. 2002, 124,1782 – 1789.

[362] M. C. Daniel, J. Ruiz, S. Nlate, J. C. Blais, D. Astruc, J. Am.Chem. Soc. 2003, 125, 2617 – 2628.

[363] Y. Zhu, H. Kuang, L. Xu, W. Ma, C. Peng, Y. Hua, L. Wang, C.Xu, J. Mater. Chem. 2012, 22, 2387 – 2391.

[364] M. H. Rashid, R. R. Bhattacharjee, T. K. Mandal, J. Phys.Chem. C 2007, 111, 9684 – 9693.

[365] Y. Bahari Mollamahalle, M. Ghorbani, A. Dolati, Electrochim.Acta 2012, 75, 157 – 163.

[366] J. You, R. Zhang, G. Zhang, M. Zhong, Y. Liu, C. S. Van Pelt, D.Liang, W. Wei, A. K. Sood, C. Li, J. Controlled Release 2012,158, 319 – 328.


Chemie


124

http://dx.doi.org/10.1021/nl050127s




http://dx.doi.org/10.1021/nl070610y

http://dx.doi.org/10.1039/c1jm13692e



http://dx.doi.org/10.1103/PhysRevLett.78.4217

http://dx.doi.org/10.1103/PhysRevLett.78.4217

http://dx.doi.org/10.1364/JOSAB.16.001824

http://dx.doi.org/10.1364/JOSAB.16.001824



http://dx.doi.org/10.1063/1.479235

http://dx.doi.org/10.1063/1.479235

http://dx.doi.org/10.1002/1521-4095(200107)13:14%3C1090::AID-ADMA1090%3E3.0.CO;2-H



http://dx.doi.org/10.1021/la053403r

http://dx.doi.org/10.1021/la053403r



http://dx.doi.org/10.1021/ja106833g

http://dx.doi.org/10.1021/ja106833g





http://dx.doi.org/10.1021/ar800018v

http://dx.doi.org/10.1021/nl070838l

http://dx.doi.org/10.1021/nl070838l





http://dx.doi.org/10.1039/c2cc32313c








http://dx.doi.org/10.1039/c1an15460e



http://dx.doi.org/10.1039/b712179m

http://dx.doi.org/10.1039/c1jm11905b

http://dx.doi.org/10.1039/c1jm11905b

http://dx.doi.org/10.1063/1.3119642





http://dx.doi.org/10.1021/nl060865w

http://dx.doi.org/10.1021/nl060865w

http://dx.doi.org/10.1016/0021-9517(89)90034-1

http://dx.doi.org/10.1016/0021-9517(89)90034-1













http://dx.doi.org/10.1021/nl072409t



http://dx.doi.org/10.1039/c2cc34178f

http://dx.doi.org/10.1039/c2cc34178f






http://dx.doi.org/10.1039/c1cc15084g

http://dx.doi.org/10.1039/c1cc15084g





http://dx.doi.org/10.1021/ac202957h

http://dx.doi.org/10.1021/ac202957h





http://dx.doi.org/10.1063/1.3460273

http://dx.doi.org/10.1063/1.3460273








http://dx.doi.org/10.1016/j.electacta.2012.04.119

http://dx.doi.org/10.1016/j.electacta.2012.04.119

http://dx.doi.org/10.1016/j.jconrel.2011.10.028

http://dx.doi.org/10.1016/j.jconrel.2011.10.028


[367] X. Huang, I. H. El-Sayed, M. A. El-Sayed, J. Am. Chem. Soc.2006, 128, 2115 – 2120.

[368] A. K. Oyelere, B. Chen, X. Huang, I. H. El-Sayed, M. A. El-Sayed, Bioconjugate Chem. 2007, 18, 1490 – 1497.

[369] A. L. Oldenburg, M. N. Hansen, D. A. Zweifel, A. Wei, S. A.Boppart, Opt. Express 2006, 14, 6724 – 6738.

[370] E. B. Dickerson, E. C. Dreaden, X. Huang, I. H. El-Sayed, H.Chu, S. Pushpanketh, J. F. McDonald, M. A. El-Sayed, CancerLett. 2008, 269, 57 – 66.

[371] E. C. Dreaden, A. M. Alkilany, X. Huang, C. J. Murphy, M. A.El-Sayed, Chem. Soc. Rev. 2012, 41, 2740 – 2779.

[372] C. Loo, L. Hirsch, M. H. Lee, E. Chang, J. West, N. J. Halas, R.Drezek, Opt. Lett. 2005, 30, 1012 – 1014.

[373] H. Ding, K. T. Yong, I. Roy, H. E. Pudavar, W. C. Law, E. J.Bergey, P. N. Prasad, J. Phys. Chem. C 2007, 111, 12552 – 12557.

[374] N. J. Durr, T. Larson, D. K. Smith, B. A. Korgel, K. Sokolov, A.Ben-Yakar, Nano Lett. 2007, 7, 941 – 945.

[375] J. L. Li, M. Gu, Biomaterials 2010, 31, 9492 – 9498.[376] W. He, H. Wang, L. C. Hartmann, J. X. Cheng, P. S. Low, Proc.

Natl. Acad. Sci. USA 2007, 104, 11760 – 11765.[377] A. Agarwal, S. W. Huang, M. O�Donnell, K. C. Day, M. Day, N.

Kotov, S. Ashkenazi, J. Appl. Phys. 2007, 102, 064701.[378] P. C. Li, C. R. C. Wang, D. B. Shieh, C. W. Wei, C. K. Liao, C.

Poe, S. Jhan, A. A. Ding, Y. N. Wu, Opt. Express 2008, 16,18605 – 18615.

[379] X. Yang, S. E. Skrabalak, Z. Y. Li, Y. Xia, L. V. Wang, NanoLett. 2007, 7, 3798 – 3802.

[380] J. Chen, D. Wang, J. Xi, L. Au, A. Siekkinen, A. Warsen, Z. Y.Li, H. Zhang, Y. Xia, X. Li, Nano Lett. 2007, 7, 1318 – 1322.

[381] See Ref. [324].[382] X. C. Yang, B. Samanta, S. S. Agasti, Y. Jeong, Z. Zhu, S. Rana,

O. R. Miranda, V. M. Rotello, Angew. Chem. 2011, 123, 497 –501; Angew. Chem. Int. Ed. 2011, 50, 477 – 481.

[383] R. Mout, D. F. Moyano, S. Rana, V. M. Rotello, Chem. Soc. Rev.2012, 41, 2539 – 2544.

[384] Y. C. Yeh, B. Creran, V. M. Rotello, Nanoscale 2012, 4, 1871 –1880.

[385] Y. Horiguchi, T. Niidome, S. Yamada, N. Nakashima, Y.Niidome, Chem. Lett. 2007, 36, 952 – 953.

[386] D. A. Giljohann, D. S. Seferos, W. L. Daniel, M. D. Massich,P. C. Patel, C. A. Mirkin, Angew. Chem. 2010, 122, 3352 – 3366;Angew. Chem. Int. Ed. 2010, 49, 3280 – 3294.

[387] S. E. Lee, D. Y. Sasaki, T. D. Perroud, D. Yoo, K. D. Patel, L. P.Lee, J. Am. Chem. Soc. 2009, 131, 14066 – 14074.

[388] C. Loo, A. Lin, L. Hirsch, M. Lee, J. Barton, N. J. Halas, J. West,R. Drezek, Technol. Cancer Res. Treat. 2004, 3, 33 – 40.

[389] See Ref. [113].[390] R. Bardhan, W. Chen, C. Perez-Torres, M. Bartels, R. M.

Huschka, L. L. Zhao, E. Morosan, R. G. Pautler, A. Joshi, N. J.Halas, Adv. Funct. Mater. 2009, 19, 3901 – 3909; L. Dykman, N.Khlebtsov, Chem. Soc. Rev. 2012, 41, 2256 – 2282.

[391] A. Barhoumi, R. Huschka, R. Bardhan, M. W. Knight, N. J.Halas, Chem. Phys. Lett. 2009, 482, 171 – 179.

[392] R. Huschka, O. Neumann, A. Barhoumi, N. J. Halas, Nano Lett.2010, 10, 4117 – 4122.

[393] W. Chen, R. Bardhan, M. Bartels, C. Perez-Torres, R. G.Pautler, N. J. Halas, A. Joshi, Mol. Cancer Ther. 2010, 9, 1028 –1038.

[394] M. Choi, R. Bardhan, K. J. Stanton-Maxey, S. Badve, H.Nakshatri, K. M. Stantz, N. Cao, N. J. Halas, S. E. Clare, CancerNano 2012, 3, 47 – 54.

[395] W. Y. Li, X. Cai, C. Kim, G. Sun, Y. Zhang, R. Deng, M. X.Yang, J. Chen, S. Achilefu, L. V. Wang, Y. N. Xia, Nanoscale2011, 3, 1724 – 1730.

