Synthesis, Functionalization, and Biomedical Application

磁性纳米材料综述

Synthesis, Functionalization, and Biomedical Applications of Multifunctional Magnetic Nanoparticles

ByRui Hao ,Ruijun Xing ,Zhichuan Xu ,Yanglong Hou, *Song Gao ,andShouheng Sun *magnetically, enabling some exciting new approaches to bioseparation, biodetection Synthesis of multifunctional magnetic nanoparticles (MFMNPs) is one of

[6and targeted drug delivery. 10] In addi-the most active research areas in advanced materials. MFMNPs that have

tion, these MNPs can also respond reso-magnetic properties and other functionalities have been demonstrated to

nantly to an alternating magnetic eld and

show great promise as multimodality imaging probes. Their multifunctional function as a heater, offering a promising surfaces also allow rational conjugations of biological and drug molecules, therapeutic solution by magnetic uid

[11,12]making it possible to achieve target-speci c diagnostics and therapeutics. hyperthermia.

To perform real-time monitoring and This review rst outlines the synthesis of MNPs of metal oxides and alloys

drug treatment with high accuracy, MNPs and then focuses on recent developments in the fabrication of MFMNPs of

are often coupled with targeting agents,

core/shell, dumbbell, and composite hybrid type. It also summarizes the

therapeutic drugs, and other functional

general strategies applied for NP surface functionalization. The review further probes. However, these multistep con-highlights some exciting examples of these MFMNPs for multimodality jugations to a single-component NP are

usually low yield processes and the pres-imaging and for target-speci c drug/gene delivery applications.

ence of different molecules on the same NP surface may interfere with targeting

capabilities and the subsequent uptake of the NP conjugates. 1. Introduction

Recent advances in NP research allow the synthesis of various

Magnetic nanoparticles (MNPs) have demonstrated great composite NPs with core/shell and dumbbell structures that

[1promise for diagnostic and therapeutic applications. 5] At offer a promising solution to this problem encountered with

diameters less than 20 nm, these MNPs are often in a super-single-component MNPs. For example, Au-Fe 3O4dumbbell

paramagnetic state at room temperature, that is, their magneti-NPs were applied by conjugating anticancer drug cisplatin

zation can be saturated under an external magnetic eld, but in ( cis -diamminedichloroplatinum) on Au and Herceptin (HER) the absence of this eld their net magnetic moments are often antibodies on Fe O with the number of cisplatin molecules

34

randomized to zero by thermal agitation. Owing to their unique and antibody molecules being controlled by the size of the Au magnetic properties and because they are of comparable size and Fe Ocomponents. [13 ] The composite NPs demonstrated 34

to biologically important objects, these MNPs are very useful the targeted speci c delivery of cisplatin to breast tumor cells for biomedical applications. Their responses to external mag-(SK-BR-3). Alternatively, by proper surface functionalization,

[14]netic elds allow biomolecules to be tagged and detected FePt NPs were found to release Fe that was highly cytotoxic.

Utilized as a therapeutic agent, these NPs might offer a prom-ising approach to the multistep conjugation problem in NP

[] R. Hao, R. J. Xing, Prof. Y. Houdelivery systems, as one would only need to anchor a targeting Department of Advanced Materials and Nanotechnologyagent on the NP surface and the number of targeting molecules College of Engineering, Peking University

could be readily controlled by NP size. Beijing 100871 (P. R. China)

This review summarizes recent progress in the design and E-mail: hou@

fabrication of multifunctional MNPs (MFMNPs) for biomedical Prof. S. Gao

Beijing National Laboratory for Molecular Sciencesapplications. It rst outlines the general synthesis of composite State Key Laboratory of Rare Earth Materials Chemistry and NPs of iron oxide, alloys, core/shell, dumbbell, and multicompo-Applications, College of Chemistry and Molecular Engineering

nent adducts. It then discusses the chemistry applied for surface Peking University

modi cation to make these MFMNPs biocompatible. Finally, the Beijing 100871 (P. R. China)

review highlights the potential applications of these MFMNPs in Dr. Z. C. Xu,[+] Prof. S. H. Sun

multimodality imaging and target-speci c drug/gene delivery. Department of Chemistry, Brown University

