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8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
Oxide and hybrid nanostructures for therapeutic applications
Sudeshna Chandra KC Barick D Bahadur
Department of Metallurgical Engineering and Materials Science Indian Institute of Technology Bombay Mumbai 400076 India
a b s t r a c ta r t i c l e i n f o
Article history
Received 2 February 2011
Accepted 8 June 2011
Available online 15 June 2011
Keywords
Nanostructures
Hybrid
Stabilizers
Cancer therapy
The research on biomedical applications of nanoparticles has seen an upsurge in recent years due to their
unique capabilities in treatment of ailments Though there are ample reviews on the advances of
nanoparticles right from their fabrication to applications comparatively fewer reviews are available for the
nanostructured materials particularly on oxidesand hybrids These materials possess unique physicochemicalproperties with an ability to get functionalized at molecular and cellular level for biochemical interactions
Keeping the enormosity of the nanostructures in mind we intend to cover only the recent and most
noteworthy developments in this area We particularly emphasize on iron oxide and its derivatives zinc
oxides layered double hydroxides silica and binaryternary metal oxides and their applications in the area of
therapeutics This review also focuses on the designing of biodegradable and biocompatible nanocarriers and
critical issues related to their therapeutic applications Several representative examples discuss targeting
strategies and stimuli responsive nanocarriers and their therapeutics
copy 2011 Elsevier BV All rights reserved
Contents
1 Introduction 1267
2 Properties of the nanostructures to be used as carriers 1268
21 Size and shape 1268
22 Surface functionality 1268
3 Stabilization of oxide and hybrid nanostructures 1269
31 Organic stabilizers 1269
311 Small molecules 1269
312 Macromolecules 1269
32 Inorganic stabilizers 1270
33 Other stabilizers 1270
4 Therapeutic applications of oxide and hybrid nanostructures 1271
41 Challenges faced in the drug delivery 1271
411 Drug loading and release 1271
412 Cellular uptake and Imaging 1274
42 Hyperthermia treatment of cancer 1276
43 Other therapeutic applications 1277
44 Towards clinical trials 1277
5 Conclusion and future scope 1278Acknowledgements 1278
References 1278
1 Introduction
Advances in nanotechnology play an important role in designing
nanomaterials with speci1047297c functional properties that can address the
shortcomings in the area of diagnostics and therapeutics The
potential of nanomaterials has sparked enormous interest in the
Advanced Drug Delivery Reviews 63 (2011) 1267ndash1281
This review is part of the Advanced Drug Delivery Reviews theme issue on ldquoHybrid
Nanostructures for Diagnostics and Therapeuticsrdquo
Corresponding author
E-mail address dhirenbiitbacin (D Bahadur)
0169-409X$ ndash see front matter copy 2011 Elsevier BV All rights reserved
doi101016jaddr201106003
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews
j o u r n a l h o m e p a g e w w w e l s ev i e r c o m l o c a t e a d d r
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
PNIPAAm microgel through LBL technique possessing both thermore-
sponsivity and magnetism withhigh speci1047297c absorption ratewhich could
open up new prospects for remotely controlled drug carriers Other
polymers that display some thermosensitivity near physiological or
hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]
pluronic triblock copolymer surfactants and block copolymers [50] The
formulationof thenanoparticulatescanalso be realized by using Foodand
Drug Administration (FDA) approved biodegradable polymers such as
poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-
ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol
polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other
polymers used for aqueous stabilization of iron oxide magnetic
nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid
(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]
32 Inorganic stabilizers
Silica (SiO2) gold (Au) and silver (Ag) are extensively used for
surface modi1047297cation of the oxide nanoparticles which forms corendash
shell structures and provides stability to the nanoparticles in solution
and further help in binding various biological molecules and drugs to
the surface of nanoparticles through suitable functional groups The
stabilization of oxide nanoparticles by silica can easily be achieved
either by Stoumlber process or microemulsion method [5859] SiO2
stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-
phorescent iridium-complex has been used for applications in
photodynamic therapy [60] Surface modi1047297cation with alumina of a
substituted garnet system in an attempt to tune the TC of the
magnetic oxides for in vivo control during hyperthermia is also
noteworthy [61]
There has been considerable interest in stabilizing oxide nano-
particles with noble metal shells such as Au and Ag The magnetic
oxide nanoparticles with metal coating can be effectively stabilized in
corrosive biological conditions and can be readily functionalized
through the well-established metal-sulfur chemistry The magnetic
corendashshell nanoparticles with tunable plasmonic properties have
great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as
target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive
breast cancer cells with strong therapeutic effects When compared to
conventional single-component iron oxide NPs the AundashFe3O4 NPs
were advantageous in facilitating stepwise attachment of an antibody
to a platin complex and also for serving as magnetic and optical probe
for tracking the drug in the cells [64] The most signi1047297cant advantage
of this composite system is that it provides controlled magneto-
optical properties long term stability to the magnetic core andfunctionality to the nanoparticles
33 Other stabilizers
The amphiphilic molecules such as liposomes and micelles have
been successfully used to stabilize oxide nanoparticles for therapeutic
applications [6566] Liposomes have also the ability to encapsulate a
large number of nanoparticles and deliver them together to the speci1047297c
target site Both hydrophilic and hydrophobic foreign molecules such as
drugs and biomolecules can be easily anchored to the amphiphilic
liposomes and micelles which can enhance the multifunctionality of a
system Martina et al [67] developed magnetic 1047298uid-loaded liposomes
by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of
egg phosphatidylcholine and DSPE-PEG2000 Further it was also found
that phospholipid molecules (egg phosphatidylcholine) which are
essential precursors for liposome formation may also in1047298uence the
nucleation and growth characteristics of MNPs The effects of phospha-
tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and
their properties have been well discussed [68] Fig 1 shows a schematic
representation of TEM micrographs of various stabilizers used for
stabilizing magnetic nanoparticles
Recently dendrimers a novel class of macromolecules with highly
ordered structure hasreceived signi1047297cantattention for functionalization
and stabilization of oxide nanoparticles Dendrimer coating alters the
surface charge functionality and reactivity and enhances the stability
and dispersibility of the nanoparticles Furthermore the presence of
multiple functional groups with symmetric perfection and nanometer
scale internal cavities enables dendritic stabilized nanoparticles for
incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully
Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)
(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John
Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)
1270 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
1272 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