[396] G. D. Moon, S. W. Choi, X. Cai, W. Y. Li, E. C. Cho, U. Jeong,L. V. Wang, Y. N. Xia, J. Am. Chem. Soc. 2011, 133, 4762 – 4765.

[397] See Ref. [327].

[398] E. Boisselier, D. Astruc, Chem. Soc. Rev. 2009, 38, 1759 – 1782.[399] A. M. Alkilany, C. J. Murphy, J. Nanopart. Res. 2010, 12, 2313 –

2333.[400] A. M. Alkilany, P. K. Nagaria, C. R. Hexel, T. J. Shaw, C. J.

Murphy, M. D. Wyatt, Small 2009, 5, 701 – 708.[401] K. Bilberg, M. B. Hovgaard, F. Besenbacher, E. Baatru, J.

Toxicol. 2012, 2012, article ID 293784.[402] D. Astruc, F. Lu, J. Ruiz, Angew. Chem. 2005, 117, 8062 – 8083;

Angew. Chem. Int. Ed. 2005, 44, 7852 – 7872.[403] W. Jiang, B. Y. S. Kim, J. T. Rutka, W. C. W. Chan, Nat.

Nanotechnol. 2008, 3, 145 – 150.[404] E. C. Cho, J. Xie, P. A. Wurm, Y. Xia, Nano Lett. 2009, 9, 1080 –

1084.[405] E. C. Cho, Q. Zhang, Y. Xia, Nanotechnology 2011, 6, 385 – 391.[406] Y. S. Chen, Y. C. Hung, I. Liau, G. S. Huang, Nanoscale Res.

Lett. 2009, 4, 858 – 864.[407] C. Lasagna-Reeves, D. Gonzalez-Romero, M. A. Barria, I.

Olmedo, A. Clos, V. M. S. Ramanujam, A. Urayama, L.Vergara, M. J. Kogan, C. Soto, Biochem. Biophys. Res.Commun. 2010, 393, 649 – 655.

[408] W. H. De Jong, W. I. Hagens, P. Krystek, M. C. Burger,A. J. A. M. Sips, R. E. Geertsma, Biomaterials 2008, 29,1912 – 1919.

[409] H. S. Choi, W. Liu, P. Misra, E. Tanaka, J. Zimmer, B. I. Ipe,M. G. Nawendi, J. V. Frangioni, Nat. Biotechnol. 2007, 25,1165 – 1170.

[410] M. Semmler-Behnke, W. G. Kreyling, J. Lipka, S. Fertsch, A.Wenk, S. Takenaka, G. Schmid, W. Brandau, Small 2008, 4,2108 – 2111.

[411] C. Zhou, M. Long, Y. Qin, X. Sun, J. Zheng, Angew. Chem.2011, 123, 3226 – 3230; Angew. Chem. Int. Ed. 2011, 50, 3168 –3172.

[412] J. L. Ferry, P. Craig, C. Hexel, P. Sisco, R. Frey, P. L. Pennington,M. H. Fulton, I. G. Scott, A. W. Decho, S. Kashiwada, C. J.Murphy, T. J. Shaw, Nat. Nanotechnol. 2009, 4, 441 – 444.

[413] Y. Xia, Y. Xiong, B. Lim, S. E. Skrabalak, Angew. Chem. 2009,121, 62 – 108; Angew. Chem. Int. Ed. 2009, 48, 60 – 103.

[414] V. V. Pushkarev, Z. W. Zu, K. J. An, A. Hervier, G. A.Somorjai, Top. Catal. 2012, 55, 1257 – 1275.

[415] J. Ye, F. F. Wen, H. Sobhani, J. B. Lassiter, P. Van Dorpe, P.Nordlander, N. J. Halas, Nano Lett. 2012, 12, 1660 – 1667.

[416] Note Added In Proof : Major contributions to the field ofanisotropic AuNPs have appeared in 2013 concerning synthe-ses,[417,418] mechanical properties,[419] polyelectrolytes,[420] DNA-directed self-assembly,[421] biomedicine,[422–424] catalysis,[425–429]

and sensing.[429]

[417] G. J. Hutchings, C. J. Kiely, Acc. Chem. Res. 2013, 46, 1759 –1772.

[418] D. Rodr�guez-Fern�ndez, T. Altantzis, H. Heidari, S. Bals, L. M.Liz-Marz�n, Chem. Commun. 2014, 50, 79 – 81.

[419] C. Yan, I. Arfaoui, N. Goubet, M. – P. Pileni, Adv. Funct. Mater.2013, 23, 2315 – 2321.

[420] S. T. Sivapalan, B. M. DeVetter, T. K. Yang, M. V. Schulmerich,R. Bhargava, C. J. Murphy, J. Phys. Chem. C 2013, 117, 10677 –10682.

[421] S. J. Varrow, A. M. Funston, X. Wei, P. Mulvaney, Nano Today2013, 8, 138 – 167.

[422] M. D. Blankschien, L. A. Pretzer, R. Huschka, N. J. Halas, R.Gonzalez, M. S. Wong, ACS Nano 2013, 7, 654 – 663.

[423] Y. Wang, K. C. L. Black, H. Luehmann, W. Li, Y. Zhang, X. Cai,D. Wan, S. – Y. Liu, M. Li, P. Kim, Z. – Y. Li, L. V. Wang, Y. Liu,Y. Xia, ACS Nano 2013, 7, 2068 – 2077.

[424] C. Leduc, S. Si, J. Gautier, M. Soto-Ribeiro, B. Wehrle-Haller,A. Gautreau, G. Giannone, L. Cognet, B. Lounis, Nano Lett.2013, 13, 1489 – 1494.

[425] T. Akita, M. Kohyama, M. Haruta, Acc. Chem. Res. 2013, 46,1773 – 1782.

.AngewandteReviews



125



http://dx.doi.org/10.1021/bc070132i

http://dx.doi.org/10.1364/OE.14.006724

http://dx.doi.org/10.1016/j.canlet.2008.04.026

http://dx.doi.org/10.1016/j.canlet.2008.04.026

http://dx.doi.org/10.1039/c1cs15237h

http://dx.doi.org/10.1364/OL.30.001012


http://dx.doi.org/10.1021/nl062962v

http://dx.doi.org/10.1016/j.biomaterials.2010.08.068



http://dx.doi.org/10.1364/OE.16.018605

http://dx.doi.org/10.1364/OE.16.018605



http://dx.doi.org/10.1021/nl070345g




http://dx.doi.org/10.1039/c2cs15294k

http://dx.doi.org/10.1039/c2cs15294k

http://dx.doi.org/10.1039/c1nr11188d

http://dx.doi.org/10.1039/c1nr11188d

http://dx.doi.org/10.1246/cl.2007.952



http://dx.doi.org/10.1021/ja904326j


http://dx.doi.org/10.1039/c1cs15166e


http://dx.doi.org/10.1021/nl102293b

http://dx.doi.org/10.1021/nl102293b

http://dx.doi.org/10.1158/1535-7163.MCT-09-0829

http://dx.doi.org/10.1158/1535-7163.MCT-09-0829

http://dx.doi.org/10.1007/s12645-012-0029-9

http://dx.doi.org/10.1007/s12645-012-0029-9

http://dx.doi.org/10.1039/c0nr00932f

http://dx.doi.org/10.1039/c0nr00932f



http://dx.doi.org/10.1007/s11051-010-9911-8

http://dx.doi.org/10.1007/s11051-010-9911-8







http://dx.doi.org/10.1007/s11671-009-9334-6

http://dx.doi.org/10.1007/s11671-009-9334-6

http://dx.doi.org/10.1016/j.bbrc.2010.02.046

http://dx.doi.org/10.1016/j.bbrc.2010.02.046













http://dx.doi.org/10.1007/s11244-012-9915-y


http://dx.doi.org/10.1021/ar300356m

http://dx.doi.org/10.1021/ar300356m

http://dx.doi.org/10.1039/c3cc47531j





http://dx.doi.org/10.1021/nn304332s




[426] A. Corma, P. Concepci�n, M. Boronat, M. J. Sabater, J. Navas,M. J. Yacaman, E. Larios, A. Posadas, M. A. L�pez-Quintela,D. Buceta, E. Mendoza, G. Guilera, A. Mayoral, Nat. Chem.2013, 5, 775 – 781.

[427] M. A. Mahmoud, R. Narayanan, M. A. El-Sayed, Acc. Chem.Res. 2013, 46, 1795 – 1805.

[428] G. Liu, K. L. Young, X. Liao, M. L. Personick, C. A. Mirkin, J.Am. Chem. Soc. 2013, 135, 12196 – 12199.

[429] P. Zhao, N. Li, L. Salmon, N. Liu, J. Ruiz, D. Astruc, Chem.Commun. 2013, 49, 3218 – 3220.


Chemie


126








Conclusion and perspectives

In this thesis, we have investigated the synthesis, functionalization, properties of AuNPs and

their applications in various fields.

