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Solubilization, dispersion and stabilization ofmagnetic
nanoparticles in water and non-aqueoussolvents: recent trends
Boris I. Kharisov,a H. V. Rasika Dias,b Oxana V. Kharissova,*a
Alejandro Vazquez,a
Yolanda Penaa and Idalia Gomeza
Recent achievements in the solubilization and stabilization
ofmagnetic nanoparticles (MNPs) are reviewed. The
majority of reported MNPs correspond to iron-based {nZVI,
superparamagnetic iron oxides (SPIONs), core
shell Fe/Au or FexOy/Au nanoparticles and ferrites}
nanoparticles, with a few numbers corresponding to
MnO and cobalt nanoparticles. Magnetic nanoparticles can be
solubilized in water or non-aqueous solvents
for short or long time periods. The main approaches for MNP
solubilization are discussed, namely, suitable
choice of precursors, pH, surfactants/coating agents, and
solvents, as well as functionalizing agents. MNPs
are generally solubilized by functionalization with
water-soluble compounds/moieties (in particular, sulfonic
acid disodium salts, soluble polym
decomposition of low stability metal
The polyol strategy is frequently app
could be achieved with the help of in
In nanotechnology, one of hottest current topics corresponds
to
DRPUNMaiSH
aUniversidad Autonoma de Nuevo Leon,
hotmail.combDepartment of Chemistry and Biochemistr
Arlington, Texas 76019, USA. E-mail: dias@
Cite this: RSC Adv., 2014, 4, 45354
Received 9th July 2014Accepted 27th August 2014
DOI: 10.1039/c4ra06902a
www.rsc.org/advances
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View Article OnlineView Journal | View Issue(2006), from Rostov
StateUniversity, Russia. He is the co-
a
cles, ve book chapters, and hNational Researchers System
(Levspecial issues of international joueditorial board of four
journals.inorganic chemistry, phthalonanotechnology.
45354 | RSC Adv., 2014, 4, 45354453magnetic nanoparticles (MNPs)
due to their extensive applica-tions in areas such as biomedicine1
(in particular as MRIagents),2 drug delivery,3 and for the
remediation of pollutants4
{generally Cr(VI), As(V), Ni(II)}. A series of recent books,57
book
r Boris I. Kharisov (born inussia in 1964) is currently
arofessor and Researcher at theniversidad Autonoma deuevo Leon
(UANL). Degrees: anS in radiochemistry (1986)nd a PhD in inorganic
chem-stry (1993) from the Moscowtate University, Russia; Drab. in
physical chemistry
Dr Rasika Dias is a Professor ofChemistry at The University
ofTexas at Arlington. Born inColombo, Sri Lanka, he receivedhis BSc
Degree from the Univer-sity of Peradeniya (Sri Lanka)and a PhD from
the University ofCalifornia, Davis (USA). Dr Diaswas a visiting
Research Scientistat the DuPont Central Research& Development,
Delawarebefore joining The University of
Monterrey, Mexico. E-mail: bkhariss@
y, The University of Texas at Arlington,
uta.eduuthor of seven books, 142 arti-as two patents.
Membership:el 2). Co-editor: three invitedrnals. He is a member of
theSpecialties: coordination andcyanines, ultrasound, and
81ers, porphyrins and calixarenes), under conditions of the
thermal
complexes, coprecipitation, microwave heating, and by
ultrasonication.
lied to increase MNP solubility. The stabilization of MNPs in
solutions
organic, monomeric and polymeric compounds.
IntroductionTexas at Arlington faculty in1992. Professor Dias
specializes in inorganic and organometallicchemistry, and is the
author or co-author of 1 book, severalpatents, and over 180
articles. He has won several awards,including the 2009 Southwest
Regional American Chemical SocietyAward.
This journal is The Royal Society of Chemistry 2014
-
chapters,8,9 reviews,1018 and a host of experimental articles
havebeen published since 2000, describing the synthesis and
char-acterization methods, functionalization, peculiarities,
andapplications of MNPs. Among these, a large majority of
recentreports are dedicated to the nanoparticles of elemental
iron{nano zero-valent iron (nZVI)}, iron oxides {super-paramagnetic
iron oxide nanoparticles (SPIONs)}, coreshelliron (or iron
oxide)gold nanoparticles,19 and, less frequently,for MnO, cobalt
nanoparticles,20 and ferrites, for instancefunctionalized
ZnxMn1xFe2O4 (x 0, 0.2, 0.4, 0.6, 0.8, 1)nanoparticles.21 To date,
most interest in the clinical applica-tions of MNPs have focused on
iron oxide because of thechemical stability, biological
compatibility, and relative ease ofthe manufacture of magnetite
(Fe3O4) and maghemite (g-Fe2O3)nanoparticles.22
Magnetic nanoparticles possess distinct solubilities inaqueous
and non-aqueous solvents, depending on their sizeand the type of
functionalizing molecules. The capacity to besolubilized or
dispersed for short or long periods and thestability of MNPs in
liquid phases is very important for theabovementioned applications,
and hence, considerable eorts
have been made to achieve a higher solubility of MNPs, rst ofall
in aqueous media. Highly soluble MNPs have much greaterapplications
in biomedicine; soluble iron oxide MNPs havestronger remediation
eects compared to the insoluble ones.When studying changes in the
solubility of MNPs, the magneticinteractions23 between them, in
particular, should be taken intoaccount, as well as strategies
toward nanoseparations24 andmagnetic separations.25 In this review,
we summarize the recentachievements in the solubilization of MNPs
and give an over-view on their stabilization in solutions. We note
that specialinvestigations on the transformations of insoluble
(alreadyprepared)/ water- or organic-soluble MNPs are rare;
instead,generally, researchers synthesize directly soluble NPs.
Denitions of solubilization anddispersion terms in relation
tonanoparticles
According to non-nanochemical classic denitions reported
inWikipedia and elsewhere, solubilization (an IUPAC denition26)
Dr Oxana V. Kharissova (born in1969 in Ukraine, former USSR)is
currently a Professor andResearcher at the UANL.Degrees: MS in
crystallographyfrom Moscow State University,Russia (1994), and a
PhD inMaterials from the UniversidadAutonoma de Nuevo Leon,Mexico
(2001). Memberships:National Researchers System(Level 2), Materials
Research
Dr Yolanda Pena was born onJune 20th, 1970 in MorelosState,
Mexico. She did her PhDat the National AutonomousUniversity of
Mexico. Currently,she works at the AutonomousUniversity of Nuevo
Leon,focusing over seven years in thearea of thin lm
semiconductorswith application in solar cells.She has published 14
papers inthe JCR and is a member of the
the Optoelectronic Materials
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5 book chapters, 65 articles, and has two patents.Specialties:
nanotechnology (carbon nanotubes, nanometals,fullerenes), microwave
irradiation, and crystallography.
Dr Alejandro Vazquez receivedhis PhD in Materials Chemistryfrom
the Universidad Autonomade Nuevo Leon (UANL) in 2011at the Facultad
de CienciasQumicas, and his MSc Degree in2008 at the Facultad de
Ingen-iera Mecanica y Electrica. Since2011, he is a Professor at
theFacultad de Ciencias Qumicas,UANL. His research interestsinclude
the synthesis of nano-particles and nanostructures
design, as well as electrophoretic deposition and the
optoelectronicproperties of inorganic nanomaterials.This journal is
The Royal Society of Chemistry 2014Group in the Chemistry
ScienceFaculty at UANL; this academicgroup has been recognized
bythe Education Public Secretaryin Mexico for its high level
ofwork. Her research areas includeMaterials Chemistry,
Nano-chemistry, and Advanced Prop-erties, such as
Photonics,Plasmonics and Spintronics. Shehas over 64 scientic
papers
published in recognized journals and has participated in
morethan 120 international congresses.technical committee in
thescientic journal Chemistry Today. She is a part of the
nationalsystem of researchers of CONACyT and has directed more than
15Bachelor, Master and PhD thesis and participated in more than
25national and international congresses.
Dr Idalia Gomez is the leader ofRSC Adv., 2014, 4, 4535445381 |
45355
dellHighlight
dellHighlight
-
is a short form for micellar solubilization, a term used
incolloidal and surface chemistry. Solubilization may occur in
asystem consisting of a solvent, an association colloid (i.e.,
acolloid that forms micelles), and at least one other
componentcalled the solubilizate (i.e., the component that
undergoessolubilization). Solubilization is distinct from
dissolution (theprocess by which a solute forms a solution in a
solvent) becausethe resulting uid is a colloidal dispersion. This
suspension isdistinct from a true solution, and the amount of the
solubilizatein the micellar system can be dierent (oen higher) than
theregular solubility of the solubilizate in the solvent.
Dispersion isa process by which (in the case of solids' becoming
dispersed ina liquid) agglomerated particles are separated from
each otherand a new interface, between an inner surface of the
liquiddispersion medium and the surface of the particles to
bedispersed, is generated.27 Dispersion is a much more compli-cated
(and less-understood) process than most people believe.
Nanoparticles in solutions present typical colloidal
systems,consisting of a continuous phase, which is a dispersed
medium(solvent) and a dispersed phase (nanoparticle).28 Such
systemswith a solid dispersed phase and a liquid dispersed medium
are
misunderstanding between the terms dispersion and
solubi-lization (in particular, a discussion of these terms related
tocarbon nanotubes (CNTs) is presented in ref. 29). Manyresearchers
use the terms interchangeably, particularly whenstating the
interaction of CNTs with liquids, which can causefurther confusion.
The fundamental question when dealingwith carbon nanotubes in
liquids, particularly in water, is: arethey dissolved or dispersed?
It has been suggested that it ismore appropriate to use the term
dispersion rather thansolution. For other nanoparticles, in
particular for magneticNPs, similar discussions might also appear
later.