[1] H Maeda J Wu T Sawa Y Matsumura K Hori Tumor vascular permeabilityand the EPR effect in macromolecular therapeutics a review J Control Rel 65(2000) 271ndash284
[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
PNIPAAm microgel through LBL technique possessing both thermore-
sponsivity and magnetism withhigh speci1047297c absorption ratewhich could
open up new prospects for remotely controlled drug carriers Other
polymers that display some thermosensitivity near physiological or
hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]
pluronic triblock copolymer surfactants and block copolymers [50] The
formulationof thenanoparticulatescanalso be realized by using Foodand
Drug Administration (FDA) approved biodegradable polymers such as
poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-
ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol
polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other
polymers used for aqueous stabilization of iron oxide magnetic
nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid
(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]
32 Inorganic stabilizers
Silica (SiO2) gold (Au) and silver (Ag) are extensively used for
surface modi1047297cation of the oxide nanoparticles which forms corendash
shell structures and provides stability to the nanoparticles in solution
and further help in binding various biological molecules and drugs to
the surface of nanoparticles through suitable functional groups The
stabilization of oxide nanoparticles by silica can easily be achieved
either by Stoumlber process or microemulsion method [5859] SiO2
stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-
phorescent iridium-complex has been used for applications in
photodynamic therapy [60] Surface modi1047297cation with alumina of a
substituted garnet system in an attempt to tune the TC of the
magnetic oxides for in vivo control during hyperthermia is also
noteworthy [61]
There has been considerable interest in stabilizing oxide nano-
particles with noble metal shells such as Au and Ag The magnetic
oxide nanoparticles with metal coating can be effectively stabilized in
corrosive biological conditions and can be readily functionalized
through the well-established metal-sulfur chemistry The magnetic
corendashshell nanoparticles with tunable plasmonic properties have
great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as
target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive
breast cancer cells with strong therapeutic effects When compared to
conventional single-component iron oxide NPs the AundashFe3O4 NPs
were advantageous in facilitating stepwise attachment of an antibody
to a platin complex and also for serving as magnetic and optical probe
for tracking the drug in the cells [64] The most signi1047297cant advantage
of this composite system is that it provides controlled magneto-
optical properties long term stability to the magnetic core andfunctionality to the nanoparticles
33 Other stabilizers
The amphiphilic molecules such as liposomes and micelles have
been successfully used to stabilize oxide nanoparticles for therapeutic
applications [6566] Liposomes have also the ability to encapsulate a
large number of nanoparticles and deliver them together to the speci1047297c
target site Both hydrophilic and hydrophobic foreign molecules such as
drugs and biomolecules can be easily anchored to the amphiphilic
liposomes and micelles which can enhance the multifunctionality of a
system Martina et al [67] developed magnetic 1047298uid-loaded liposomes
by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of
egg phosphatidylcholine and DSPE-PEG2000 Further it was also found
that phospholipid molecules (egg phosphatidylcholine) which are
essential precursors for liposome formation may also in1047298uence the
nucleation and growth characteristics of MNPs The effects of phospha-
tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and
their properties have been well discussed [68] Fig 1 shows a schematic
representation of TEM micrographs of various stabilizers used for
stabilizing magnetic nanoparticles
Recently dendrimers a novel class of macromolecules with highly
ordered structure hasreceived signi1047297cantattention for functionalization
and stabilization of oxide nanoparticles Dendrimer coating alters the
surface charge functionality and reactivity and enhances the stability
and dispersibility of the nanoparticles Furthermore the presence of
multiple functional groups with symmetric perfection and nanometer
scale internal cavities enables dendritic stabilized nanoparticles for
incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully
Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)
(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John
Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)
1270 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
1272 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
PNIPAAm microgel through LBL technique possessing both thermore-
sponsivity and magnetism withhigh speci1047297c absorption ratewhich could
open up new prospects for remotely controlled drug carriers Other
polymers that display some thermosensitivity near physiological or
hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]
pluronic triblock copolymer surfactants and block copolymers [50] The
formulationof thenanoparticulatescanalso be realized by using Foodand
Drug Administration (FDA) approved biodegradable polymers such as
poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-
ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol
polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other
polymers used for aqueous stabilization of iron oxide magnetic
nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid
(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]
32 Inorganic stabilizers
Silica (SiO2) gold (Au) and silver (Ag) are extensively used for
surface modi1047297cation of the oxide nanoparticles which forms corendash
shell structures and provides stability to the nanoparticles in solution
and further help in binding various biological molecules and drugs to
the surface of nanoparticles through suitable functional groups The
stabilization of oxide nanoparticles by silica can easily be achieved
either by Stoumlber process or microemulsion method [5859] SiO2
stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-
phorescent iridium-complex has been used for applications in
photodynamic therapy [60] Surface modi1047297cation with alumina of a
substituted garnet system in an attempt to tune the TC of the
magnetic oxides for in vivo control during hyperthermia is also
noteworthy [61]
There has been considerable interest in stabilizing oxide nano-
particles with noble metal shells such as Au and Ag The magnetic
oxide nanoparticles with metal coating can be effectively stabilized in
corrosive biological conditions and can be readily functionalized
through the well-established metal-sulfur chemistry The magnetic
corendashshell nanoparticles with tunable plasmonic properties have
great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as
target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive
breast cancer cells with strong therapeutic effects When compared to
conventional single-component iron oxide NPs the AundashFe3O4 NPs
were advantageous in facilitating stepwise attachment of an antibody
to a platin complex and also for serving as magnetic and optical probe
for tracking the drug in the cells [64] The most signi1047297cant advantage
of this composite system is that it provides controlled magneto-
optical properties long term stability to the magnetic core andfunctionality to the nanoparticles
33 Other stabilizers
The amphiphilic molecules such as liposomes and micelles have
been successfully used to stabilize oxide nanoparticles for therapeutic
applications [6566] Liposomes have also the ability to encapsulate a
large number of nanoparticles and deliver them together to the speci1047297c