The first chapter demonstrated the development of various syntheses of AuNPs and their

morphology variations. These numerous synthetic methods lead to property and morphology

differences of AuNPs, indicating a wide range of applications. Two classic methods of

synthesis are presented: “bottom up” and “top down” approaches, each strategy having its

limitations. The “bottom up” approach was comparatively preferred in terms of morphology

control and further functionalization of AuNPs. This investigation gives us ideas of the

preparation, and in particular the categories of stabilizers. In this chapter, the significance of

novel ligand design and morphology control of AuNPs are emphasized.

The Brust-Schiffrin method leads to stable monodispersed AuNPs of small size due to the

relatively strong Au-S partially polarized covalent bond. The ligand-substitution process

allows the introduction of azido-terminated thiol access to the AuNPs surface and provides

opportunities to graft functional groups via “click” reactions in the presence of a Cu(I)-tren

catalyst. Carborane derivatives were successfully grafted on the periphery of AuNPs either by

the above-mentioned “click” process or one-step stabilization of AuNPs with pre-functional

carborane-branched thiol dendrons. The combination of PEG contributed to the solubility in

water and the bio-compatibility of carborane-functionalized AuNPs (Chapter 2). The

bifunctional AuNPs that were obtained provide a biocompatible platform in therapeutical

BNCT investigation.

A family of triazole linear molecules that contain PEG and (or) another functional fragment

were synthesized and utilized in the stabilization AuNPs. This new general strategy that

involves the use of common “click” chemistry to stabilize AuNPs with triazole ligands in

aqueous or organic media opens promising applications toward sensing, catalysis,

supramolecular encapsulation and synthesis of highly functionalized thiolated-AuNPs

(Chapter 3).

127

As an extension and comparitive study of linear PEG-triazole stabilized AuNPs, two arene-

cored nona-branched dendrimers that were terminated by various lengths of PEG chains were

synthesized via “click” chemistry and were employed to stabilize AuNPs of various sizes. The

dendritic structure significantly influences the formation of AuNPs, and the catalysis

efficiency of 4-NP reduction catalyzed by these AuNPs. The dendrimer acts not only template

but also as a nanoreactor owing to the combination of the dendrimer structure and the flexible

Au-trz bonding.

Importantly, 4-NP reduction reactions effectively serves as a model reaction describing the

size, species and the surface properties of metal NPs. AuNPs as electron reservoir redox

catalysts show the strong stereoelectronic ligand influence in catalytic 4-NP reduction. In our

investigation of AuNP catalyzed 4-NP reduction, it was found that the AuNPs surface

behaves as an “electron reservoir”, because the storage of electrons at the AuNP surface upon

NaBH4 reduction is crucial in the inner-sphere redox catalysis of substrate trtansformation at

the AuNP surface (Chapter 4).

The systematic introduction of anisotropic AuNPs in the last chapter of this thesis broadens

our view of synthesis, morphology and applications of AuNPs in many fields. The advantage

of anisotropic AuNPs compared to classic gold nanospheres are not only their better

definition as precise nanostructures, but also their excellent optical and catalytic properties.

These gold nanocrystals are promising materials in nanomedicine and nanotechnology in the

close future.

In summary, this thesis has illustrated the state-of-the-art in AuNPs synthesis, properties,

morphologies and various applications as well as the development of trends of Au

nanoscience. With these basis, AuNPs with various functionalities and capabilities were

prepared involving development of new strategies, with significant influence towards

nanoscience applications.

128

ANNEX

Synthesis and in vitro Studies of AuNPs

Loaded with Docetaxel

129

Introduction

In the ANNEX of this thesis, a targeted anticancer drug delivery system was

constructed involving biocompatible AuNPs. To prepare biocompatible AuNPs, a

variety of water-soluble PEG-thiols were synthesized and used as ligands. The

enhanced permeability and retention (EPR) effect of PEG species contributed to the

biocompatibility and also vectorization of these PEGylated AuNPs. Folate that is a

broadly used targeting agent was introduced to the periphery of the PEG-AuNPs. The

bifunctional AuNPs were then loaded with docetaxel that is known as one of the most

efficient anticancer drugs but of very poor water solubility. The cytotoxicity towards

LnCaP prostate cancer cell was estimated in vitro to confirm the biocompatibility of

multifunctional nanocarrier. It was found that the drug- loaded AuNPs reduced the

cell viability in more than 50% in treatment.

Such in vitro studies in Bordeaux were initiated by Professor Jacques Robert from the

Bergonie Anti-Cancer Institute of Bordeaux, and the first collaborative paper between

the group of Professor Jacques Robert and our group was reported in 2011 (1). The

present publication represent an on-going study report.

The present study published in the paper (2) of this ANNEX was conducted in

collaboration with the group of Dr. Gillian Barratt from the Pharmacy department of

Chatenay-Malabry (Institut Galien, Paris-Sud University). Rachel Oliveira from that

group carried out experimental in vitro studies, and Dr. Pengxiaing Zhao (primarily)

and myself in ISM constructed the nanovectors. All the chemical synthesis of ligands,

and the preparations of various functionalized AuNPs containing PEG and folate at

the periphery were completed in our laboratory of the Bordeaux University.

(1) A. François, A. Laroche, N. Pinaud, L. Salmon, J. Ruiz, J. Robert, D. Astruc

Encapsulation of docetaxel into PEGylated gold nanoparticles for

vectorization to cancer cells and in vitro results ChemMedChem 2011, 6,

2003-2008.

(2) R. Oliveira, P. Zhao, N. Li, L. C de Santa Maria, J. Vergnaud-Gauduchon, J.

Ruiz; D. Astruc, G. Barratt.Synthesis and in-vitro studies of gold nanoparticles

loaded with docetaxel. Internat. J. Pharmaceutics, 2013, 454, 703-711.

130

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International Journal of Pharmaceutics 454 (2013) 703– 711

Contents lists available at SciVerse ScienceDirect

International Journal of Pharmaceutics

j o ur nal ho me page: www.elsev ier .com/ locate / i jpharm

ynthesis and in vitro studies of gold nanoparticlesoaded with docetaxel

achel de Oliveiraa,b, Pengxiang Zhaoc, Na Li c, Luiz Claudio de Santa Mariaa,uliette Vergnaudb, Jaime Ruizc, Didier Astrucc, Gillian Barrattb,∗

Universidade do Estado do Rio de Janeiro, Instituto de Química, BrazilInsitut Galien Paris-Sud, UMR CNRS 8612, Faculté de Pharmacie, Univ. Paris-Sud, LabEx LERMIT, Châtenay-Malabry, FranceInstitut de Sciences Moléculaires, Université Bordeaux I, France

a r t i c l e i n f o

rticle history:eceived 11 February 2013eceived in revised form 6 May 2013ccepted 11 May 2013vailable online 21 May 2013

a b s t r a c t

The aim of these studies was to synthesize, characterize and evaluate the efficacy of pegylated goldnanoparticles (AuNPs) that differed in their PEG molecular weight, using PEG 550 and PEG 2000. The syn-thesis of the gold nanoparticles was carried out by modified Brust method with a diameter of 4–15 nm.The targeting agent folic acid was introduced by the covalent linkage. Finally, the anti-cancer drug doce-taxel was encapsulated by the AuNPs by non covalent adsorption. The nanoparticles were characterizedby transmission electron microscopy and used for in vitro studies against a hormone-responsive prostate

eywords:old nanoparticlesEGolateocetaxelrostate cancernCaP cells

cancer cell line, LnCaP. The loaded nanoparticles reduced the cell viability in more than 50% at concen-trations of 6 nM and above after 144 h of treatment. Moreover, observation of prostate cancer cells byoptical microscopy showed damage to the cells after exposure to drug-loaded AuNPs while unloadedAuNPs had much less effect.

© 2013 Elsevier B.V. All rights reserved.

. Introduction

Prostate cancer is the second most important cancer in termsf incidence in both sexes and the sixth in terms of mortality foren throughout the world according to the International Agency

or Research on Cancer (Ferlay et al., 2010). At the moment, thisancer is treated with hormone therapy, but this is usually onlyffective for 24–36 months before the patient develops resistanceHolzbeierlein et al., 2004). Docetaxel was the first cytotoxic ther-py to show a survival benefit in castration-resistant prostateancer. For this reason, it remains an important part of the treat-ent against metastatic prostate cancer despite its toxicity and

ther limitations (Hwang, 2012).Like paclitaxel, docetaxel belongs to the family of taxanes,

hich are diterpenes produced by plants of the genus Taxus (Zhao
nd Astruc, 2012). Docetaxel is a semi-synthetic taxane that bindsrreversibly to �-actin, thus altering microtubule polymerizationynamics, disrupting cell mitosis and interphase microtubule
∗ Corresponding author at: Institut Galien Paris-Sud, UMR CNRS 8612, Faculté deharmacie, 5 rue J.B. Clément, 92290 Châtenay-Malabry, France.el.: +33 0146835627; fax: +33 0146835946.