Nanoparticles have a particular tendency to want to lowertheir
very high surface energy, which is the origin of their
ther-modynamic instability. Bare nanoparticles tend to
stabilizethemselves either by the sorption of molecules from
thesurroundings or by lowering their surface area through
coagu-lation and agglomeration. In order to avoid this,
nanoparticleshave to be stabilized; the stabilization of NPs30 is a
very importantaspect in nanochemistry. There are two modes of
stability ofcolloidal solutions.28Kinetic stability is the
stability of the systems
Overview of the main synthesis
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solvents are frequentlycalled organosols, while analogous
dispersions in water arecalled hydrosols. A distinctive feature of
colloidal solutions istheir relatively low stability, which is
attributed to their largeparticle size and perceptible free surface
energy. Each nano-particle appears to be an aggregate of atoms or
of more or lesssimple molecules. Any change in conditions could
result inaggregate size variation and precipitate fallout. The
stability ofcolloidal solutions is considered to be one of the key
problemsof colloidal chemistry. A system is stable when its
dispersedphase can exist as separate individual particles for a
long time (afew months or even years).28
Applying both terms above (solubilization and dispersion)
tonanoparticles and then analyzing the published scienticresearch
articles, it is evident that there is an important issue or
Fig. 1 Synthesis methods for magnetic nanoparticles.45356 | RSC
Adv., 2014, 4, 4535445381techniques for magnetic nanoparticles
A plethora of techniques are nowadays used for MNP fabrica-tion
(Fig. 1). However, not all of them are suitable for
obtainingsoluble MNPs. Among the techniques, the surface
functionali-zation of MNPs with organic materials31,32 {relatively
smallmolecules (amino acids,33 citric acid salts,34
vitamins,35relative to gravity forces. Some crucial factors that
determine thekinetic stability of colloids are Brownian motion,
dispersion,viscosity of the medium, etc. Aggregation stability is
the ability ofthe system topreserve thedegree
ofparticledispersity.28This typeof stability is attributed to the
ability of nanoparticles to createlarge aggregates to adsorb
low-molecular ions on their surfacefrom the solution, leading to
formation of an adsorption layer.This journal is The Royal Society
of Chemistry 2014
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cyclodextrin,36 etc.) and surfactants,37 polymers,38,39
biologicalmolecules,40,41 etc.} or with inorganic materials
(silica,42,43
metals,44 metal oxides or suldes45) are the most common inorder
to obtain soluble MNPs. Other techniques for the prepa-ration of
soluble or insoluble MNPs include coprecipitation,46
synthesis in reverse micelles,47 sonolysis,48
electrochemicaldeposition,49 mechanochemical dispersion,50 solution
plasma51
and solgel processes,52 arc discharge,53 spray54 and laser55
pyrolysis, ow injection synthesis,56 thermal
decomposition,57
hydrothermal,58,59 microwave60 and microwave solvothermal,61
combustion synthesis,62 high-temperature annealing63 andother
high temperature syntheses,64 micro-65 and nanoreactorssuch as
protein cages,66 vesicles,67 and microemulsions.68 Interms of the
advantages and disadvantages for preparing ironoxide nanoparticles
(IONPs), regarding their size andmorphology control, thermal
decomposition by the hydro-thermal synthetic route seems to be the
optimal method. Forobtaining water-soluble and biocompatible iron
oxide nano-particles (IONPs), coprecipitation is oen employed, but
thismethod presents low control of the particle shape, and can
(generally hydrophobic group, suchas the fatty acid, alkyl
phenol(n 610, linear or branched)). Water-soluble IONPs are
func-tionalized IONPswith chemical groups on the surface that have
astrong attraction for the solvent environment (generally
hydro-philic groups, such as the ammonium salt, polyol,
lycine).Amphiphilic IONPs are functionalized IONPs with both
hydro-philic and hydrophobic chemical groups on the surface;
where,the main chain of these functionalized small molecules
orsurfactants showed the concurrence of hydrophobic andhydrophilic
structural regions, which give the functionalizedIONPs both
oil-solubility and water solubility.
A special form of soluble MNPs are magnetic uids, i.e.,stable
colloidal systems ofne single-domainmagnetic particles(for example,
Fe3O4, g-Fe2O3, Co, MnFe2O4, etc.) coated withsurfactants, and
suspended in a liquid carrier, such as water,mineral oil, damping
oil, paran, kerosene, and so on. Theproperties of magnetic uids can
be eectively controlled by anexternal magnetic eld, which opens up
broad possibilities fortechnical and biomedical applications.73,74
The most commonlyused ferrouid contains sphericalmagnetic
particleswith typicalsizes of 10 nm, dispersed in an apolar
solvent. Sedimentation of
ms
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aggregation of theparticles. Thus, as a time-competitive
alternative, the sono-chemical route can also be used to synthesize
iron oxide NPswith unusual magnetic properties. Among more rare
methods,we can mention the greener synthesis of a-Fe2O3 NPs
usingpotato as the starch template,69 plant extracts,70 or the use
ofmicroorganisms for obtaining Fe3O4 and Fe3S4.71
Iron-based nanoparticles and uids:denitions and solubility
IONPs are the most common MNPs. IONPs functionalized bysmall
molecules or surfactants can be divided into three
types:oil-soluble, water-soluble, and amphiphilic.72 Oil-soluble
IONPsare functionalized IONPs with chemical groups on the
surfacethat have a weak attraction for the solvent environment
Fig. 2 Magnetic nanoparticles with various shells. Reproduced
with perWilczewska, K. Niemirowicz, K. H. Markiewicz and H. Car,
NanoparticleThis journal is The Royal Society of Chemistry
2014these particles is suciently counteracted by Brownian motionto
keep them dispersed for years. To prevent aggregation, thecolloids
can be coveredwith a thin layer of surfactant, commonlya monolayer
of oleic acid (steric repulsion), or the particles canbe prevented
from sticking to each other by an electrostaticbilayer
(electrostatic repulsion), which gives the particlesstability in
many liquid carriers. They have found wide applica-tion in a
variety of elds, such as electronic packing, mechanicalengineering,
aerospace, and bioengineering. One of manyunique properties of
ferrouids is their tunable viscosity by anexternal magnetic eld
(the so-called magnetoviscous eect).
Iron oxide nanoparticles, due to the favorable features
theyexhibit, are the only type of MNPs approved for clinical use
bythe Food and Drug Administration.75 Their attributes
includefacile single step synthesis by the alkaline coprecipitation
of
ission of Institute of Pharmacology, Polish Academy of Sciences
{A. Z.as drug delivery systems, Pharmacol. Rep., 2012, 64,
10201037}.RSC Adv., 2014, 4, 4535445381 | 45357
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Fe2+ and Fe3+, chemical stability in physiological
conditions,and the possibility of chemical modication by coating
the ironoxide cores with various shells, e.g., golden, polymeric,
silane,or dendrimeric (Fig. 2). In addition, their extremely low
toxicityallows remediation uses based on their the reactions, shown
inFig. 3. In this respect, this is why the nZVI, IONPs, and
others(about 15 compounds) are the most frequently used MNPs,
andhence why they attract so much attention from researchers.
Solubilization of MNPs byfunctionalization
The functionalization of MNPs by a variety of distinct
organiccompounds is the standard route to increase their
solubility.The MNPs, formed by reduction reactions from metal
salts, can
be functionalized directly or step-by-step by the substitution
ofthe primary coating organic layer by another compound. Amongthe
compounds most widely used in the rst step of the
func-tionalization of MNPs, we note oleic acid77 (Fig. 4),
sodiumoleate,78 and oleylamine.7982 Oleic acid is frequently used
inferrite nanoparticle synthesis, because it can form a
denseprotective monolayer, thereby producing highly uniform
andmonodisperse particles. Generally, MNP composites
function-alized with oleic acid are rst prepared and then the oleic
acidmoiety is substituted by other compounds. Due to its
longhydrophobic tail, colloidal Fe3O4 NPs prepared using oleic
acidare highly soluble in organic solvents, such as toluene,
hexane,chloroform, etc.83
Among a host of MNPs with functionalizing agents, dopa-mine
(DA)-coated superparamagnetic iron oxide nanoparticles
Fig. 3 Schematic model of magnetic nanoparticles (nZVI, Fe3O4
andg-Fe2O3, Memetal). The zero-valent iron in the coremainly
providesthe reducing power for the reactions with contaminants. The
oxideshell provides sites for sorption. Adsorption also occurs on
the ironoxides (Fe3O4 and g-Fe2O3) surface, while Fe3O4 possesses
reducingpower.76 Reproducedwith permission of Elsevier Science {S.
C. N. Tangand I. M. C. Lo, Magnetic nanoparticles: essential
factors for sustainableenvironmental applications, Water Res.,
2013, 47(8), 26132632}.
t
Fig. 5 Schematic diagram for the synthesis of uorescent
AuFe3O4hybrid nanoparticles (FITC uorescence probe uorescein
iso-thiocyanate). Reproduced with permission of Wiley {Z. Liang
andX. Wu, A Facile Approach to Fabricate Water-soluble
AuFe3O4Nanoparticle for Liver Cancer Cells Imaging, Chin. J. Chem.,
2012, 30,13871392}.
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with iron oxide nanoparticle (righ45358 | RSC Adv., 2014, 4,
4535445381).This journal is The Royal Society of Chemistry 2014
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(SPIONs, Fe3O4@DA) were synthesized using a one-step processby a
modied coprecipitation method, and then 23 nm goldnanoparticles
were easily conjugated to Fe3O4@DA nano-particles by the
electrostatic force between the gold nano-particles and the amino
groups of dopamine, to aord water-soluble AuFe3O4 hybrid
nanoparticles (Fig. 5).84 Theseformed hybrid nanoparticles show
good water solubility andwere easily functionalized with a targeted
small peptide A54 andthe uorescence probe uorescein isothiocyanate
(FITC) forliver cancer cell BEL-7402 imaging. In a related
report,85
monodisperse, ultrasmall, water dispersible super-paramagnetic
IONPs were initially synthesized in organicsolvents using oleic
acid as a dispersant, and then underwentsubsequent ligand exchange
of oleic acid for dopamine andTiron
(4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt)(Fig. 6 and
7), which allowed for superior colloidal stability inaqueous media.
Zeta potential measurements conrmed thestability of the
nanoparticles upon redispersal in water or bio-logically relevant
buers. The synthesized particles alsoretained their general shape,
size, and crystallinity aer theligand exchange. This exchange
method is quick, consumes
minimal reagents, and can be conducted at room
temperature,making it an ecient synthetic procedure. Earlier, this
ligandexchange process of oleic acid for dopamine was studied
indetail.86 Both oleic acid and dopamine are covalently bound tothe
surface via a chelating bidentate interaction to the ironspecies.