target site Both hydrophilic and hydrophobic foreign molecules such as
drugs and biomolecules can be easily anchored to the amphiphilic
liposomes and micelles which can enhance the multifunctionality of a
system Martina et al [67] developed magnetic 1047298uid-loaded liposomes
by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of
egg phosphatidylcholine and DSPE-PEG2000 Further it was also found
that phospholipid molecules (egg phosphatidylcholine) which are
essential precursors for liposome formation may also in1047298uence the
nucleation and growth characteristics of MNPs The effects of phospha-
tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and
their properties have been well discussed [68] Fig 1 shows a schematic
representation of TEM micrographs of various stabilizers used for
stabilizing magnetic nanoparticles
Recently dendrimers a novel class of macromolecules with highly
ordered structure hasreceived signi1047297cantattention for functionalization
and stabilization of oxide nanoparticles Dendrimer coating alters the
surface charge functionality and reactivity and enhances the stability
and dispersibility of the nanoparticles Furthermore the presence of
multiple functional groups with symmetric perfection and nanometer
scale internal cavities enables dendritic stabilized nanoparticles for
incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully
Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)
(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John
Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)
1270 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
1272 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
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[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
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[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
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[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
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[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
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[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
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[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
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[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
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[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
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stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
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[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
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[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
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nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
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8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
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[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
PNIPAAm microgel through LBL technique possessing both thermore-
sponsivity and magnetism withhigh speci1047297c absorption ratewhich could
open up new prospects for remotely controlled drug carriers Other
polymers that display some thermosensitivity near physiological or
hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]
pluronic triblock copolymer surfactants and block copolymers [50] The
formulationof thenanoparticulatescanalso be realized by using Foodand
Drug Administration (FDA) approved biodegradable polymers such as
poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-
ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol
polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other
polymers used for aqueous stabilization of iron oxide magnetic
nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid
(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]
32 Inorganic stabilizers
Silica (SiO2) gold (Au) and silver (Ag) are extensively used for
surface modi1047297cation of the oxide nanoparticles which forms corendash
shell structures and provides stability to the nanoparticles in solution
and further help in binding various biological molecules and drugs to
the surface of nanoparticles through suitable functional groups The
stabilization of oxide nanoparticles by silica can easily be achieved
either by Stoumlber process or microemulsion method [5859] SiO2
stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-
phorescent iridium-complex has been used for applications in
photodynamic therapy [60] Surface modi1047297cation with alumina of a
substituted garnet system in an attempt to tune the TC of the
magnetic oxides for in vivo control during hyperthermia is also
noteworthy [61]
There has been considerable interest in stabilizing oxide nano-
particles with noble metal shells such as Au and Ag The magnetic
oxide nanoparticles with metal coating can be effectively stabilized in
corrosive biological conditions and can be readily functionalized
through the well-established metal-sulfur chemistry The magnetic
corendashshell nanoparticles with tunable plasmonic properties have
great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as
target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive
breast cancer cells with strong therapeutic effects When compared to
conventional single-component iron oxide NPs the AundashFe3O4 NPs
were advantageous in facilitating stepwise attachment of an antibody
to a platin complex and also for serving as magnetic and optical probe
for tracking the drug in the cells [64] The most signi1047297cant advantage
of this composite system is that it provides controlled magneto-
optical properties long term stability to the magnetic core andfunctionality to the nanoparticles
33 Other stabilizers
The amphiphilic molecules such as liposomes and micelles have
been successfully used to stabilize oxide nanoparticles for therapeutic
applications [6566] Liposomes have also the ability to encapsulate a
large number of nanoparticles and deliver them together to the speci1047297c
target site Both hydrophilic and hydrophobic foreign molecules such as
drugs and biomolecules can be easily anchored to the amphiphilic
liposomes and micelles which can enhance the multifunctionality of a
system Martina et al [67] developed magnetic 1047298uid-loaded liposomes
by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of
egg phosphatidylcholine and DSPE-PEG2000 Further it was also found
that phospholipid molecules (egg phosphatidylcholine) which are
essential precursors for liposome formation may also in1047298uence the
nucleation and growth characteristics of MNPs The effects of phospha-
tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and
their properties have been well discussed [68] Fig 1 shows a schematic
representation of TEM micrographs of various stabilizers used for
stabilizing magnetic nanoparticles
Recently dendrimers a novel class of macromolecules with highly
ordered structure hasreceived signi1047297cantattention for functionalization
and stabilization of oxide nanoparticles Dendrimer coating alters the
surface charge functionality and reactivity and enhances the stability
and dispersibility of the nanoparticles Furthermore the presence of
multiple functional groups with symmetric perfection and nanometer
scale internal cavities enables dendritic stabilized nanoparticles for
incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully
Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)
(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John
Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)
1270 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
1272 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