E-mail address: [email protected] (G. Barratt).

378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ijpharm.2013.05.031

131

function and triggering apoptosis (Kraus et al., 2003). In phase-IIstudies, combinations of drugs including docetaxel have beenshown to result in a significantly higher PSA decline ≥50% inhormone-refractory prostate cancer patients (Ferrero et al., 2006;Mezynski et al., 2012; Oudard et al., 2005). However, the toxicityof the drug remains a concern.

Much research is currently being directed toward developingtargeted delivery systems for docetaxel, in order to increase theamount of drug reaching the cancer cells and spare normal cells.Lipid nanocapsules (Sánchez-Moreno et al., 2012), nanoparticlespiloted by aptamers (Farokhzad et al., 2006) and block copolymermicelles (Gao et al., 2008; Gaucher et al., 2005; Mei et al., 2009;Ungaro et al., 2012) are some examples of nanocarriers contain-ing docetaxel designed to target various types of cancer, such aslung, breast and prostate cancer. The encapsulation of this moleculewithin gold nanoparticles bearing folate on their surface and thusable to target the prostate cancer cells is an original therapeuticapproach to improve its effectiveness.

Gold nanoparticles of various sizes and morphologies haveattracted considerable interest for medical applications (Boisselier
and Astruc, 2009; Zhao et al., 2013), including photothermal ther-apy (Lal et al., 2008; Niidome et al., 2006; Pissuwan et al., 2006),cancer diagnosis (Lee, 2007; Llevot and Astruc, 2012; Zeng et al.,2011), tumor imaging (Copland et al., 2004; Kim et al., 2010,) and
dx.doi.org/10.1016/j.ijpharm.2013.05.031

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dx.doi.org/10.1016/j.ijpharm.2013.05.031

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rug delivery (Brown et al., 2010; Ghosh et al., 2008; Paciotti et al.,006; Llevot and Astruc, 2012). The plasmon resonance propertiesf these nanoparticles allow their characterization and detection iniological systems (Jain et al., 2007).

There are several synthesis routes for this type of nanoparti-les (Daniel and Astruc, 2003). Surface functionalization can imparthe required properties to the nanoparticles; for example, specificecognition (Raschke et al., 2003; Wang et al., 2005) or biocompat-bility (Mout et al., 2012). The effective use of these nanoparticlesequires controlled interactions with biomacromolecules (Moutt al., 2012) and their toxicity must be carefully evaluated (Murphyt al., 2008).

Folic acid has high capacity for targeting cell membrane recep-ors on a range of cell types, allowing nanoparticle endocytosisMansouri et al., 2006). Moreover, folic acid has high affinity forrostate-specific membrane antigen (PSMA), overexpressed onrostate cancer cells (Ghosh and Heston, 2004).

This work concerns the development of a multifunctional drugelivery system (DDS) based on gold nanoparticles (AuNPs). Theanoparticle surface was modified with poly(ethylene glycol) torevent opsonization, delay their capture by macrophages andhereby allow them to circulate longer in the body and reach theumor by the EPR (enhanced permeation and retention) effect (Lyert al., 2006). The targeting agent, folic acid, was introduced by theovalent linkage on the amino-terminus of PEG. Docetaxel wasssociated with the AuNPs by non covalent adsorption.

. Materials and methods

.1. Materials

All solvents and chemicals were used as received. 1H NMRpectra were recorded at 25 ◦C with a Bruker 300 (300 MHz) spec-rometer. All the chemical shifts are reported in parts per millionı, ppm) with reference to Me4Si for the 1H and 13C NMR spec-ra. Absorption spectra were measured with Perkin-Elmer Lambda9 UV–vis. spectrometer. The CellTiter 96® AQueous One Solutioneagent (MTS) reagent was purchased from Promega (Madison,SA). Cell culture reagents were from Lonza (Basel, Belgium). Doce-

axel (DOC) and folate-binding protein (FBP) were purchased fromigma–Aldrich (Illkirch, France) and DMSO was from Carlo ErbaMilan, Italy).

.2. Synthesis of gold nanoparticles

.2.1. Synthesis of gold nanoparticles modified with PEG:uPEG550 and AuPEG2000

Gold nanoparticles containing PEG were synthesized by directodified (single-phase) Brust type method using a mixture ofAuCl4 methanol and of two thiol-PEG ligands: one type ligand

s thiol-PEG550 or thiol-PEG2000, and the other type is functionalhiol-PEG400-NH2·HCl. PEG-thiol ligands were described previ-usly (Zhao et al., 2012). Only one PEG chain length was used forhe functional thiol-PEG-ammonium: 400 Daltons (PEG 400).

.2.2. Synthesis of gold nanoparticles modified with PEG andolate: AuPEGFol550 and AuPEGFol2000.2.2.1. Synthesis of HS-PEG-NH2·HCl. The thiolate-PEG-NH2·HClHS-PEG-NH2·HCl) was synthesized as described previously bynionic ring-opening polymerization of ethylene oxide using thellyl alcohol/potassium naphthalene initiator system (Yoshimotot al., 2008). 1H NMR (CDCl3, 300 MHz) 3.58 (40H, CH2CH2O ),
.17 (2H, CH2NH2HCl), 2.70 (2H, HSCH2 ).
.2.2.2. Synthesis of HS-mPEG. The synthesis route of thiolate-PEG (HS-mPEG) was as described in Zheng et al. (2004). To

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f Pharmaceutics 454 (2013) 703– 711

summarize, the starting material for synthesizing HS-mPEG ismPEG-Br. After refluxing with thiourea in ethanol, the bromogroup was converted to an isothiourionium bromide and then toa SNa group after a second refluxing with sodium hydroxide.Neutralization with dilute HCl generated mPEG-SH. Distillation ofthe extracted HS-mPEG produced the pure compound with 74%yield. 1H NMR (CDCl3, 300 MHz) 3.60 (40H, CH2CH2O ), 3.33 (3H,

OCH3), 2.68 (2H, HSCH2 ).

2.2.2.3. Synthesis of FA-NHS. The synthesis of FA-NHS (Folate-NHS)was carried out as described previously (Zhang et al., 2010). Folicacid (FA) and anhydrous triethylamine were added to anhydrousDMSO. To this solution, N-hydroxy succinimide of dicyclohexyl car-bodiimide were added and the reaction mixture was stirred for 48 h.After filtration, the filtrate was poured into ethyl acetate. The yel-low precipitated powder was collected by filtration and washedtwice with ethanol. The crude product was further purified by pre-cipitation in ether, with a yield 77%. 1H NMR (DMSO-d6, 300 MHz)8.60 (1H, pyrazine ring), 7.61 (1H, arom ring), 6.97 (1H, CH2NHarom ring), 6.63 (1H, arom ring), 4.64 (2H, CH2NH arom ring),2.82 (4H, NOC CH2CH2 CON ), 2.29 (2H, CH2CH2COO ), 1.99(2H, CH2CH2CH2COOH).

2.2.2.4. Synthesis of AuPEGNPs. Thiolate-mPEG (Mw = 550 mg;55 mg, 0.1 mmol) and thiolate-PEG-NH2HCl (Mw = 490; 49 mg,0.1 mmol) were dissolved in 10 mL MeOH, and this solution addedinto a solution of HAuCl4 (100 mg) in 30 mL (MeOH:H2O 1:1). Afterstirring for 5 min, 1 mL of a freshly prepared NaBH4 (100 mg) aque-ous solution was added dropwise and stirred vigorously for anotherhour. Then, MeOH was evaporated under reduced pressure, and thewater phase was salted into 30 mL CH2Cl2 with a minimum amountof NaCl. The organic phase was separated and dried over Na2SO4.After evaporation of the solvent under vacuum, the crude productwas dissolved in 30 mL distilled water followed by dialysis. Yield:45 mg (61%). 1H NMR (CDCl3, 300 MHz) 3.58 (40H, CH2CH2O ),3.33 (3H, OCH3), 3.17 (2H, CH2NH2HCl), UV–vis: Plasmon bandat 530 nm.

2.2.2.5. Synthesis of AuPEGNPs bearing folate residues. 20 mg ofAuPEGNPs from the above synthesis was dissolved in 4 mL CH2Cl2,and 0.02 mmol FA-NHS was dissolved in 4 mL DMSO and added,0.2 mL triethylamine (TEA) was added to the mixture and stirredovernight at room temperature. After evaporating CH2Cl2 undervacuum, 50 mL ether was poured into the solution, and then theprecipitate was collected and dissolved into CH2Cl2, and filteredover paper. The filtrate was evaporated to obtain the productas 14 mg of deep red crystals. 1H NMR (DMSO-d6, 300 MHz)6.97(1H, CH2NH arom ring), 6.63 (1H, arom ring), 3.58 (40H,

CH2CH2CO ), 3.33 (3H, OCH3), 2.29 ( CH2CH2COO ), 1.99 (2H,CH2CH2CH2COOH). UV–vis: Plasmon band at 530 nm.