Iron oxide NPs, upon this new functionalization,becomemore
hydrophilic. The origin of the improvement in themagnetic
properties of the Fe3O4 nanoparticles upon func-tionalization was
hypothesized to lie in the steric interactionbetween the surfactant
molecules, the oleic acid, and dopa-mine, and arising from their
strongly covalent interaction withthe Fe atoms on the oxide NP
surface to form a chelatingbidentate bond.
1,3-Dialkylimidazolium-based ionic liquids were
chemicallysynthesized and bonded on the surface of magnetic
Fe3O4nanoparticles with facile reactions (Fig. 8).87 The solubility
ofthese NPs in organic solvents depends on the alkyl chain
lengthand the anions of the ionic liquids. Moreover, the resulting
NPsshowed a specic extraction eciency to the organic
pollutants,polycyclic aromatic hydrocarbons, while the
superparamagneticproperty of the NPs facilitated the convenient
separation ofMNPs from the bulk water samples. The modied NPs were
notsoluble in water, regardless of the alkyl chain and
anions,although they could be dispersed ultrasonically. However,
they
Fig. 6 Structural formula for Tiron at neutral pH.
in
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oleic acid (OA) for dopamshaking or sonication was used to
facilitate the ligand exchange at eachstable in water and a variety
of buers.This journal is The Royal Society of Chemistry 2014were
soluble and stable in polar organic solvents (e.g., MeOH,EtOH, and
CH2Cl2); indicating their solubility and stabilitydepend on the
solvent. In strong polar solvents like MeOH andEtOH, the modied NPs
with chloride as the anion were moresoluble than those with PF6
as the anion. The solubilitydecreased with increasing alkyl
chain length: hexyl > octyl >decyl. On the other hand, in
CH2Cl2, a weak polar solvent, themodied NPs with PF6
as the anion were more soluble, withthe solubility increasing
with the increasing chain length: decyl
e (DA) or DA and Tiron on the iron oxide nanoparticle surface.
Eitherstep. IONP-DA was only stable in water; whereas, IONP-DA/T
iron wasRSC Adv., 2014, 4, 4535445381 | 45359
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NP-OTIMPF6 (1-octyl-3-TIM hexa-uorophosphate) had the highest
solubility in both strong andweak polar solvents (Fig. 9). Neither
naked NP nor modied NPswere soluble in nonpolar organic solvents,
such as hexane.
Certain attention is being paid to citrates88 and the
mecha-nisms for their interactions with MNPs. Thus, molecular
func-tionalization of the promising manganite
nanoparticlesLa0.67Sr0.33MnO3 (LSMO) in citrate media for their
solubiliza-tion in aqueous environments was studied.89 It was
revealedthat citrates are covalently attached to the surface of the
NPs(Fig. 10). The calculated donoracceptor distance is 2.24
nm,which indicates a very high eciency of energy transfer
andclearly supports the idea that 2AP was in close proximity to
thesolubilized LSMO NP surface. The prepared LSMO nano-particles
were rendered water-soluble using the reactivity of thecarboxylate
group of the citrate with the Mn center in LSMO, bytwo hours of
extensive mixing using the cyclo-mixer. These
Fig. 8 Synthesis of ionic liquid-modied Fe3O4 NPs (alkyl hexyl,
octyl
45360 | RSC Adv., 2014, 4, 4535445381functionalized manganite
NPs could nd application in theeld of nanobiotechnology, as the
solubilizing layer (citrate)provides multiple functional groups
(hydroxyl and carboxylicacids) for covalent conjugation with other
biological macro-molecules, such as small peptides, DNA, RNA, and
biocompat-ible polymers. In a related report,90 large-scale
hydrophilicsuperparamagnetic Fe3O4 nanoparticles (Fig. 11; 2040 nm
insize) were prepared in the presence of citrate and sodiumnitrate
from ferrous ion alone. The Fe3O4 NPs were found to bequite stable
and could be freely dispersed in water; the 20 nmparticles had the
best stability in water. A possible formationmechanism was proposed
by the authors to explain why themagnetic nanoparticles are highly
soluble in water; whereby,since the NPs are soluble in water but
cannot be dissolved inalcohol, the charge of the citrate ions as
surfactant must play akey role. The authors' proposal suggests that
since there arethree carboxyl groups in every citrate ion, the
repulsive forces
, and decyl).
This journal is The Royal Society of Chemistry 2014
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Fig. 11 Gram-scale highly soluble hydrophilic Fe3O4 NPs
wereprepared by using a facile one-step method. (a) Samples of
solid state
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in methanol and CH2Cl2.between the electric charges of the radical
ions make the NPsmore dispersed in water. At the same time, when
the mass ofNaNO3 is added into the reactive solution, the ionic
strength ishighly increased. This increase of ionic strength makes
thecharges of the NPs surrounding the citric acid radical
becomeequally distributed. The presence of a large amount of salt
thuschanges the solubility of organic molecules. The presence
ofanions with a bigger hydrated ion radius will steady the wateroil
interface and thus increase the solubility between the waterand
surfactant. It was also concluded that in the synthesis withferrous
ions alone (Reactions (1)(3)), Fe3O4 is formed as aresult of the
dehydration reaction of ferrous hydroxide andferric hydroxide, in
which the latter compound is produced bythe partial oxidation of
ferrous hydroxide by O2 dissolved inwater. The formation of Fe(OH)2
would be the rst process inthe synthesis. The transition
temperature of Fe(OH)2 to Fe3O4was found to be 60 C.
Fig. 10 Functionalization of manganite nanoparticles (NPs)
withcitrate ligands. Covalent attachment of the uorescent probe
NPA(4-nitrophenylanthranilate) and non-covalent adduction of one of
theDNA base mimics 2AP (2-aminopurine) are also shown. The
ecientenergy transfer (FRET) from the uorescent ligands to the NPs
and thecorresponding donoracceptor distances are also
indicated.
hydrophilic Fe3O4 NPs powder. (b) Dispersion in water, which can
bemoved by a magnet. Reproduced with permission of The
AmericanChemical Society {C. Hui, C. Shen, T. Yang, L. Bao, J.
Tian, H. Ding, C. Li
This journal is The Royal Society of Chemistry 2014Fe2+ + 2OH
Fe(OH)2 (1)
3Fe(OH)2 + O2 Fe(OH)2 + 2FeOOH + H2O (2)
Fe(OH)2 + 2FeOOH Fe3O4 + 2H2O (3)
It was also found that the concentration of the Fe2+ ions is
akey factor for controlling Fe3O4 NPs' sizes. A decrease of
theferrous precursor concentration from 0.1 M to 0.02 M allows
an
and H.-J. Gao, Large-Scale Fe3O4 Nanoparticles Soluble in
WaterSynthesized by a Facile Method, J. Phys. Chem. C, 2008, 112,
1133611339}.increase in the average size from 20 nm to 40 nm; a
meandiameter of NPs of about 20 nm were prepared by using 0.10
MFe2+ solution. If the concentration of the Fe2+ ions decreased
to0.05 M and 0.02 M, 25 nm and 40 nm Fe3O4 NPs could be
Fig. 12 Schematic illustration of the solventless synthesis
process.Reproduced with permission of Elsevier Science {Z. Wang, L.
Zhao,P. Yang, Z. Lv, H. Sun and Q. Jiang, Water-soluble amorphous
ironoxide nanoparticles synthesized by a quick pestling and
nontoxicmethod at room temperature as MRI contrast agents, Chem.
Eng. J.,2014, 235, 231235}.
RSC Adv., 2014, 4, 4535445381 | 45361
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obtained. In addition, citrates can be used for the
functionali-zation of MNPs without any solvent for further
solubilization.Thus, amorphous citrate-coated iron oxide
nanoparticles withexcellent water solubility were synthesized from
FeCl3$2H2Oand FeSO4$7H2O as the precursors at room
temperaturewithout the presence of any solvents (Fig. 12).91 The
advantagesof this method are based not only on its simplicity and
non-toxicity, but also on its low cost, making it highly suitable
forfurther applications. The authors proposed that the
citrateformed a complex compound with Fe atoms in the rst
stage,which then facilitated the binding of carboxylate groups to
thesurface of iron oxide NPs in the second step. The citrate in
thisreaction plays a dual role as a complexing agent and as
astabilizer to prevent interparticle aggregation. The
uniquehydrophilic surface structure of the particles leads to
theparticles being stable in aqueous solution with dierent pHvalues
from 5 to 7 (Fig. 13).
Derivatives of porphyrin-type macrocycles have also beenobserved
as functionalizing units for MNP dissolution. Thus,
aphotofunctional magnetic nanoparticle, where the
photo-functionality was provided by the photosensitizer (PS) of
[5,15-bis(phenyl)-10,20-bis(4-methoxycarbonylphenyl)-porphyrin]-platinum
(Fig. 14), thus generating singlet oxygen in highquantum yield, was
strategically designed and prepared by amodication process.92 Fe3O4
nanoparticles covered witholeylamine, prepared from Fe(acac)3,
1,2-hexadecanediol,oleylamine, and phenyl ether, were used as
precursors. It wasshown that the immobilized PS molecules retain
their opticaland functional properties, including the high eciency
forsinglet oxygen generation. The photofunctional
magneticnanoparticles have good solubility and stability in
water,induced by the surface modication process. In a
relatedreport,93 PS-conjugated magnetic nanoparticles of 20 nm
in
Fig. 13 Photographs of iron oxide NPs dispersed in aqueous
solutionwith dierent pH values of 3, 5, 7, 9, and 11 (from left to
right).Reproduced with permission of Elsevier Science {Z. Wang, L.
Zhao,P. Yang, Z. Lv, H. Sun and Q. Jiang, Water-soluble amorphous
ironoxide nanoparticles synthesized by a quick pestling and
nontoxic
l
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agents, Chem. Eng. J.,2014, 235, 231235}.