Providence, RI 02912 (USA)

E-mail: ssun@brown.edu

[+] Current address: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)

REVIEW

2. Chemical Synthesis of MNPs

he general strategy for preparing monodisperse NPs in solution T

phase is to separate the nucleation and growth of nanocrystals.

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[15]

In La Mer theory, a burst nucleation event rst occurs when the monomer concentration quickly increases over critical super-[16] saturation without further formation of nuclei afterwards.

The produced nuclei then grow at the same rate, giving mono-disperse particles. Once formed, these NPs have a high surface area and agglomerate easily to minimize their surface energy. A suitable capping agent has to be used to stabilize these NPs to prevent them from agglomerating.

Numerous synthetic methods have been developed to synthe-

[17[18[19size MNPs, ] including coprecipitation, ] sol-gel synthesis, ]

[20[21microemulsion synthesis, ] sonochemical reaction, ] hydro-[22[23thermal reaction, ] thermal decomposition, ] electrospray syn-[24[25thesis, ] and laser pyrolysis. ] Here we brie y review recent

advances in the synthesis of monodisperse MNPs.

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2.1. Iron Oxide NPs

Yanglong Hou earned his

Ph.D. in Materials Science from Harbin Institute of Technology (P. R. China) in 2000. After a short post-doctoral training at Peking University, he worked at the University of Tokyo 2002–2005 as a JSPS foreign special researcher and also at Brown University 2005–2007 as a postdoctoral researcher. He joined Peking University

in 2007, and is now the Professor of Materials Science. His research interests include the design and chemical synthesis of functional nanoparticles, and their biomedical

and energy-related applications.

3+ and Fe 2+ salts is a classical method used o-precipitation of Fe C

[26]to prepare iron oxide NPs. Iron oxide NPs can be obtained on Shouheng Sun received his

a large scale by aging a stoichiometric mixture of inorganic salts PhD in Chemistry from Brown in aqueous media. A series of experimental parameters, such University in 1996. He was a as pH, reaction temperature, and precursor, have been studied postdoctoral fellow 1996–1998 to control NP morphology, size, and quantity. The solvothermal and a research staff member process uses a high pressure reaction to obtain well-crystallized 1998–2004 at the IBM T. J. MNPs. However, using these two methods it is dif cult to pro-Watson Research Center. duce MNPs with a narrow size distribution. He joined the Chemistry High temperature decomposition of metal complexes is now Department of Brown routinely applied to prepare MNPs with controlled size and mor-University in 2005. He is now

[27,28]phology. A typical thermal decomposition method requires the Professor of Chemistry

the presence of a metal complex and surfactant in an organic and Engineering at Brown. solvent with a high boiling point. In the reaction, the precursors His research interests are in are either added via a hot-injection process or directly heated nanomaterials synthesis, self-assembly, and applications in

[29]up. In the hot-injection process, the thermally unstable metal nanomedicine, catalysis, and energy storage. complexes are rapidly injected into a hot solution in the presence of surfactant to create an instant nucleation event, followed by a