Four different gold nanoparticles were synthesized using themethodology described above:

AuPEG550 – Gold nanoparticles modified with PEG 400 and PEG550AuPEG550Fol – Gold nanoparticles modified with PEG 400 withfolate and PEG 550AuPEG2000 – Gold nanoparticles modified with PEG 400 and PEG2000AuPEG2000Fol – Gold nanoparticles modified with PEG 400 withfolate and PEG 2000.

2.3. Characterization of the nanoparticles

Transmission electron microscopy (TEM) with a PhilipsEM208 (1996) instrument equipped with wide-field CCD camera

R. de Oliveira et al. / International Journal of Pharmaceutics 454 (2013) 703– 711 705

HS

HS

HAuCl4 NaBH4

MeOH:H2O 1:1

Au SS

S

S S

S

S

S

S

S

DMSO

Au SS

S

S S

S

S

S

S

SNHS-Folate

NEt3

H2O r.t. 5d

Docetaxel

Au SS

S

S S

S

S

S

S

S

HNO

O

OH

OO

O

O

HO

OH

H

O

O

O

HO O

Docetaxel

1 2

HS O O NH3+Cl-

10

HS OO11CH3

HS

HS

S O O N10

N

NN

N

NH2

OH

NH

O

NH

O

O

HO

S

N

O

O

N

NN

N

NH2

OH

NH

O

NH

O

O

HO

O

(N -hydroxysuccinimide ester of folate)

NHS-Folate

articl

agmtP

2

swBdu

2

ls

a1

Scheme 1. Synthesis of gold nanop

cquisition (AMT) was used to evaluate the size and possible aggre-ation of nanoparticles containing PEG 550. A 120 kV electronicicroscope 1400 equipped with wide-field CCD camera acquisi-

ion (Gatan) was used to observe the gold nanoparticles containingEG 2000.

.4. Surface plasmon resonance measurement

The interactions between FBP covalently immobilized on theurface of a CM5 sensor chip and the gold nanoparticles modifiedith folate were analyzed by surface plasmon resonance with aiacore T100 instrument (GE Healthcare). Functionalization of theifferent channels of the chip was carried by amine coupling of FBPsing EDC and NHS in the presence of ethanolamine.

.5. Docetaxel loading

DOC was weighed accurately docetaxel (XP105 DeltaRange Ana-ytical Balance – Mettler Toledo, Zurich, Switzerland) and a stock
olution in DMSO at 29, 6 mg/mL was prepared.
Docetaxel was associated with the AuNPs by non covalentdsorption (Franc ois et al., 2011). 1 mL of a suspension of AuNPs at0 mg/mL was added to 14.3 mL of an aqueous solution of DOC at

133

H

es and encapsulation of docetaxel.

0.28 mg/mL. Both solutions were sterilized using a 0.2 �m celluloseacetate sterile syringe filter and handled in a sterile environmentin order to prevent microbial contamination during the associationprotocol. The mixture was stirred for 5 days at 30 ◦C. Previous work(Franc ois et al., 2011) using a spectroscopic technique showed thatthis protocol leads to association of all the added DOC. Therefore,the mixtures were used directly to evaluate cytotoxicity againsthuman prostate cancer cells, without any separation step.

The addition of DOC to the different types of nanoparticlesdescribed above generated four batches of loaded nanoparticles:

AuPEG550DOC – AuNPs containing DOC, PEG 400 and PEG 550AuPEG550DOCFol – AuNPs containing DOC, PEG 400 with folateand PEG 550AuPEG2000DOC – AuNPs containing DOC, PEG 400 and PEG 2000AuPEG2000DOCFol – AuNPs containing DOC, PEG 400 with folateand PEG 2000.

2.6. Cytotoxicity evaluation

The human prostate cell line LnCap (ECACC Reference89110211) was obtained from the Institut Bergonié, Bordeaux.Cells were routinely grown in RPMI-1640 medium supplemented

706 R. de Oliveira et al. / International Journal of Pharmaceutics 454 (2013) 703– 711

550 (A

wpa

i(c

pAapwip

hsnrac

wa

Fig. 1. TEM images of aggregates of AuPEG

ith l-glutamine, 10% of fetal bovine serum and 1%enicillin–streptomycin. Cells were incubated at 37 ◦C in antmosphere containing 5% CO2 and passaged once a week.

Cell viability was estimated by mitochondrial metabolic activ-ty using the Promega CellTiter 96® Aqueous One Cell ProliferationMTS) assay (Malich et al., 1997). The absorbance recorded in thisolorimetric assay reflects the number of viable cells.

The cells were seeded in 96-well plates (5000 cells in 50 �Ler well). Twenty-four hours later, free DOC, unloaded AuNPs anduNPs loaded with DOC were suspended in culture medium, seri-lly diluted and added 96-well microtiter plates (50 �L/well). Thelates were incubated for a further 24, 48 or 144 h. Triplicate wellsere used for each condition, and each experiment was performed

n triplicate. Ninety minutes prior to the end of each exposureeriod, the MTS reagent (20 �L/well) was added.

The absorbance of the formazan product was read with a 492 nmigh-pass filter in a Multiskan MS microwell plate reader (Lab-ystem, Ramat-Gan, Israel). Background absorbance due to theon-specific reaction between the test compounds and the MTSeagent or to light scattering was measured in wells without cellsnd was subtracted from the values measured in the presence of
ells (Hayes and Markovic, 2002).
The relative cell viability was calculated with respect to controlells containing cell culture medium without nanoparticles or DOC

ccording to the formula [A]test/[A]control × 100, in which [A]test is

134

–B) and AuPEG550Fol (C–D). Bar = 100 nm.

the absorbance of the tested sample and [A]control is the absorbanceof control sample (Braydich-Stolle et al., 2005).

2.7. Statistical analysis

Cell culture data are reported as means of three experiments(each with triplicate wells) ±SD. Statistical analysis on the raw datawas performed by one-way analysis of variance (ANOVA) followedby appropriate post hoc test (Tukey’s multiple comparison) forcomparison between groups. A significance level of 95% (p < 0.05)was accepted (Viviani et al., 2005).

3. Results and discussion

As shown in Scheme 1, AuNP were synthesized by modifiedBrust method (Brust et al., 1994). From the relative integrationsof the peaks of the aryl group of the folate in the PEG-400- orPEG-2000-folate ligand and the PEG groups in the 1H NMR spec-trum of AuNP 1 (not shown), it can be seen that the AuNP surfacewas capped by 50% HS-mPEG and 50% HS-PEG-NH2·HCl. Indeed,the integration at 3.17 ppm belongs to the CH2NH2·HCl on HS-
PEG-NH2·HCl and the integration at 3.3 ppm belongs to the OCH3on mPEG, compared with the two integrations.
This indicated that 50% of capped ligand on AuNP modified withthe two types of PEG (1 on Scheme 1) could be functionalized by


Fig. 2. TEM images showing non-lyophilized AuPEG550Fol (A–B), AuPEG2000 (C–D) and AuPEG2000Fol (E–F). Bar = 100 nm.

Nb

b53

HS-folate through the coupling reaction, leading to AuNPs withearing folate groups at their surface (2 on Scheme 1).

The folate functionalization at the termini of AuNP is confirmedy the 1H NMR spectrum (sSI). The plasmon band is observed at30 nm which also confirms that the size of the AuNPs is more than

nm (not shown).

135

The AuNPs with or without folate were used to encapsulate DOCfor the assessment of its in vitro activity. During the incubation
of DOC with the nanoparticles numerous weak hydrogen bondsform between the OH and NH group of DOC (Scheme 1) and thenumerous oxygen atoms of the PEG polymer. In this way, PEG actsas a solvent for the DOC molecules.

708 R. de Oliveira et al. / International Journal of Pharmaceutics 454 (2013) 703– 711

F ntrol wf tratio

3

tss

mofpsei(e

3

tnntltw

wss3a

ig. 3. Optical microscopy images of LnCaP cells after 144 h of contact with: (A) coree DOC; (D) cells incubated with AuPEG550FolDOC. In (C) and (D) the DOC concen

.1. Characterization of AuPEG550 and AuPEG550Fol

Fig. 1 shows TEM images of AuPEG550 before click functionaliza-ion (A and B) and AuPEG550Fol (C and D), both freeze-dried. Fig. 2hows AuPEG550Fol, AuPEG2000 and AuPEG2000Fol in aqueoususpension without freeze-drying.

The AuNPs prepared by the Schiffrin–Brust (Brust et al., 1994)ethod showed individualized particles with a gold core diameter

f 7 ± 3 nm for the nanoparticles containing PEG 550 and 10 ± 5 nmor the nanoparticles containing PEG 2000 with a narrow polydis-ersity, as determined by TEM (Fig. 2). The freeze-drying processeems to provoke the aggregation of some nanoparticles becauseven after 30 min of treatment in an ultrasound bath, the TEMmages showed aggregates with irregular shapes up to 400 nmFig. 1). This phenomenon has already been described in the lit-rature (Franc a et al., 2010).