Fig. 14 Fabrication procedure of photofunctional magnetic
nanopartic45362 | RSC Adv., 2014, 4, 4535445381diameter were
strategically designed (Fig. 15) and prepared forgastric cancer
imaging and therapy. The second generation PSchlorin e6 (Ce6) was
covalently anchored onto the surface ofmagnetic nanoparticles with
a silane coupling agent. Theprepared Ce6-MNPs had high water
solubility, non-cytotoxicity,good biocompatibility, and a
remarkable photodynamic ecacyupon irradiation. Compared with
MNPs-NH2, the zeta poten-tials of Ce6-MNPs all bear a negative
charge (23.72, 27.09,24.94, 23.92, 21.91), which may be responsible
for theprepared Ce6-MNPs' high water dispersibility and
solubility.Finally, highly soluble superparamagnetic manganese
oxidenanoparticles (Fig. 16) were synthesized by the
thermaldecomposition of manganese(II) oleate in 1-octadecene
atelevated temperatures and then functionalized using a
hydro-philic ligand containing protoporphyrin IX as PS (Fig. 17).94
Theoptical properties of protoporphyrin IX were found to be
notsignicantly changed by binding to the MnO surface.
Thesehydrophilic functionalized MnO nanoparticles showed
thepotential for application not only as imaging agents for MRI
anduorescence microscopy but also as target systems for
photo-dynamic therapy. In addition to porphyrins, we note that
cal-ixarenes, for example, water-soluble calix[4,6]arene
appendedmagnetic nanoparticles (p-C[4]-MN and p-C[6]-MN, Fig.
18),have been used for the removal of some carcinogenic
aromaticamines.95 It was shown that sulfonic acid groups play a
major
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Fig. 15 Synthetic procedure for making Ce6-MNPs.
Fig. 16 Transmission electron microscopic (TEM) images of
sphericalmanganese oxide nanoparticles: (a) as-prepared, (b)
functionalizedwith DA-PEG-NH2 (DA 3,4-dihydroxyhydrocinnamic acid),
and (c)functionalized with DA-PEG-PP (b and c in water; PP
protopor-phyrin). (d) Aqueous solutions of DA-PEG-NH2 (odd numbers)
and DA-PEG-PP functionalized MnO nanoparticles after more than two
weeks:1 and 2 in human blood serum (stored at 4 C), 3 and 4 in
human bloodserum (at 37 C), 5 and 6 in deionized water (at 4 C),
and 7 and 8 indeionized water (at 37 C).
Fig. 17 MnO nanoparticles functionalized via a multifunctional
poly-meric ligand with suitable anchor groups and carrying amine
moieties.Protoporphyrin is bound to the PEG800 shell via an amide
bond. Theprotoporphyrin IX-tagged MnO nanoparticles are used as
photody-namic therapeutic agents to induce localized and
intracellularlyinduced apoptosis in Caki-1 cells.
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electrostatic
Fig. 18 Water-soluble calix[4,6]arene appended magnetic
nano-particles. Reproduced with permission of Springer {T. Aksoy,
S. Erde-mir, H. B. Yildiz and M. Yilmaz, Novel Water-Soluble
Calix[4,6]areneAppended Magnetic Nanoparticles for the Removal of
the Carcino-genic Aromatic Amines,Water, Air, Soil Pollut., 2012,
223, 41294139}.interactions, similar to the
Tiron-functionalizedMNPs observedabove.
Among all the functionalizing compounds, a variety of
water-soluble polymers predominate in the experiments to
solubilizeMNPs; of which, we will show only the most
representativeexamples. For instance, highly monodispersed
magnetite NPswere prepared in organic solvents and subsequently
transferredto water using a biocompatible amphiphilic polymer, in
order toprepare them for use as suitable materials for Magnetic
FluidHyperthermia.96 {It is known97 that, in the above method,
theheat dissipated from the superparamagnetic nanoparticles, inan
alternating magnetic eld can be used to locally raise
thetemperature by 5 C or more above the physiological tempera-ture
(37 C) in targeted tumor tissues, thereby encouragingeither cell
damage or death.} Indomethacin-loaded bilayer-surface magnetite
nanoparticles (9 nm in size) are alsodescribed.98 These particles
were rst stabilized with oleic acidas a primary surfactant,
followed by a poly(ethylene glycol)methyl
ether-poly(3-caprolactone) (mPEG-PCL) amphiphilicblock copolymer as
a secondary surfactant, to form nano-particles with a hydrophobic
inner shell and hydrophiliccorona. Studies on the transfer eciency
of the particles fromhexane to the water phase showed that
dispersibility of theparticles in water was promoted by increasing
the mPEG blocklengths. This enables the possible tuning of their
dispersibilityin water by adjusting the ratio of the hydrophilic to
hydrophobicmoieties in the copolymer composition. The percentage
ofmagnetite transferred to the water phase ranged from 78.9% to
RSC Adv., 2014, 4, 4535445381 | 45363
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91.2%, with the standard deviation ranging from 1.0% to 1.5%.The
particles were stable in water, but with some aggregationobserved
aer a one month period.
In addition to the example of the PEG-containing polymersabove,
iron oxide nanoparticles were also decorated onto thesurface of
fullerene (C60), and then a PEGylation was performedto improve the
solubility and biocompatibility of C60-IONP,leading to a
multifunctional C60-IONP-PEG nanocomposite withstrong
superparamagnetism and a powerful photodynamictherapy capacity
(Fig. 19).99 The resulting C60-IONP-PEGexhibited excellent
stability in water (Fig. 20) and in variousphysiological solutions,
including saline, cell medium, andserum. Then, hematoporphyrin
monomethyl ether (HMME), anew photodynamic anti-cancer drug, was
conjugated to C60-IONP-PEG, forming a C60-IONP-PEG/HMME drug
deliverysystem (Fig. 21). In in vitro and in vivo studies,
C60-IONP-PEG/HMME showed excellent PDT ecacy, magnetic
targetingproperties and MRI abilities, indicating the great
potential ofC60-IONP-PEG/HMME for cancer theranostic
applications.
The gold surface of the Fe@Au NPs was functionalized(Fig. 22)
with stained PEG thiol conjugates that enableddispersion of the
Fe@Au NPs into aqueous media.100 By using a
site preparation.
Fig. 20 Characterization of fullerenes: photos of (a) C60, (b)
C60-COOH, (c) C60-IONP, and (d) C60-IONP-PEG in water.
Reproducedwith permission of Elsevier Science {J. Shi, X. Yu, L.
Wang, Y. Liu, J. Gao,J. Zhang, R. Ma, R. Liu and Z. Zhang,
PEGylated fullerene/iron oxidenanocomposites for photodynamic
therapy, targeted drug deliveryand MR imaging, Biomaterials, 2013,
34, 96669677}.
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C60-IONP-PEG/HMME nanocompo45364 | RSC Adv., 2014, 4, 4535445381
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two bimetallic ferrites with biomedical applications.101
Thismethod is a cost-eective and easily scalable preparative
tech-nique that allows the sensitive evaluation and isolation
ofhomogeneous, water-soluble nanoparticles. In particular,cobalt
ferrite nanocrystals with a mean diameter of 6.0 nm werecoated with
1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene
glycol)-2000] (DSPE-PEG-2000) byhydrating a dry lm containing a
mixture of nanocrystals
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served as a nano-electrode for the spontaneous deposition of gold
onto thesurface of NPs, without the need for any additional agent.
70%(w/w) of particles were found to be magnetic, and the
thicknessof the gold layer was about 1.8 nm. In addition,
water-solublecobalt ferrite and manganese ferrite were used as
modelnanocrystals to illustrate the exibility of sucrose
gradientultracentrifugation, since they are representative examples
of
stabilized by oleic acid and DSPE-PEG-2000 (Fig. 23).Three kinds
of water-soluble magnetic nanoparticles (2030
nm in size) capped with dierent surface functional groups,such
as 2-pyrrolidone, triethylene glycol (TREG, see also thesection on
the polyol strategy below), and polyacrylic acid,were synthesized
by the thermal decomposition method fromFe(acac)3 (Fig. 24).102 To
investigate and improve the hydrophi-licity of nanoparticles,
polyacrylic acid (PAA, third route) wasselected by the authors for
functionalization of the magneticnanoparticle surface, because of
the copious amount ofcarboxylate groups along the polymer chain.
These functionalgroups may enhance the interaction between water
and themagnetic nanoparticles, because the free carboxylate
groupsextended in water may facilitate the dispersibility of
polyacrylicacid magnetic nanoparticles in the aqueous solution. All
threekinds of magnetic nanoparticles exhibited very
hydrophilicproperties and can be stably dissolved in water, even
aer being
Fig. 21 Scheme of C60-IONP-PEG/HMME and its
biofunctions.Reproduced with permission of Elsevier Science {J.
Shi, X. Yu, L. Wang,Y. Liu, J. Gao, J. Zhang, R. Ma, R. Liu and Z.
Zhang, PEGylated fullerene/iron oxide nanocomposites for
photodynamic therapy, targeted drugdelivery and MR imaging,
Biomaterials, 2013, 34, 96669677}.
Fig. 22 General procedure to obtain the pegylated
iron@gold(core@shell) NPs.
This journal is The Royal Society of Chemistry 2014Fig. 23
Qualitative evaluation of nanoparticle preparations. Sampleswere
initially prepared at an iron to DSPE-PEG-2000 weight ratio of (i)1
: 5, (ii) 1 : 10, and (iii) 1 : 20 by solvent exchange. (A) Samples
wereanalyzed by agarose gel electrophoresis (0.6%, 100 V, 60 min)
prior to(B) sucrose gradient ultracentrifugation. The markings in B
indicate theapproximate position of the density gradient steps
(water, 30, 40, 50,60, 70, and 80% sucrose). Reproduced with
permission of TheAmerican Chemical Society {A. M. Prantner, J.
Chen, C. B. Murray andN. Scholler, Coating Evaluation and
Purication of Monodisperse,Water-Soluble, Magnetic Nanoparticles
Using Sucrose DensityGradient Ultracentrifugation, Chem. Mater.,
2012, 24, 40084010}.RSC Adv., 2014, 4, 4535445381 | 45365
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and compared in terms of their stability. Related applications
ofpolymethacrylic acid (PMAA)104 and PAA105 to obtain water-soluble
NPs of iron oxides are also known.
Among the other uses of polymers for MNPs solubilization,
aone-step, template-free synthesis method (Fig. 26) for
preparingsuperparamagnetic polymeric microcapsules with iron oxide
(g-Fe2O3) magnetic nanoparticles embedded in the polymer shell(Fig.