Zhichuan Xu received a B.S. controlled growth process. In the heating up procedure, all the

degree in chemistry in 2002 precursors are mixed and heated, MNPs are made by tailoring

and a Ph.D. degree in ana-reaction temperatures and precursor concentrations. Oleic acid

lytical chemistry in 2008, both and oleylamine are two common surfactants used for NP sta-from Lanzhou University. He bilization and for the control of NP size and morphology. The

studied at Brown University as [30]metal precursors are usually metal acetylacetonates and metal

an exchange graduate student [31]oleates. For example, iron(III) acetylacetonate, Fe(acac) 3,from 2005 to 2007 and then was mixed with 1,2-hexadecanediol, oleic acid, and oleylamine

worked at the State University in benzyl ether and the mixture was heated up to 300 °C to

of New York at Binghamton [30]make monodisperse Fe NPs with a size range of 4–8 nm. 3O4

as a visiting research The same procedure worked for the synthesis of CoFe 2O4and

associate in 2008. Now he [32]MnFe ( Fig.1 ). Recent developments in this synthesis indi-2O4

is a postdoctoral research cated that an alkyl diol was not necessary in Fe NP synthesis 3O4

associate at MIT. His research interests include the design and monodisperse Fe 3O4 NPs could be made by heating the

and synthesis of nanostructures for energy conversion and

[33]mixture of Fe(acac) 3 and oleylamine in benzyl ether. Thermal

storage, and biology-related applications. decomposition of Fe(acac) 3 in a mixture of oleic acid and

[34]oleylamine led to the formation of wüstite (FeO) NPs. The size

of the FeO NPs was controlled in the range 14–100 nm and the shapes were either polyhedra or truncated octahedra, depending on the molar ratio of oleic acid to oleylamine. The FeO NPs Iron(III) oleate was used to prepare monodisperse iron oxide

[31]can be converted to magnetite, maghemite (γ-Fe ), hematite NPs on a large scale. The cations of oleate salts, such as 2O3

(α-Fe ) NPs and Fe/Fe , offering a general approach to the hydrion, sodium, potassium, and dibutylammonium, were found 2O33O4

[34]synthesis of NPs of various iron oxides. to have great in uence on the shape of NPs, and monodisperse

2

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Figure 1. a) Schematic illustration of the synthesis of monodisperse fer-rite NPs by employing metal acetylacetonates as the precursor. b) Trans-mission electron microscopy (TEM) image of Fe NPs. Reproduced 3O4

with permission.[ 32 ] Copyright 2004 American Chemical Society.

Figure 2. a) A protocol for Fe 3O4 nanooctahedra synthesis. b) TEM image

of octahedral Fe NPs with projection axis {111}. Reproduced with per-3O4

[36]

mission. Copyright 2009 Royal Society of Chemistry.

[40and their applications have made considerable progress. 43]

spherical, cubic, and bipyramidal iron oxide NPs were FePt NPs are normally synthesized by the thermal decomposi-[40 42][35]tion of Fe(CO) The size obtained. Monodisperse octahedral Fe 5 and the reduction of Pt(acac) 2. 3O4 NPs were obtained

[36]by using oleylamine as a stabilizer and reducing agent ( Fig. 2), and composition of FePt NPs are tuned by tailoring the ratio

of precursors and the solvent. Alternatively, FePt alloy NPs the reaction temperature and the molar ratio of precursor to sta-can be prepared by reducing FeCl bilizer are the key for the formation of the octahedral shape. 2 and Pt(acac) 2 by LiBEt 3H[41]

Porous or hollow iron oxide nanostructures have also been in the presence of oleic acid and oleylamine. Recently, one-dimensional FePt nanostructures such as nanowires have been synthesized. Iron oxide nanocapsules were made by a wrap–

[44[37]synthesized by a solvothermal route ] or a thermal decomposi-bake–peel process from akagenite (β-FeOOH) nanorods. The

process involved the coating of akagenite with silica, followed by tion process in which oleylamine was used both as a solvent and

as a surfactant, while dioctyl ether was added to dilute the con-a heat treatment and silica removal, as illustrated in Figure 3.[45centration of oleylamine, nanorods were obtained at 160 °C. ] Porous hollow iron oxide NPs were also produced by con-Figure 5 shows typical TEM images of FePt nanowires/nanorods. trolled oxidation of metallic iron NPs in a high temperature

[39](>200 °C) solution phase by the Kirkendall process ( Fig. 4). The molar ratio of solvent to surfactant is the key to deter- Trimethylamine N -oxide was used as an oxidant. The rate of mining the aspect ratio of the FePt nanostructures.