.2. In vitro cytotoxicity toward LnCaP prostate cancer cells

The morphology of the cells was observed after 6 days ofreatment using an optical microscope (Leitz Diaplan) at 100× mag-ification. Typical photomicrographs are shown in Fig. 3. There waso difference in the morphology of untreated cells and that of cellsreated with unloaded AuNPs. However, both the nanoparticlesoaded with docetaxel and the free drug at the same concentra-ion clearly reduced the number of LnCaP cells remaining in theells.

The toxicity toward LnCaP cells of the unloaded nanoparticlesas estimated using the MTS after 24, 48 and 144 h of contact, as

een in Fig. 4. The concentrations of AuNPs were chosen to corre-pond to those of the loaded NPs and ranged between 35 pg/ml and5 �g/ml. The overall difference was not statistically significant forll concentrations and times (one-way ANOVA test).

136

ithout treatment; (B) cells incubated with AuPEG550Fol; (C) cells incubated withn was 60 �M. The bar represents 50 �m.

Fig. 5 summarizes the cell viability measured by the MTS testafter treatment with free DOC or the different AuNPs formulationscontaining DOC. The results are expressed as a percentage of theappropriate control (DMSO or empty nanoparticles).

Fig. 5A shows LnCaP viability after a 24-h exposure to DOC-loaded gold nanoparticles with PEG 550 chains, with or withoutfolate, compared with free DOC. The presence of folate did not affectthe cytotoxicity of the loaded nanoparticles at any concentration.

Free DOC produced a statistically significantly greater effect atthe two lower concentrations than the loaded NPs. However, above6.10−7 M docetaxel, the difference decreased making the effects ofall treatments statistically equivalent.

Fig. 5B shows the results of LnCaP viability after 24 h of expo-sure to DOC-loaded gold nanoparticles with longer PEG chains (PEG2000). At the lowest concentration, the AuPEG2000DOCFol wereless effective than AuPEG2000DOC; however this trend was notreproduced at other concentrations, where the two formulationsyielded similar results. Unlike AuNPs with PEG 550, the effect offree DOC was statistically significantly greater than that of loadedAuNPs at all concentrations.

Fig. 5C shows the viability after 48 h of exposure to free doce-taxel and AuNPs bearing PEG 550. The effect of AuPEG550DOC wasconcentration-dependent. AuDOCPEG550Fol showed a less evidenteffect of concentration. There was no statistically significant differ-ence between the effects of free DOC and the loaded AuNPs at anyconcentration.

Fig. 5D shows cell viability after 48 h of exposure to freeDOC and AuNPs (PEG 2000). Like the AuNPs with shorter PEG,AuPEG2000DOCFol demonstrated a statistically significant effecton cell viability for the two most concentrated suspensions com-
pared with the control. The AuNPs without folate only hadsignificant activity at 6.10−5 M. At all concentrations, treatmentwith AuPEG2000DOCFol resulted in significantly lower viabilitythan the same AuNPs without folate, except at 6.10−9 M.


Fig. 4. Mitochondrial enzyme activity of LnCaP after 24 h (A, B), 48 h (C, D) and 144 h(E, F) exposure to free DOC or to unloaded nanoparticles containing PEG 550 (A-C-E)and PEG 2000 (B-D-F). Results are expressed as a percentage of untreated control.Values are the means ± SD of three experiments.

Fig. 5. Mitochondrial enzyme activity of LnCaP after 24 h (A, B), 48 h (C, D) and 144 h(E, F) exposure to free DOC or to loaded nanoparticles containing PEG 550 (A-C-E)and PEG 2000 (B-D-F). Results are expressed as a percentage of untreated control.Values are the means ± SD of three experiments.

137

7 rnal o

(Tiew(dc

L1cto

eeeopctbtt

iadmofiwfitsAPs

lmwocislr

4

Pdfc(tittc

10 R. de Oliveira et al. / International Jou

Fig. 5E shows the cell viability after a longer exposure time144 h) for the loaded AuNPs with the shorter PEG chains (PEG 550).he DOC-loaded nanoparticles produced a significant reductionn the cell viability at all concentrations. There was no differ-nce between AuNPs with and without folate. Similar resultsere obtained with the AuNPS with longer PEG chains at 144 h

Fig. 4F). At this exposure time, the free drug showed a markedose-response, with significant reductions in viability at all con-entrations except the lowest concentration tested (6.10−11 M).

In general, free DOC showed significant cytotoxicity towardnCaP cells at all exposure times and concentrations except after44 h at the lowest concentration, confirming the sensitivity of thisell line to DOC. The decrease in the efficacy of the lower concentra-ions of DOC at long incubation times could be due to precipitationf this very hydrophobic molecule in the culture medium.

Compared with free DOC, the loaded nanoparticles were lessffective against LnCaP cells over the first 48 h. After 144 h ofxposure the nanoparticles containing DOC were in general moreffective than the free drug suggesting that there is a slower releasef the incorporated drug and that its association with the AuNPsrevented its precipitation in the medium. An effect of the PEGhain length could only be observed after 48 h of exposure, whenhe AUNPS bearing shorter chains (PEG 550) had more effect on via-ility than those with longer chains (PEG 2000). This may indicatehat the higher molecular weight PEG chains retained the DOC inhe AuNPs longer and it was therefore less available to cells.

The DOC-loaded nanoparticles reduced the mitochondrial activ-ty by 50% or more at concentrations of 6.10−9 M and abovefter 144 h of treatment (Fig. 4E and F). However, no significantifference was observed between folate-bearing AuNPs and nonodified ones. This might indicate that the folate residues are not

rientated correctly for binding to PSMA, or that the non modi-ed PEG chains cause steric hindrance, especially since these chainsere longer than those carrying the folate. This hypothesis was con-rmed by surface plasmon resonance measurements made withhe Biacore instrument (data not shown). AuNPs bearing folatehowed no specific interactions with folate-binding protein (FBP).

similar observation had been made concerning liposomes bearingEG terminated with folate residues and was considered to indicateteric hindrance from the PEG chains (Botosoa et al., 2011).

The decrease in the number of cells after contact with DOC-oaded nanoparticles was confirmed by observation with an optical

icroscope. Fig. 3 shows far fewer cells after 144 h of treatmentith free or AuNP-associated DOC compared with control cultures

r cultures treated with unloaded nanoparticles, where the cellsan be seen to be growing as aggregates typical for this line. Cellsncubated with AuPEG2000DOC and AuPEG2000FolDOC (data nothown) showed similar changes in the appearance of the cell mono-ayer to AuPEG550DOC (Fig. 3B) and AuPEG550FolDOC (Fig. 3D),espectively.

. Conclusion

In this study, gold nanoparticles have been functionalized withEG 550 and PEG 2000 by “click” chemistry in order to encapsulateocetaxel by non covalent interactions. The nanoparticles were alsounctionalized with folate. The unloaded nanoparticles were notytotoxic to LnCaP cells at the concentrations used in this studybetween 35 pg/ml and 35 �g/ml). When DOC was adsorbed ontohe AuNPs it produced a sustained cytotoxic effect on LNCaP cells
n an in vitro test. These small particles could be useful for concen-rating drug in solid tumors by the EPR effect, and the properties ofhe gold core could be exploited for tumor imaging and for thermalytolysis of the tumor cells.
138

f Pharmaceutics 454 (2013) 703– 711

Acknowledgments

We thank the Bergonié Institut, Bordeaux, France for the LnCaPcells; Ludivine Houel-Renault from the Electronic Microscopy plat-form – CNRS Orsay, France and Claire Boulogne from the Imagifplatform – CNRS Gif-sur-Yvette, France for the TEM images, MagaliNoiray from the CIBLOT platform for the Biacore analysis, the Brazil-ian Ministry of Education (CAPES Nanobiotec Project 04/CII-2008,23038.019135/2009-63 and CAPES PDSE Program n◦ 05560/12 fora PhD grant to ROO, the University of Bordeaux 1 and the ChineseScholarship Council (CSC) for a PhD grant to PZ and NL.

References

Boisselier, E., Astruc, D., 2009. Gold nanoparticles in nanomedicine: preparations,imaging, diagnostics, therapies and toxicity. Chem. Soc. Rev. 38, 1759–1782.

Botosoa, E.P., Maillasson, M., Mougin-Degraef, M., Remaud-Le Saec, P., Gestin, J.-F., Jacques, Y., Barbet, J., Faivre-Chauvet, A., 2011. Antibody-hapten recognitionat the surface of functionalized liposomes studied by SPR: steric hindrance ofpegylated phospholipids in stealth liposomes prepared for targeted radionuclidedelivery. J. Drug Deliv. 2011, 368535, http://dx.doi.org/10.1155/2011/368535.