27) was reported.106 Using an emulsication of the multi-phase
mixture containing liquid prepolymer (UV curable liquidphotopolymer
NOA 61) and nanoparticles in chloroform solu-tion, double emulsions
comprising a chloroform core and MPs/polymer shell were
spontaneously formed. On exposure to UVlight, these double
emulsions were converted to microcapsuleswith a polymerized
composite shell and could be moved andcollected by external
magnetic elds. One interesting propertyof these hybrid
microcapsules is their ability to reversiblyexchange water with the
environment. When the emulsionswere exposed to water by dilution of
the glycerin medium, theircores readily swelled, due to the diusion
of water into thecapsule interior. The authors believe that this
core swelling is ofosmotic origin and is due to the presence of a
small amount of
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as novel draw solutesin forward osmosis was investigated. Magnetic
nanoparticlescapped with polyacrylic acid can yield the highest
driving forceand subsequently highest water ux among the others.
Theused magnetic nanoparticles can be captured by a magneticeld and
recycled back into the stream as draw solutes in theforward osmosis
(FO) process.
Hydrophobically modied water-soluble polymers (HMWSPs){comprised
of a poly(sodium methacrylate) (PMANa) or poly-(sodium acrylate)
(PANa) backbone and pendent dodecylmethacrylate (DMA) or dodecyl
acrylamide (DAAm) chains,respectively} were synthesized, and the
hydrophobic CoFe2-O4@OAm {oleylamine coated, solvothermally
prepared fromFe(acac)3 and Co(acac)3 as precursors} MNPs were
encapsulatedinto the hydrophobic cores of the structures formed
bythe copolymers above CMC (critical micelle concentration)
Fig. 24 Synthesis routes of surface-functionalized magnetic
nano-particles. Reproduced with permission of The American
ChemicalSociety {Ming Ming Ling, Kai Yu Wang and Tai-Shung Chung,
HighlyWater-Soluble Magnetic Nanoparticles as Novel Draw Solutes
inForward Osmosis for Water Reuse, Ind. Eng. Chem. Res., 2010,
49,58695876}.through a solvent mixing procedure, resulting
inhydrophilic CoFe2O4@HMWSP nanohybrids (Fig. 25).103 Twoalternate
phase transfer approaches were also used to convertCoFe2O4@OAm MNPs
to hydrophilic ones: (a) the addition of acoating layer by
cetyltrimethyl ammonium bromide (CTAB),and (b) by the ligand
exchange procedure with 2,3-dimercapto-succinic acid (DMSA).
Aqueous CoFe2O4@HMWSP, CoFe2-O4@CTAB, and CoFe2O4@DMSA dispersions
were prepared,
Fig. 25 Schematic depiction of the stabilization of
CoFe2O4@HMWSPnanohybrids in water.
45366 | RSC Adv., 2014, 4, 4535445381glycerin in the core.
Moreover, when the shrunken driedcapsules were redispersed in water
aer the chloroform in thecore had completely evaporated, they
reswelled to their initialspherical shape. Up to seven
drying/watering cycles wererepeated, and the capsules showed fully
reversible shaperestoration.
As a rare example of the special studies into the
trans-formation of initially insoluble MNPs to soluble ones, we
noteda facile and highly ecient method, described for
transferringhydrophobic magnetic Fe3O4 nanoparticles from an
organic toaqueous solution by wrapping a thermo-responsive and
photo-crosslinkable poly(N-isopropylacrylamide) (PNIPAm)terpolymer
encapsulating the particles (Fig. 28 and 29).107 Thewrapping
procedure was introduced by the co-nonsolventtransition of PNIPAm
in the mixing solvent, so that the
Fig. 26 Schematics of the process for the synthesis of
organic/inor-ganic hybrid microcapsules. The bottom frames are
optical micro-graphs of the actual system (scale bar 10 mm). (1)
The mixturecontaining NOA prepolymer and iron oxide nanoparticles
in chloro-form is emulsied in the glycerin medium. After
emulsication, doubleemulsions containing the chloroform core and
nanoparticle contain-ing polymeric shell are spontaneously formed.
(2) After dilution of theglycerin medium with water, the inner
chloroform core swells, due towater permeation. (3 and 4) Curing
and drying of the liquid mediumresults in organic/inorganic hybrid
microcapsules, which reversiblyswell in water. Reproduced with
permission of The American ChemicalSociety {Hye Young Koo, Suk Tai
Chang, Won San Choi, Jeong-HoPark, Dong-Yu Kim and O. D. Velev,
Emulsion-Based Synthesis ofReversibly Swellable, Magnetic
Nanoparticle-Embedded PolymerMicrocapsules, Chem. Mater., 2006, 18,
33083313}.This journal is The Royal Society of Chemistry 2014
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Fe3O4 nanoparticles bynoncovalent interactions. A related organic
system was used toobtain amagnetically responsivemicrogel (Fig.
30), consisting ofsmall IONPs (15 nm in diameter) embedded in a
Fig. 27 Microscopy images of the organic/inorganic hybrid
microcapsuleTEM of the microtomed capsule. The sample is formed
from a 750 mL mixspeed of 500 rpm (the average capsule diameter is
12 3.28 mm). ReproKoo, Suk Tai Chang, Won San Choi, Jeong-Ho Park,
Dong-Yu Kim and ONanoparticle-Embedded Polymer Microcapsules, Chem.
Mater., 2006, 1
Fig. 28 Schematic depiction of the water-soluble process
forproducing hydrophobic Fe3O4 MNPs through a
poly(NIPAAm-co-MaBP-co-MAA) terpolymer and subsequent
photo-crosslinking.Reproduced with permission of Wiley {Z. Cheng,
S. Liu, H. Gao,W. Tremel, N. Ding, R. Liu, P. W. Beines and W.
Knoll, A Facile Approachfor Transferring Hydrophobic Magnetic
Nanoparticles into Water-Soluble Particles, Macromol. Chem. Phys.,
2008, 209, 11451151}.
Fig. 29 TEM images of (a) OA-coated Fe3O4 nanoparticles, and
(b)hydrogel-encapsulated Fe3O4 nanoparticles after
photo-crosslinking.Reproduced with permission of Wiley {Z. Cheng,
S. Liu, H. Gao,W. Tremel, N. Ding, R. Liu, P. W. Beines and W.
Knoll, A Facile Approachfor Transferring Hydrophobic Magnetic
Nanoparticles into Water-Soluble Particles, Macromol. Chem. Phys.,
2008, 209, 11451151}.
This journal is The Royal Society of Chemistry 2014s obtained by
(a) SEM, (b) TEM, and (c) ultrathin (100 nm) cross-sectionture of
the MPs/chloroform and NOA polymer (1 : 2 v/v), emulsied at aduced
with permission of The American Chemical Society {Hye Young. D.
Velev, Emulsion-Based Synthesis of Reversibly Swellable, Magnetic8,
33083313}.
Fig. 30 Photographs of the separation (A to B) and dispersion (B
to A)of the microgel magnetic particles (MMP): (A) without
externalmagnetic eld, (B) with external magnetic eld (the magnetic
eldstrength of the magnet is 2000 G). A color change from saddle
brownto transparent was observed when an external magnetic eld
wasapplied. Reproduced with permission of Elsevier Science {A.
Khan,biocompatible microgel varying from 65 nm to 110 nm
indiameter, which was obtained from FeCl3$6H2O andFeCl2$4H2O as
precursors.108 Polymeric microgels wereprepared by the
emulsion-free copolymerization of thermores-ponsive
N-isopropylacrylamide and acrylic acid with a water-soluble
persulfate initiator.
Also, superparamagnetic nanoparticles (magnetite Fe3O4)with a 5
nm diameter and stabilized in water (pH > 6.5) by ashell of
water-soluble poly(ethylene oxide) (PEO) chains werereported.109
Two types of diblock copolymers, i.e.,
poly(acrylicacid)-b-poly(ethylene oxide), PAA-PEO, and poly(acrylic
acid)-b-poly(acrylate methoxy poly(ethyleneoxide)), PAA-PAMPEO,
wereprepared as stabilizers with dierent compositions andmolecular
weights. On the basis of the synthesized nano-particles, the
ferrouids could be a source of heat when sub-jected to an
alternating magnetic eld. In addition, an ecientMRI T2-weighted
contrast agent incorporating potential livertargeting functionality
was synthesized via the combination ofsuperparamagnetic iron oxide
(SPIO) nanoparticles with multi-walled carbon nanotubes
(MWCNTs).110 Poly(diallyl-dimethylammonium chloride) (PDDA) was
coated onto thesurface of acid-treated MWCNTs via electrostatic
interactions,and SPIO nanoparticles modied with a potential
targetingagent, lactose-glycine adduct (Lac-Gly), were
subsequentlyimmobilized onto the surface of the PDDA-MWCNTs (Fig.
31).Dispersion tests were conducted to determine the water
Preparation and characterization of magnetic
nanoparticlesembedded in microgels, Mater. Lett., 2008, 62,
898902}.
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Fig. 33 TEM images of SPIO@Lac-Gly (a and b) and
CNT-PDDA-SPIO@Lac-Gly (c and d). Reproduced with permission of
Elsevier
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of CNT-PDDA-SPIO@Lac-Gly nanocomposites.dispersion stability of the
product (CNT-PDDA-SPIO@Lac-Gly)in comparison with the starting
material (MWCNTs) and theintermediate (CNT-PDDA). Pristine MWCNTs,
CNT-PDDA, andCNT-PDDA-SPIO@Lac-Gly were initially dispersed in
water withthe assistance of ultrasonication for 30 min. As shown
inFig. 32, pristine MWCNTs could not be dispersed in water,
evenwith assistance of ultrasound. However, CNT-PDDA and
CNT-PDDA-SPIO@Lac-Gly could maintain a stable dispersion formore
than 72 h, indicating that the PDDA coating improved theMWCNTs
dispersions in aqueous solution. Fig. 33 shows TEMimages of
SPIO@Lac-Gly and CNT-PDDA-SPIO@Lac-Gly,respectively. Most of the
SPIO@Lac-Gly particles had diame-ters of around 9 nm and were
spherical in shape; the MWCNTswere covered with small clusters of
magnetic nanoparticles, andno free nanoparticles were observed. The
fabrication of water-soluble magnetic nanoparticles by ligand
exchange withthermo-responsive polymers111 and chitosan112,113 is
also known.
In additional to the compounds above for functionalizationof
MNPs, peptides can also be used for their solubilization.