Owing to their high magnetic moment, FeCo alloys are a oxygen diffusion towards the core is slower than diffusion of

[46 ] FeCo iron outwards from the core, leading to the formation of hollow promising material for various magnetic applications.

NPs with well-controlled particle size were synthesized by reduc-structures. The Fe 3O4 shell can be further crystallized at higher

reaction temperatures, forming larger crystalline domains and tive decomposition of Fe(acac) 3 and Co(acac) 2 in the presence of

a mixture of oleic acid, oleylamine and 1,2-hexadecanediol under pore structures around the shell. By using technical grade trioc-[47]

tylphosphine oxide (TOPO) as both the solvent and the etchant, a gas mixture of 93% Ar + 7% H 2 at 300 °C. Alternatively

FeCo NPs were made by sodium borohydride reduction of hollow MnO or Fe 3O4 NPs can also be obtained by using relevant

[48 ] Replacing the reducing agent with nanocrystals as the starting materials. The alkylphosphonic acid ferrous and cobalt salts.

impurity in TOPO is believed to be responsible for the etching potassium borohydride resulted in FeCo hollow NPs.

process and the Kirkendall effect also plays a key role in the for-[38]mation of hollow NPs.

3. Chemical Synthesis of MFMNPs

2.2. Alloy NPs

ePt and FePd NPs possess high magnetocrystalline anisotropy F

and good chemical stability. Controlled synthesis of these NPs

[49 n addition to the synthesis of MNPs, I ] great progress has also

[50[51been made in the synthesis of quantum dots, ] gold NPs, ]

[52and nanosilicas, ] making it possible to integrate different func-tional NPs into one single nanoentity. Recently, several types of

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[37Figure 3. Wrap–bake–peel process to obtain nanocapsules from akagenite. Reproduced with permission. ] Copyright 2008 Nature Publishing

Group. MNP-based multifunctional nanostructures, including core/

[53[58 , 54 ] dumbbell, [55 57] and multicomponent hybrid ] types shell,

of nanostructures, have been developed. In these MFMNPs, the MNPs can be combined either with quantum dots (QDs),

[59or with plasmonic metallic NPs. 61] The MFMNPs exhibit

unique combinations of magnetic and optical properties and

[62have shown great potential for biomedical applications. , 63 ] 3.1. Core/Shell NPs

ore/shell NPs are the most common type of multicomponent C

NPs and have been studied extensively. Core/shell structures

[64were rst realized in semiconductor NPs, , 65 ] where the het-erostructures can lead to carrier con nement or separation,

depending on the band alignment of the two semiconductor

[66materials with different gap energies. ] Bimagnetic core/shell

FePt/Fe NPs were synthesized by reductive decomposition 3O4

[67,68]

of Fe(acac) 3 in the presence of monodisperse FePt NPs. Other core/shell NPs with a variety of material combinations have also been realized using similar approaches. Core/shell NPs with a magnetic core and metallic shell, such as Fe /Au, 3O4

NPs Figure 4. Synthesis of core–shell–void Fe–Fe 3O4 and hollow Fe 3O4

[39]

from Fe–Fe NP seeds. Reproduced with permission. 3O4Figure 5. TEM images of FePt nanowires and nanorods. Reproduced with

[45]

permission.