Braydich-Stolle, L., Hussain, S., Schlager, J.J., Hofmann, M.-C., 2005. In vitro cyto-toxicity of nanoparticles in mammalian germline stem cells. Toxicol. Sci. 88,412–419.

Brown, S.D., Nativo, P., Smith, J.-A., Stirling, D., Edwards, P.R., Venugopal, B., Flint, D.J.,Plumb, J.A., Graham, D., Wheate, N.J., 2010. Gold nanoparticles for the improvedanticancer drug delivery of the active component of oxaliplatin. J. Am. Chem. Soc.132, 4678–4684.

Brust, M., Walker, M., Bethell, D., Schiffrin, D.J., Whyman, R., 1994. Synthesis of thiol-derivatised gold nanoparticles in a two-phase liquid–liquid system. J. Chem. Soc.Chem. Commun. 0, 801–802.

Copland, J.A., Eghtedari, M., Popov, V.L., Kotov, N., Mamedova, N., Motamedi, M.,Oraevsky, A.A., 2004. Bioconjugated gold nanoparticles as a molecular basedcontrast agent: implications for imaging of deep tumors using optoacoustictomography. Mol. Imaging Biol. 6, 341–349.

Daniel, M.-C., Astruc, D., 2003. Gold nanoparticles: assembly, supramolecularchemistry, quantum-size-related properties, and applications toward biology,catalysis, and nanotechnology. Chem. Rev. 104, 293–346.

Farokhzad, O.C., Cheng, J., Teply, B.A., Sherifi, I., Jon, S., Kantoff, P.W., Richie, J.P.,Langer, R., 2006. Targeted nanoparticle–aptamer bioconjugates for cancerchemotherapy in vivo. Proc. Natl. Acad. Sci. U.S.A. 103, 6315–6320.

Ferlay, J., Shin, H.R., Bray, F., Forman, D., Mathers, C., Parkin, D.M., 2010. CancerIncidence and Mortality Worldwide, vol. 10. International Agency for Researchon Cancer. IARC CancerBase (accessed on 02/10/2012).

Ferrero, J.-M., Chamorey, E., Oudard, S., Dides, S., Lesbats, G., Cavaglione,G., Nouyrigat, P., Foa, C., Kaphan, R., 2006. Phase II trial evaluating adocetaxel–capecitabine combination as treatment for hormone-refractoryprostate cancer. Cancer 107, 738–745.

Franc a, Á., Pelaz, B., Moros, M., Sánchez-Espinel, C., Hernández, A., Fernández-López, C., Grazú, V., de la Fuente, J.M., Pastoriza-Santos, I., Liz-Marzán, L.M.,González-Fernández, Á., 2010. Sterilization matters: consequences of differentsterilization techniques on gold nanoparticles. Small 6, 89–95.

Franc ois, A., Laroche, A., Pinaud, N., Salmon, L., Ruiz, J., Robert, J., Astruc, D., 2011.Encapsulation of docetaxel into PEGylated gold nanoparticles for vectorizationto cancer cells. ChemMedChem 6, 2003–2008.

Gao, Y., Chen, L., Gu, W., Xi, Y., Lin, L., Li, Y., 2008. Targeted nanoassembly loaded withdocetaxel improves intracellular drug delivery and efficacy in murine breastcancer model. Mol. Pharm. 5, 1044–1054.

Gaucher, G., Dufresne, M.-H., Sant, V.P., Kang, N., Maysinger, D., Leroux, J.-C., 2005.Block copolymer micelles: preparation, characterization and application in drugdelivery. J. Control. Release 109, 169–188.

Ghosh, A., Heston, W.D.W., 2004. Tumor target prostate specific membrane antigen(PSMA) and its regulation in prostate cancer. J. Cell. Biochem. 91, 528–539.

Ghosh, P., Han, G., De, M., Kim, C.K., Rotello, V.M., 2008. Gold nanoparticles indelivery applications. Adv. Drug Deliv. Rev. 60, 1307–1315.

Hayes, A.J., Markovic, B., 2002. Toxicity of australian essential oil backhousia cit-riodora (Lemon myrtle), Part 1. Antimicrobial activity and in vitro cytotoxicity.Food Chem. Toxicol. 40, 535–543.

Holzbeierlein, J., Lal, P., LaTulippe, E., Smith, A., Satagopan, J., Zhang, L., Ryan, C.,Smith, S., Scher, H., Scardino, P., Reuter, V., Gerald, W.L., 2004. Gene expres-sion analysis of human prostate carcinoma during hormonal therapy identifiesandrogen responsive genes and mechanisms of therapy resistance. Am. J. Pathol.164, 217–227.

Hwang, C., 2012. Overcoming docetaxel resistance in prostate cancer: a perspectivereview. Ther. Adv. Med. Oncol. 4, 329–340.

Jain, P.K., Huang, W., El-Sayed, M.A., 2007. On the universal scaling behavior of the
distance decay of dlasmon doupling in metal nanoparticle pairs: a plasmon rulerequation. Nano Lett. 7, 2080–2088.
Kim, D., Jeong, Y.Y., Jon, S., 2010. A drug-loaded aptamer–gold nanoparticle biocon-jugate for combined CT imaging and therapy of prostate cancer. ACS Nano 4,3689–3696.

http://refhub.elsevier.com/S0378-5173(13)00434-1/sbref0005

















dx.doi.org/10.1155/2011/368535


































































































































































































































































































































































































rnal o

K

L

L

L

L

M

M

M

M

M

M

N

O

R. de Oliveira et al. / International Jou

raus, L., Samuel, S., Schmid, S., Dykes, D., Waud, W., Bissery, M., 2003. The mech-anism of action of docetaxel (Taxotere®) in xenograft models is not limited tobcl-2 phosphorylation. Invest. New Drugs 21, 259–268.

al, S., Clare, S.E., Halas, N.J., 2008. Nanoshell-enabled photothermal cancer therapy:impending clinical impact. Acc. Chem. Res. 41, 1842–1851.

ee, S.B., 2007. Focus on nanoparticles for cancer diagnosis and therapeutics.Nanomedicine 2, 647–648.

levot, A., Astruc, D., 2012. Applications of vectorized gold nanoparticles to thediagnosis and therapy of cancer. Chem. Soc. Rev. 41, 242–257.

yer, A.K., Khaled, G., Fang, J., Maeda, H., 2006. Exploiting the enhanced permeabilityand retention effect for tumor targeting. Drug Discov. Today 11, 812–818.

alich, G., Markovic, B., Winder, C., 1997. The sensitivity and specificity of the MTStetrazolium assay for detecting the in vitro cytotoxicity of 20 chemicals usinghuman cell lines. Toxicology 124, 179–192.

ansouri, S., Cuie, Y., Winnik, F., Shi, Q., Lavigne, P., Benderdour, M., Beaumont, E.,Fernandes, J.C., 2006. Characterization of folate-chitosan-DNA nanoparticles forgene therapy. Biomaterials 27, 2060–2065.

ei, L., Zhang, Y., Zheng, Y., Tian, G., Song, C., Yang, D., Chen, H., Sun, H., Tian, Y., Liu, K.,Li, Z., Huang, L., 2009. A novel docetaxel-loaded poly (�-Caprolactone)/pluronicF68 nanoparticle overcoming multidrug resistance for breast cancer treatment.Nanoscale Res. Lett. 4, 1530–1539.

ezynski, J., Pezaro, C., Bianchini, D., Zivi, A., Sandhu, S., Thompson, E., Hunt, J.,Sheridan, E., Baikady, B., Sarvadikar, A., Maier, G., Reid, A.H.M., Mulick Cassidy,A., Olmos, D., Attard, G., de Bono, J., 2012. Antitumour activity of docetaxelfollowing treatment with the CYP17A1 inhibitor abiraterone: clinical evidencefor cross-resistance? Ann. Oncol. 23, 2943–2947.

out, R., Moyano, D.F., Rana, S., Rotello, V.M., 2012. Surface functionalization ofnanoparticles for nanomedicine. Chem. Soc. Rev. 41, 2539–2544.

urphy, C.J., Gole, A.M., Stone, J.W., Sisco, P.N., Alkilany, A.M., Goldsmith, E.C., Baxter,S.C., 2008. Gold nanoparticles in biology: beyond toxicity to cellular imaging.Acc. Chem. Res. 41, 1721–1730.

iidome, T., Yamagata, M., Okamoto, Y., Akiyama, Y., Takahashi, H., Kawano, T.,Katayama, Y., Niidome, Y., 2006. PEG-modified gold nanorods with a stealthcharacter for in vivo applications. J. Controlled Release 114, 343–347.

udard, S., Banu, E., Beuzeboc, P., Voog, E., Dourthe, L.M., Hardy-Bessard, A.C.,
Linassier, C., Scotté, F., Banu, A., Coscas, Y., Guinet, F., Poupon, M.-F., Andrieu,J.-M., 2005. Multicenter randomized phase II study of two schedules of doce-taxel, estramustine, and prednisone versus mitoxantrone plus prednisone inpatients with metastatic hormone-refractory prostate cancer. J. Clin. Oncol. 23,3343–3351.
139

f Pharmaceutics 454 (2013) 703– 711 711

Paciotti, G.F., Kingston, D.G.I., Tamarkin, L., 2006. Colloidal gold nanoparticles:a novel nanoparticle platform for developing multifunctional tumor-targeteddrug delivery vectors. Drug Dev. Res. 67, 47–54.