Fig. 32 Dispersion stability test of
CNT-PDDA-SPIO@Lac-Glycomposite in water. Reproduced with permission
of Elsevier Science{Y. Liu, T. C. Hughes, B. W. Muir, L. J.
Waddington, T. R. Gengenbach,C. D. Easton, T. M. Hinton, B. A.
Moat, X. Hao and J. Qiu, Water-dispersible magnetic carbon
nanotubes as T2-weighted MRI contrastagents, Biomaterials, 2014,
35, 378386}.
45368 | RSC Adv., 2014, 4, 4535445381Thus, a method for the
selective marking of amyloid brils, e.g.,insulin and Ab40, by both
uorescent and non-uorescentg-Fe2O3 nanoparticles (15 nm in size)
was developed.114 TheseIONPs of narrow size distribution were
synthesized by nucle-ation, followed by the controlled growth of
maghemite thinlms onto gelatiniron oxide nuclei, with further
surface coat-ings with a functional uorinated polymer and peptides,
e.g.,Leu-Pro-Phe-Phe-Asp (LPFFD) and Ab40, through various
acti-vation methods. The authors note that, in contrast to many
Science {Y. Liu, T. C. Hughes, B. W. Muir, L. J. Waddington, T.
R.Gengenbach, C. D. Easton, T. M. Hinton, B. A. Moat, X. Hao and J.
Qiu,Water-dispersible magnetic carbon nanotubes as T2-weighted
MRIcontrast agents, Biomaterials, 2014, 35, 378386}.uorescent
nanoparticles that have their uorescent moietiesbound to the
surface, their nanoparticles contained uorescentdye, covalently
encapsulated within the nanoparticles. Thisindicates a retention of
the surface properties, including thezeta potential and the surface
bound ligand capacity.
Coprecipitation
Coprecipitation generally consists in the simultaneous
reduc-tion of Fe2+/Fe3+ or Fen+/Au+ precursors, and it is
frequently therst step before the functionalization of formed
nakednanoparticles with organic moieties, as described above.
Severalsurfactant coating and/or stabilizing agents could be added
tothe reaction system and the temperature may also vary. As
anexample, magnetite Fe3O4 nanoparticles were synthesized
bycoprecipitating a Fe2+/Fe3+ mixed solution (molar ratio ofFe2+ :
Fe3+ 1 : 2) with a NH4OH solution in air and mixed witholeic acid
for coating with a single surfactant layer for furtherdispersion
into methylene chloride.115 Water-soluble andbiocompatible
monodispersed ultrasmall magnetic iron nano-particles (3.3 nm in
diameter) were synthesized (Fig. 34) fromFeCl3$6H2O and FeSO4$7H2O
as precursors via a high-temperature coprecipitation method using
thiol-functionalized
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acid and oleylamine, as mentioned in the sections above and
inTable 1 below) and an organic carrier liquid.118 The nano-
important biocompatible polymer that facilitates the
solubili-
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powders wereobserved to be close to spherical in shape, whereas
those of Co,SmCo, and Nd-Fe-B showed elongated rod shapes.
Thenanoparticles showed superparamagnetic behavior at
roomtemperature, except for SmCo nanoparticles, which
wereferromagnetic. When a surfactant was used along with
heptaneduring the milling, a colored liquid (for nanoparticles
smallerthan 30 nm) was obtained, along with coarse particles,
whichsedimented at the bottom of the milling vial; when
surfactantspoly(methacrylic acid) as the stabilizer.116 In
addition, SPIONwith a mean size of 12 nm were prepared under N2
atmosphere,with the support of natural polymeric starch, by
controllingchemical coprecipitation of the magnetite phase from
aqueoussolutions containing suitable salt ratios of Fe2+ and
Fe3+.117 Thesurfaces of the SPION-nanoparticles were treated with a
coor-dinatable agent (starch, dextran, PEG, or MPEG) for a
higherdispersion ability in water and to retain the
superparamagneticbehavior.
Use of surfactants and capping agents
Surfactants are classical agents in nanotechnology and arewidely
used to prevent nanoparticle aggregation. As an
example,nanoparticles of Fe, Co, FeCo, SmCo, and NdFeB systems
withsizes smaller than 30 nm and a narrow size distribution
wereprepared by ball milling in the presence of surfactants
(oleic
Fig. 34 Preparation of ultrasmall magnetic iron oxide
nanoparticles.were not added to heptane, the solvent remained clear
aermilling, because there were no nanoparticles dispersed in
theliquid.
Table 1 presents the most representative examples of
classicmagnetic nanoparticles, mainly soluble in water, as well as
insome nonpolar organic solvents, and some examples of thesolvents,
surfactants, and capping agents applied for thesynthesis and
solubilization of magnetic nanoparticles. Here,we observe that
nanoparticle synthesis, leading to dispersions,could be carried out
both in water and in organic solvents.The use of sodium citrate and
polyols generally leads towater-soluble polymers, while very
frequent applications ofoleylamine and oleic acid could assist the
solubility in solventsof a specic nature. 1-Octadecene, polyols,
and especially water
This journal is The Royal Society of Chemistry 2014zation and
long-term circulation of proteins, viruses, and otherbiological
macromolecules. Thus, magnetite nanoparticles(Fig. 35) were
synthesized in liquid polyols at elevatedtemperatures.121 Polyol
solvent was found to play a crucial rolein determining the
morphology and colloidal stability of theresulting particles. The
magnetite nanoparticles were found toare themost used solvents;
sometimes the same compound actsas the solvent, surfactant, capping
agent, and/or reductant (PAAor polyols). Water (greener solvent)
possesses obviousadvantages compared to organic solvents and so it
is mostfrequently used.
Polyol strategy
The polyol process is a versatile chemical approach, whichrefers
to the use of polyols {for example, ethylene glycol (EG),diethylene
glycol (DEG), triethylene glycol (TREG), and tetra-ethylene glycol
(TEG)} to reduce metal salts to metal particles,and that has
successfully been used to prepare a great varietyof non-aggregated
particles of inorganic compounds.Poly(ethylene glycol) (PEG, an
amphiphilic polymer andcommonly regarded as a non-specic
interaction reducingreagent), already mentioned in the sections
above, isfrequently used for the functionalization of MNPs.120 The
pol-yols in this method oen serve as a high-boiling solvent
andreducing agent, as well as a stabilizer to control particle
growthand prevent interparticle aggregating. In addition, PEG is
anbe monodisperse, highly crystalline, and superparamagnetic
atr.t., and could be easily dispersed in aqueous media and
otherpolar solvents, due to being coated by a layer of
hydrophilicpolyol ligands in situ. A distinguishing property of
themagnetite nanoparticles obtained by the current
synthesisapproach from others obtained from a non-aqueous route
isthat the resulting magnetite nanoparticles exhibit excellentwater
solubility and no detectable aggregation is found. It iswell known
that magnetic colloidal particles attract each otherby van der
Waals forces and magnetic dipolar interactions. Theauthors
hypothesize that the reason the as-prepared magnetitenanoparticles
can be easily dissolved in high quantities inwater to aord a stable
aqueous solution is due to theformation of a steric barrier, which
arises from the strong
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synthesis of magnetic nan
Nanoparticles, size (nm)Solvent(s) during thesynthesis
Coatifunctsurfa
Au- and Ag-coated Fe3O4,12 nm
Chloroform Au orand oFurthCTAB
Fe3O4, 2040 nm Water SodiuFe3O4, 30 nm Benzyl ether OleylFe3O4
and g-Fe2O3, CoFe2O4,615 nm; CoO, 50 nm
1-Octadecene Sodiu
Fe3O4, 9 nm Benzyl ether, furtherredispersion in hexane
OleylPEGhydrophilic TREG ligands coated on the particles during
thesynthesis procedure. In addition, only a single iron
richprecursor was used, and no further reducing agent or
surfac-tants were required, which makes this process easy to
scale-upfor mass production. Also, the size distribution of the
nano-particles is much narrower than the particles produced
fromtraditional methods. Magnetite nanoparticles obtained
fromFe(acac)3 in TREG remained stable for several months,
withoutnoticeable precipitation.122
The synthesis of spinel-type cobalt ferrite
nanoparticlesdispersed in diethylene glycol (DEG) was carried out
via thepolyol-mediated technique (Reaction (4)). The crystal
sizecontrol could be achieved through successive synthesis
steps;123
Fe3O4, 9 nm Benzyl ether Oleylamethoglycol)
Fe3O4, 20 nm Ethylene glycol (EG),diethylene glycol
(DEG),triethylene glycol (TREG)and tetraethylene glycol(TEG)
EG, DE
Fe3O4, 9 nm MPEG MPEGreducimodify
Fe3O4, 5 nm 1,2-Hexadecanediol andphenyl ether;
furtherredispersion in hexane
Oleylabis(phmethoporphy
g-Fe2O3, Fe3O4 Water DextraFe3O4, 20 nm 2-Pyrrolidone,
triethylene
glycol, and polyacrylic acid2-Pyrroglycol,(PAA)
Fe3O4, 5 nm Toluene Poly(etCoFe2O4, 57 nm Diethylene glycol
DiethyCoFe2O4, 6 nm 1,2-Dis
phosp[methoglycol)2000)
MnO, 14 nm 1-Octadecene; thenchloroform and a solution of30 mg
DA-PEG-NH2 (3,4-dihydroxy-hydro-cinnamicacid) or
DA-PEG-PP(dopamine-PEG-protoporphyrin IX)
Manga(precu
45370 | RSC Adv., 2014, 4, 4535445381articles
g/capping ornalizing agent/tant NPS solubles in References
and Ag, oleylamineeic acid
Nonpolar solvents 88
r treatment withand sodium citrate
Water
citrate Water 90mine Hexane and toluene 80oleate Water 78 and
96
mine and oleic acid;iacid
Water or phosphate bueredsaline (PBS)
120whereby, the technique was repeated in subsequent steps,
usingferrite particles each time as seed, to nely tune the average
sizeof the particles in the 57 nm range. The nal concentrations
ofcobalt ferrite in stable dispersions for the specially
preparedsamples were found to be in the range of 0.152.88%. In
addi-tion, an interesting nd observed in the case of iron oxide
inPEG-containing systems, was that the high binding anity
ofpoly(ethylene glycol)-gallol (PEG-gallol) allows the
freeze-dryingand re-dispersion of 92 nm iron oxide cores
individually stabi-lized with 9 nm-thick stealth coatings, aording
particlestability for at least 20 months.124 Fig. 36 shows the
preventionof particle agglomeration even in the presence of a small
externalmagnet, when the surfactant is used. In all other
interactions of
mine; mono-xypoly(ethylene(mPEG)
Both hexane and PBS 82
G, TREG or TEG Water
(used as a solvent,ng agent, anding agent)
Water 125
mine; [5,15-enyl)-10,20-bis(4-xy-carbonyl-phenyl)-rin] platinum
(t-PtCP)
Water 92
n, sucrose Water 119lidone, triethyleneand polyacrylic acid
Water 102
hylene oxide) (PEO) Water 109lene glycol Diethylene glycol
123tearoyl-sn-glycero-3-ho-ethanolamine-N-xy(polyethylene-2000]
(DSPE-PEG-
Water 101
nese(II) oleatersor)
Water 94
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for heat distribution. Microwave radiation heats
materialsthrough the much more ecient dielectric heating, as
molec-ular dipoles attempt to align with the alternating electric
eld.