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nanoparticles Conjugation and release of doxorubicin for therapeutic
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[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
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[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
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[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
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[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
1272 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
[1] H Maeda J Wu T Sawa Y Matsumura K Hori Tumor vascular permeabilityand the EPR effect in macromolecular therapeutics a review J Control Rel 65(2000) 271ndash284
[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
1272 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
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[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
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[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
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induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
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[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
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[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
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[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
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[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
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[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
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stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
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[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
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[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
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in the micron size range Coll Interf Sci 26 (1968) 62ndash
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nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
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[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
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8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
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discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
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[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
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[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
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[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
[1] H Maeda J Wu T Sawa Y Matsumura K Hori Tumor vascular permeabilityand the EPR effect in macromolecular therapeutics a review J Control Rel 65(2000) 271ndash284
[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
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8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
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[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
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[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
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[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
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induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
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[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
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reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
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[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
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discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
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[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
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delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
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J Pharma 365 (2009) 180ndash189
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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
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[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
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[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
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[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
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[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
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[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
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[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
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[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
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[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
[1] H Maeda J Wu T Sawa Y Matsumura K Hori Tumor vascular permeabilityand the EPR effect in macromolecular therapeutics a review J Control Rel 65(2000) 271ndash284
[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
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[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
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nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
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[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
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[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
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[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
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[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
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[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
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[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
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[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
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[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
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induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
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[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
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stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
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[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
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in the micron size range Coll Interf Sci 26 (1968) 62ndash
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nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
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[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
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[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
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discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
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[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
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J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
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[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281