Pissuwan, D., Valenzuela, S.M., Cortie, M.B., 2006. Therapeutic possibilities of plas-monically heated gold nanoparticles. Trends Biotechnol. 24, 62–67.

Raschke, G., Kowarik, S., Franzl, T., Sönnichsen, C., Klar, T.A., Feldmann, J., Nichtl, A.,Kürzinger, K., 2003. Biomolecular recognition based on single gold nanoparticlelight scattering. Nano Lett. 3, 935–938.

Sánchez-Moreno, P., Boulaiz, H., Ortega-Vinuesa, J.L., Peula-García, J.M., Aránega, A.,2012. Novel drug delivery system based on docetaxel-loaded nanocapsules asa therapeutic strategy against breast cancer cells. Int. J. Mol. Sci. 13, 4906–4919.

Ungaro, F., Conte, C., Ostacolo, L., Maglio, G., Barbieri, A., Arra, C., Misso, G.,Abbruzzese, A., Caraglia, M., Quaglia, F., 2012. Core-shell biodegradablenanoassemblies for the passive targeting of docetaxel: features, antiproliferativeactivity and in vivo toxicity. Nanomedicine 8, 637–646.

Viviani, B., Bartesaghi, S., Corsini, E., Villa, P., Ghezzi, P., Garau, A., Galli, C.L.,Marinovich, M., 2005. Erythropoietin protects primary hippocampal neuronsincreasing the expression of brain-derived neurotrophic factor. J. Neurochem.93, 412–421.

Wang, Z., Lévy, R., Fernig, D.G., Brust, M., 2005. The peptide route to multifunctionalgold nanoparticles. Bioconjugate Chem. 16, 497–500.

Yoshimoto, K., Hoshino, Y., Ishii, T., Nagasaki, Y., 2008. Binding enhancementof antigen-functionalized PEGylated gold nanoparticles onto antibody-immobilized surface by increasing the functionalized antigen using [smallalpha]-sulfanyl-[small omega]-amino-PEG. Chem. Commun. 0, 5369–5371.

Zeng, S., Yong, K.-T., Roy, I., Dinh, X.-Q., Yu, X., Luan, F., 2011. A review on function-alized gold nanoparticles for biosensing applications. Plasmonics 6, 491–506.

Zhang, C., Gao, S., Jiang, W., Lin, S., Du, F., Li, Z., Huang, W., 2010. Targeted minicircleDNA delivery using folate–poly(ethylene glycol)–polyethylenimine as non-viralcarrier. Biomaterials 31, 6075–6086.

Zhao, P., Astruc, D., 2012. Docetaxel nanotechnology in anticancer therapy.ChemMedChem 7, 952–972.

Zhao, P., Grillaud, M., Salmon, L., Ruiz, J., Astruc, D., 2012. Click functionalization ofgold nanoparticles using the very efficient catalyst copper(I) (hexabenzyl)tris(2-aminoethyl)-amine bromide. Adv. Synth. Catal. 354, 1001–1011.

Zhao, P., Li, N., Astruc, D., 2013. State of the art in gold nanoparticle synthesis. Coord.Chem. Rev. 257, 638–665.

Zheng, M., Li, Z., Huang, X., 2004. Ethylene glycol monolayer protected nanopar-ticles: synthesis, characterization, and interactions with biological molecules.Langmuir 20, 4226–4235.






















































































































































































































































































































































































































































































































Publications

1． N. Li, P. Zhao, L. Salmon, J. Ruiz, M. Zabawa, N. S. Hosmane, D. Astruc, “Click”

Star-Shaped and Dendritic PEGylated Gold Nanoparticle-Carborane Assemblies.

Inorg. Chem. 2013, 52, 11146-11155.

2． N. Li, P. Zhao, D. Astruc, The multiple shapes of anisotropic gold nanoparticles :

synthesis, properties, applications and toxicity.

Angew. Chem., Int. Ed. 2014, 52, 1756-1789.

3． N. Li, P. Zhao, N. Liu, M. Echeverría, S. Moya, L. Salmon, J. Ruiz, D. Astruc,

“Click” Chemistry Mildly Stabilizes Bifunctional Gold Nanoparticles for Sensing

and Catalysis. Chem. Eur. J., 2014, 20, 8363-8369.

4． N. Li, M. Echeverría, S. Moya, J. Ruiz, D. Astruc, “Click” Synthesis of Nona-

PEG-branched Triazole Dendrimers and Stabilization of Gold Nanoparticles that

Efficiently Catalyze p-Nitrophenol Reduction.

Inorg. Chem. 2014, 53, 6954-6961.

5． N. Li, P. Zhao, M. Echeverria, A. Rapakousiou, L. Salmon, S. Moya, J. Ruiz, D.

Astruc, stabilization of AuNPs by monofunctional triazole linked to ferronene,

ferricenium or coumarin and applications to synthesis, sensing and catalysis.

Submitted to Inorg. Chem.

6． P. Zhao, N. Li, L. Salmon, N. Liu, J. Ruiz, D. Astruc, How a simple clicked”

PEGylated 1,2,3-triazole ligand stablilizes gold nanoparticles for multiple usage.

Chem. Commun. 2013, 49, 3218-3220.

7． R. Ciganda, N. Li, C. Deraedt, S. Gatard, P. Zhao, L. Salmon, R. Hernández, J.

Ruiz, D. Astruc, Gold nanoparticles as electron reservoir redox catalysts for the 4-

nitrophenol reduction: strong stereoelectronic ligand influence.

Chem. Commun. 2014, 50, 10126-10129.

8． P. Zhao, N. Li, D. Astruc, State of the Art in the Synthesis of Gold Nanoparticles.

Coord. Chem. Rev., 2013, 257, 638-665.

9． R. Oliveira, P. Zhao, N. Li, L. C de Santa Maria, J. Vergnaud-Gauduchon, J.

Ruiz; D. Astruc, G. Barratt, Synthesis and in-vitro studies of gold nanoparticles

loaded with docetaxel.

Internat. J. Pharmaceutics, 2013, 454, 703-711.

140

Nanoparticules d’or fonctionnelles pour les applications

biomédicales et catalytiques

Résumé :

Le design et l’ingénierie de nanoparticules d’or (AuNPs) polyfonctionnelles suscitent un intérêt considérable en vue d’applications en nanomédecine, reconnaissance moléculaire, dans le domaine des capteurs et en catalyse dans un environnement aqueux. Cette thèse a été dédiée à une variété de fonctionnalisations, en particulier à l’aide de la méthode “click” impliquant la catalyse par le cuivre (I) de la cycloaddition des alcynes terminaux avec les azotures avec le catalyseur [Cu(hexabenzyltren)] Br pour l’introduction de polyéthylène glycol, carborane, ferrocène, coumarine, cyclodextrine, médicaments et molécules fluorescentes sur les AuNPs. Les ligands dits “click”, c’est-à-dire des 1,2,3-triazoles fonctionnalisés en positions 1,4 et formés de cette façon ont été ici largement utilisés afin de stabiliser des AuNPs pour des applications biomédicales et catalytiques en collaboration.

Mots clés : Nanoparticule d’or, chimie “click”, application biomédicale, catalyse,

capteur fluorescent

Title :Functionalization of gold nanoparticles for biomedical and catalytic applications

Abstract : The design and molecular engineering of multi-functional gold nanoparticles (AuNPs) is of considerable interest towards applications in nanomedicine, molecular recognition, sensing and catalysis in aqueous environments. This thesis has been devoted to a variety of functionnalizations, in particular with the copper(I)-catalyzed Alkyne Azide cycloaddition (CuAAC) using the catalyst [Cu(I)(hexabenzyltren] Br for the introduction of polyethylene glycol, carborane, ferrocene, coumarin, cyclodextrin, drugs and fluorescent probes. The so-called “clicked” ligands, 1,4-bifunctional triazoles, that were formed in this way have been exensively used to stabilize AuNPs for biomedical and catalytic collaborative applications.

Keywords : Gold nanoparticles, “click” chemistry, biomedical application, catalysis, fluorescent sensing

Unité de recherche Institut des Sciences Molécuaires (ISM, UMR CNRS 5255) Université de Bordeaux, 351 Cours de la Libération, 33405 TALENCE Cedex, France

DOCTEUR DE L'UNIVERSITÉ DE BORDEAUX

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