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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. View Article OnlineSociety. She is the co-author offour books, 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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. View Article Onlinecalled sols. Colloidal systems in organic 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

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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. View Article Onlineresult in a broad distribution of sizes and 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

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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. View Article OnlineFig. 4 Oleic acid (left) and its linkage with iron oxide nanoparticle (righ45358 | RSC Adv., 2014, 4, 4535445381).This journal is The Royal Society of Chemistry 2014

(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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. View Article OnlineFig. 7 Summary of the ligand exchange of 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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. View Article Online> octyl > hexyl. Strangely, 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).

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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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. View Article OnlineFig. 9 Solubility of naked and modied NPs 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

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

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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

es.This journal is The Royal Society of Chemistry 2014

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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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

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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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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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. View Article Onlineredox transmetalation process, the Fe core 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

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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. View Article Onlinestored for three months. Their application 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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. View Article Onlinepolymer could dissolve in water carrying 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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. View Article OnlineFig. 31 Synthetic route for the production 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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. View Article Onlineparticles prepared by milling Fe and FeCo 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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. View Article OnlineTable 1 Solvents and coating agents in the 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

This journal is The Royal Society of Chemistry 2014

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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. View Article Onlinesuspended MNPs magnet, observed in other 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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. View Article Onlinethrough a hydrothermal approach using 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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. View Article Onlinenanoparticles dispersed in water and 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

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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. View Article OnlineThe simulation was performed by calculating 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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. View Article Onlinebecome soluble in water, but insoluble in 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

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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