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reports, MNPswere attracted by magnets.
(4)
Thermal decomposition
Fig. 35 SEM image of the products synthesized in ethylene glycol
(a),and diethylene glycol (b); TEM images of the products
synthesized intriethylene glycol (c), and tetraethylene glycol (d),
the samples aredispersed in ethanol. Reproduced with permission of
Elsevier Science{W. Cai and J. Wan, Facile synthesis of
superparamagnetic magnetitenanoparticles in liquid polyols, J.
Colloid Interface Sci., 2007, 305,366370}.The thermal decomposition
of the low stability precursors ofMNPs (generally acetylacetonates
or other iron coordination ororganometallic compounds) can be
carried out with or withoutthe use of solvents. If the solvent is
chosen appropriately, noother agents might be needed to obtain
soluble MNPs. Thus,water-soluble superparamagnetic Fe3O4
nanoparticles with anaverage diameter of 9.5 1.7 nm were
synthesized by thethermal decomposition of Fe(acac)3 in MPEG (Fig.
37; methoxypolyethylene glycol, which was used as a solvent,
reducingagent, and modifying agent in the shown reaction, and
nofurther reducing agent or surfactants were required)125 or inTREG
(triethylene glycol).126 MPEG molecules were shown to becovalently
bound to the surface of the magnetite nanoparticlesvia the partial
oxidation of the terminal OH group of the MPEG.
Microwave heating
The reaction system treatment with microwaves (MW) isnowadays a
classic tool in material chemistry and also innanotechnology, and
oers a number of advantages, asdescribed elsewhere. In general,
microwave synthesis has beenshown to signicantly reduce reaction
time, increase yields,reduce side reactions, enhance
reproducibility, and provide amore energy ecient, greener process.
Microwave heating
This journal is The Royal Society of Chemistry 2014presents
signicant benets over traditional heating methods(such as an oil
bath), which rely on conduction and convection
Fig. 36 (a) The biotin-PEG(3400)-gallol/mPEG(550)-gallol
dispersantlayer surrounding the iron oxide nanoparticle cores is
stable and thickenough to prevent particle agglomeration even in
the presence of asmall external magnet, even after the particles
have been dispersed inPBS formore than 1 year. (b) In the absence
of the dispersant layer, ironoxide cores agglomerate and thus
sediment instantaneously uponapproaching a small external magnet.
Reproduced with permission ofWiley {E. Amstad, S. Zurcher, A.
Mashaghi, J. Y. Wong, M. Textor andE. Reimhult, Surface
Functionalization of Single SuperparamagneticIron Oxide
Nanoparticles for Targeted Magnetic Resonance Imaging,Small, 2009,
5(11), 13341342}.As an example of MW applications for the
preparation ofsoluble MNPs, a rapid, straightforward
microwave-assistedsynthesis of superparamagnetic dextran-coated
iron oxidenanoparticles was carried out.127 Two approaches were
used: (1)uncoated iron oxide nanoparticles, basically iron cores
with nocoating, were prepared by the hydrazine reduction of
ferricchloride with microwave heating at 100 C for 10 minutes.
Asubsequent dextran coating of the nanoparticles was achievedin a
second stage of microwave heating at 100 C for 2 minutes.In the
presence of additional ferric chloride, sodium hydroxide,and
reduced dextran. (2) The nanoparticles were synthesized ina one-pot
single step microwave reaction. Ferric chloride andreduced dextran
were reacted with hydrazine in the microwaveoven at 100 C for 10
minutes. The two methods resulted indierent sized nanoparticles.
The dextran coating imparts thewater solubility and
biocompatibility necessary for in vivoutilization.
Hydrothermal technique
A few reports have described the preparation of soluble Fe3O4NPs
in specic reaction systems. In one report, water-solubleFe3O4
nanoparticles with a suciently high solubility(28mgmL1) and
stability (at least onemonth) were synthesized
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sodium citrate andethylene diamine at 200 C for 12 hours. It was
found that theyexhibited excellent removal ability for heavy-metal
ions fromwastewater.128 It is important that the adsorption ability
of thewater-soluble Fe3O4 NPs with Pb
2+and Cr6+ is stronger thanwater-insoluble Fe3O4 NPs alone. In
addition, the water-solubleFe3O4 NPs exhibited relatively high
saturation magnetization(83.4 emu g1), which allowed their highly
ecient magneticseparation fromwastewater.Water-solublemagnetite
used as anadsorbent could directly dissolve in water without the
need formechanical stirring or any extraneous forces. In a
relatedreport,129 water-soluble superparamagnetic Fe3O4
nanocrystals,prepared through a hydrothermal approach (using Na2CO3
andascorbic acid) at 160 C for 3 h and capped with C6H6O6
(theoxidation state of ascorbic acid), could be readily dispersed
inhydrated aqueous systems. The formation reactions
(Reactions(5)(7)) are as follows:
2Fe3+ + 3CO32 + 6H2O/ 2Fe(OH)3 + 3H2CO3 (5)
2Fe(OH)3 + C6H8O6/ 2Fe(OH)2 + C6H6O6 + 2H2O (6)
2Fe(OH)3 + Fe(OH)2/ Fe3O4 + 2H2O (7)
It was revealed that ascorbic acid not only serves as areducing
reagent for the reaction, but also the oxidation state ofascorbic
acid takes part in surface coordination, which rendersthe magnetite
nanocrystals water soluble and the colloidalsolution stable. At the
same time, these nanocrystals are di-
Fig. 37 Preparation of the magnetite nanoparticles in MPEG.cult
to be dispersed in ethanol. In the rinsing process, theproducts
were washed by water, but the nanoparticles could notbe separated
from the solution by centrifugation. Therefore, thesame volume of
ethanol was introduced to this solution, andthe magnetic particles
were separated either by centrifugationor magnetic separation.
Stabilization of magnetic particles
MNPs, transferred to water or organic solvents, or
synthesizeddirectly in situ, could be present in these phases
during verydierent periods, depending on a series of factors,
namely,particle size, surfactant/coating/functionalizing agent,
tempera-ture, etc. In terms of practical uses, the aggregation
and
45372 | RSC Adv., 2014, 4, 4535445381sedimentation of magnetic
nanoparticles can signicantly aecttheir mobility and reactivity,
which can subsequently inuencethe interaction between them and
environmental contaminants,for instance, among other applications.
So, dispersing barenanoparticles into a stable suspension within
the nanoscalerange is an important step for studying the
interaction of NPswith contaminants (e.g., toxic metals). Common
treatments, suchas ultrasound, frequently cause a temporal
dispersion, in themajority of cases, with further precipitation.
Stabilization of themagnetic particles can be achieved by acting on
one or both ofthe two repulsive forces: electrostatic and steric
repulsion(Fig. 38).130 Controlling the strength of these forces is
a keyparameter to elaborate particles with good stability. Steric
forcesare dicult to predict and quantify; whereas,
electrostaticrepulsion can be followed through knowledge of the
diusionpotential, which may be very close to the zeta potential,
and theDebyeHuckel length, which mainly depends upon the
ionicstrength, and the pH of the solution. Fig. 39 shows themain
typesof stabilizers for magnetic particles.
As a representative example for studying the stabilization
ofMNPs in aqueous media, hydrophilic 2,3-dimercaptosuccinnicacid
{HOOCCH(SH)CH(SH)COOH, DMSA, Fig. 40}-coatedmonodisperse magnetic
nanoparticles (Fe3O4) were dispersedin water, RPMI-1640 with 10%
(v/v) fetal calf serum, RPMI-1640,PBS, and MES
(4-morpholineethanesulfonic acid), respectively,to investigate
their stability under biologically relevant condi-tions.131 It was
elucidated that DMSAFe3O4 nanoparticles existas aggregates under
biological conditions. The stability ofDMSAFe3O4 nanoparticles
dispersed in water, RPMI-1640 with
10% (v/v) fetal calf serum, RPMI-1640, PBS, and MES, was
alsoquantied (Fig. 41). Nanoparticles that are not stable and
thatsedimentate rapidly can be monitored by the decreased
absor-bance as a function of time. It was shown that DMSAFe3O4
Fig. 38 (a) Particles stabilized by the electrostatic repulsion.
(b)Particles stabilized by steric repulsion.
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Special studies on MNPs solubilizationand stabilityInuence of
precursors
Pure magnetite nanoparticles (Fe3O4) were synthesized in
water
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RPMI-1640 with fetal calfserum both present excellent stability,
whereas those dispersedin RPMI-1640 without fetal calf serum, PBS,
and MES exhibitedpoor stability, as demonstrated by a loss of less
than 20% aerve days for the former, whereas the latter lost more
than 80%.
by coprecipitation using two dierent approaches, i.e., from:
(a)ferrous sulfate, and (b) a mixture of ferrous and ferric
chlo-rides.132 It was observed that the magnetite produced
usingferrous sulfate could not be disaggregated, whereas
magnetiteproduced from a mixture of ferrous and ferric chlorides
couldbe disaggregated to a quasi-monodispersed form. Thedispersing
agents were tetramethyl ammonium hydroxide,Disperbyk 190, and
polyacrylic acid (PAA). It was observed thatthe magnetic response
of the washed, dispersed nanoparticleswas signicantly lower than
that of the original material. Theauthors noted that type a
reactions produced magnetiteparticles that were rhombic in shape,
with sizes ranging from 30nm to 150 nm diameter (Fig. 42a), when
the reaction was stirredin excess OH; whereas, material prepared
under unstirredconditions and without excess OH exhibited a nearly
mono-
Fig. 40 DMSA molecule.
Fig. 41 Normalized UV-Vis absorbance of DMSAFe3O4 nano-particles
dispersed in (a) water, (b) RPMI-1640 with 10% (v/v) fetal
calfserum, (c) RPMI-1640, (d) PBS, and (e) MES, respectively, as a
functionof time. Reproduced with permission of American Scientic
Publishers{Z. P. Chen, Y. Zhang, K. Xu, R. Z. Xu, J. W. Liu and N.
Gu, Stability ofHydrophilic Magnetic Nanoparticles Under
Biologically RelevantConditions, J. Nanosci. Nanotechnol., 2008, 8,
62606265}.
Fig. 39 Compounds used for the stabilization of
magneticnanoparticles.
This journal is The Royal Society of Chemistry 2014dispersed,
spherical morphology of 40 nm diameter. Nano-particles produced
using this method appeared to aggregate inan ordered fashion
(chain, Fig. 42b). Whereas, type b reac-tions produced ultrasmall
magnetite nanoparticles, with sizes10 nm diameter (Fig. 42c). When
TMAOH (tetramethylammonium hydroxide) was included in the synthesis
(replacingNH4OH), the product consisted of quasispherical
nanoparticlesof 10 nm diameter (Fig. 42d). This material did not
appear toaggregate in the same fashion as that of type (a)
reactionproducts.
Simulation of the state of dispersion
Monte Carlo simulation results predicting the state of
disper-sion (single, dimer, trimer, and so on) of citric-coated
super-paramagnetic iron oxide (Fe3O4) nanoparticles in an
aqueousmedium were compared with same the experimental data.133
Fig. 42 TEM micrographs of magnetite nanoparticles: (a) prepared
bytype a reactions in the presence of excess OH; (b) prepared by
typea reactions without stirring and without excess OH or Fe2+;
(c)prepared by type b reactions in the presence of NH4OH; (d)
preparedby type b reactions in the presence of the dispersing agent
TMAOHbut without NH4OH.RSC Adv., 2014, 4, 4535445381 | 45373
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magnetic NP and native surface ligands. (c) The ligand
exchangereplaces the native surface ligands. These routes present
polar orcharged functional groups onto the outer surface of the NP
for watersolubility. Reproduced with permission ofWiley {S. R. Dave
and X. Gao,Monodisperse magnetic nanoparticles for biodetection,
imaging, anddrug delivery: a versatile and evolving technology,
Wiley Interdiscip.
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the total interac-tion potential between two nanoparticles as a
function of their
Fig. 43 (a) Stable aqueous dispersion containing citric acid-
and PAA-coated Fe3O4 nanoparticles. (b) Schematic representation of
twoparticles with diameters of d1 and d2 separated by a
surface-to-surfacedistance (s) and a center-to-center distance (r).
Reproduced withpermission of The American Chemical Society {S.
Kumar, C. Ravikumarand R. Bandyopadhyaya, State of Dispersion of
Magnetic Nanoparticlesin an Aqueous Medium: Experiments and Monte
Carlo Simulation,Langmuir, 2010, 26(23), 1832018330}.interparticle
distance (Fig. 43) and applying a criterion for thetwo particles to
aggregate, with the criterion being that theminimum depth of the
secondary minima in the total interac-tion potential must be at
least equal to kBT. The experimentsshowed that the citric
acid-coated particles were mostly in theform of aggregates, whereas
PAA-coated particles were isolatedas individual particles. Both of
these states of dispersion werepredicted by the simulation. It was
also observed that aminimum shell thickness was required for
particles with aparticular diameter, volume percentage, and graing
density inorder for the dispersion to remain as isolated particles
and in astable state. For both the coating agents, suitable ranges
ofthese experimentally controllable parameters, which can
beexperimentally realized to obtain a stable dispersion of
indi-vidual isolated nanoparticles, were established.
Additional ideas on the direct hydrophobic/
hydrophilictransformation of MNPs
In general, there are three routes to modify hydrophobic NPsand
render them soluble in aqueous biological buers, asillustrated in
Fig. 44.134 In the rst approach, i.e., ligandexchange, the native
monolayer of hydrophobic surface ligandsis exchanged with ligands
containing head groups that bind themagnetic NP surface and
hydrophilic tails that interact withaqueous solvent. The
ligand-exchange reaction is the majorapproach taken for the
transformation of oil-soluble type
45374 | RSC Adv., 2014, 4, 4535445381Fig. 44 The three general
surface modication schemes for MNPs. (a)The inorganic surface
coating with tetraethoxysilane produces anamorphous silica shell.
(b) The polymer coating encapsulates thefunctionalized IONPs into
water-soluble type functionalizedIONPs. The second approach
involves an alternative solubilizationstrategy, in which the native
hydrophobic ligands are retainedon the magnetic nanoparticle
surface through the adsorption ofamphiphilic polymers onto the
nanoparticle. These two generalsurface modication strategies
present water-solubilizinggroups, such as carboxyl acids and amines
that are capable ofcovalent conjugation, with appropriate
functional groups onthe desired biomolecules. The third approach
for magnetic NPsurface modication is the fabrication of an
inorganic shell,typically consisting of silica or gold, by one of
two generalschemes, namely by precipitation and reaction at the
NPsurface, or by the deposition of preformed colloids onto the
NPsurface. As a representative example of this third
approach,magnetic nanoparticles, MnFe2O4 and Fe3O4, were stabilized
bythe deposition of an Al(OH)3 layer via a hydrolysis
process.135
The particles displayed excellent colloidal stability in water
anda high anity to 18F-uoride and bisphosphonate groups.
Theproperties of the particles were found to be strongly
dependenton the thickness and hardness of the Al(OH)3 layer, which
couldin turn be controlled by the hydrolysis method. In
particular,the nanoparticulate MnFe2O4 was soluble in hexane,
butinsoluble in water, due to the organic layer (oleylamine
andoleic acid) on the surface. Once coated with Al(OH)3, the
NPs
Rev.: Nanomed. Nanobiotechnol., 2009, 1, 583609}.
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hexane (Fig. 45). All of
Fig. 45 Photographs of MnFe2O4 (left) and MnFe2O4@Al(OH)3
(right)NPs in a two-phase mixture of hexane (upper layer) and water
(lowerlayer).these features suggest that a coating of Al(OH)3
replaced theoleylamine on the iron oxide NPs. However, it is
necessary totake into account that there were no obvious dierences
in sizeor morphology before and aer the coating with Al(OH)3.
Ultrasonic treatment
When one needs to disperse insoluble NPs, the rst thought
isnormally to apply ultrasonic treatment. Ultrasonic techniquesin
chemistry and technology are now classic tools, and havebeen
described elsewhere. Sometimes, several studies arecarried out to
compare its eectiveness with other techniques.Thus, dierent
techniques to disperse bare IONPs (e.g., vortex,bath sonication,
probe ultrasonication) and the eects ofimportant environmental
factors, such as dissolved organicmatter and ionic strength in the
stability of IONPs dispersions,were investigated.136 As a result,
it was seen that the vortexminimally dispersed IONPs, with the
hydrodynamic diameterbeing outside of the nanosize range (6982400
nm). Similar toa vortex, bath sonication could also not disperse
IONPs e-ciently. Probe ultrasonication was found to be more eective
atdispersing IONPs (50% or more), with hydrodynamic
diametersranging from 120 nm to 140 nm with minimal changes in
sizeand sedimentation of IONPs for a prolonged period of
time,although probe ultrasonication did not break the IONPs
downinto their primary particle size. In addition, although
sedi-mentation occurred to some extent, a considerable amount
ofIONPs remained in suspension in the presence and absence of
This journal is The Royal Society of Chemistry 2014100 mg L1 HA
(humic acid) and 0.1 mM NaCl. The authorsshowed that high ionic
strengths increased the colloidal insta-bility, by compressing the
electrical double layer thickness,causing rapid aggregation and
sedimentation. On the otherhand, electrostatic repulsive forces
dominated at low ionicstrengths, resulting in reduced
destabilization of thedispersions.
Use of magnetic elds
We observed in dierent reports that magnetic elds can beapplied
both for the aggregation and deaggregation of nano-particles in
general. Thus, for non-magnetic nanoparticles (forexample, silica
or alumina), magnetohydrodynamic nano-particle dispersion is an
energy ecient method to deaggregatenanoparticles, combining
hydrodynamic forces of turbulentow with Lorentz forces generated by
a magnetic eld.137 On theother hand, for MNPs, nanoparticle
aggregation inuenced bymagnetic elds was studied using FeO(OH).138
The nano-particles were shown to exist not only in stable (pH 2)
andocculated (pH 6) states, but also in a metastable
aggregatedstate at an intermediate pH between 3 and 5. Thus,
colloidallystable nanoparticle suspensions of iron hydroxide
FeO(OH) atpH 2 were prepared and shown to be non-magnetic.
However,when the pH of the dispersion was raised to destabilize
thesuspension, aggregates near 200 nm diameter were detected,and
these were inuenced by magnetic elds in the 50 kA m1
range. These aggregates were unusual in that they were
colloi-dally stable and did not behave as ocs. The authors
called
Fig. 46 (a) Schematic of the dispersion containing metastable
nuclei,dened as nucleags. (b) The square well interaction potential
betweennanoparticles.them nucleags (Fig. 46) to distinguish them
from conventionalocculated agglomerates. By increasing the pH,
occulation ofthe nanoparticles was observed and a brown sludge,
which wasnot inuenced by magnetic elds, was deposited on the base
ofthe container. These metastable aggregates were inuenced bysmall
pH changes, showing that the adhesion between thenanoparticles was
small. The concentration of these metastableaggregates was very
low, typically 5 ppb at pH 3.
Conclusions and further outlooks
Magnetic nanoparticles (generally based on iron) could
besolubilized in water (most frequently, due to their potential
inmedical applications) or non-aqueous solvents for short or
long
RSC Adv., 2014, 4, 4535445381 | 45375
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. View Article Onlinetime periods. The main approaches needed to
carry out thisgoal are the suitable choice of precursors, pH,
surfactants/coating agents, and solvents, as well as functio