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Figure 7. a) Schematic illustration of the growth of Au-Fe 3O4dumbbell NPs. b) TEM and c) HRTEM images of the 8–14nm Au–Fe 3O4dumbbell

[73NPs. Reproduced with permission. ] Copyright 2005 American Chemical

Society. Figure 6. a) Schematic illustration of the surface coating of (i) Fe 3O4 NPs with Au, to form (ii) hydrophobic Fe /Au NPs and (iii) hydrophilic 3O4Fe O/ Au NPs. b) Schematic illustration of the formation of Fe 343O4/Au and

[69 ]Fe /Au/Ag. Reproduced with permission. Copyright 2007 American 3O4

Chemical Society.

process, the lattice spacings of the two components are gen-erally well matched to lower the energy required for epitaxial

[72

] However, lattice mis-are promising multifunctional nanostructures. The magnetic nucleation of the second component.

core provides magnetic functionality and delivery power and match can also be applied to make dumbbell NPs by a surface

[59

61] Electron the Au shell offers a well-developed surface for biomolecule de-wetting process of the core/shell structure.

attachment and plasmonically active components for optical transfer at the interface of two components in the nucleation

[69,70]imaging. A schematic illustration of the synthetic strategy process may play a key role in controlling the dumbbell mor-phology, and this transfer process can be modulated by the for Fe /Au core/shell NPs is shown in Figure 6 . The syn-3O4

[73 ] thesis starts with low-temperature coating of Au on the surface polarity of the solvent.

Dumbbell Au–Fe 3O4 NPs are now well-known and have been of Fe NPs by reducing HAuCl 3O44 in a chloroform solution of

oleylamine. Oleylamine is used as a mild reducing agent as well extensively studied. They are prepared by the decomposition of as surfactant. After the synthesis, Fe /Au NPs are transferred iron pentacarbonyl, Fe(CO) 5 , over the surface of the pre-made Au 3O4

NPs, followed by oxidation in air, as illustrated in Figure 7a.[73 ] from the organic environment to water with hexadecyl-trimethyl-The size of the Au NPs is controlled either by tailoring the ratio ammmonium bromide (CTAB) and sodium citrate. The water-of HAuCl soluble NPs serve as seeds for the formation of Fe /Au NPs 4 to oleylamine, or by controlling the temperature at 3O4

which the HAuCl with thicker Au coatings achieved by adding more HAuCl 4 solution is injected. The size of the Fe 3O4 4

[69]NPs is tuned by adjusting the Fe(CO) /Au ratio, as shown in under reductive conditions. Similarly, starting from Fe 3O4/Au, 5

Figure 8 . Figure 7 b,c are typical TEM and HRTEM images of Fe /Au/Ag NPs can be synthesized by adding AgNO 3O4 3 to the

a dumbbell NP with an Fe component of 14 nm and Au reaction solution. Recently, FePt/CoS 3O42 core/shell NPs were also

component of 8 nm. In the structure, an Fe synthesized by the sequential growth of CoS 3O4 (111) plane 2porous nanoshells

[63]grows onto a Au (111) plane, giving the dumbbell-like struc-over FePt NPs.

ture. Similarly, dumbbell NPs of Pt-Fe 3O4 can be produced by controlled nucleation and growth of Fe on Pt NPs, followed by

[713.2. Dumbbell NPs oxidation in air. ]

FePt–Au NPs were prepared by the growth of Au over FePt [74]Dumbbell NPs are generally obtained by sequential growth of NPs. Other dumbbell NPs composed of various combina-a second component on pre-formed NP seeds. This is similar tions of metals (Au, Ag, Pt, or Ni) and oxides (Fe or MnO) 3O4

to the synthesis of core/shell NPs with the difference that the were synthesized from thermal decomposition of mixtures

[75]nucleation and growth are anisotropically centered on one of metal-oleate and metal-oleylamine complexes. In this

speci c crystal plane around the seed NPs, and not uniformly case, noble metal NP seeds were formed rst by employing distributed over the seed NP surface. Therefore, the successful oleylamine as a reductant. Then, MnO or Fe components 3O4synthesis of dumbbell NPs relies critically on promoting het-grew on the noble metal NP seeds by a seed-mediated growth

erogeneous nucleation while suppressing homogeneous nucle-process at 300 °C through the thermal decomposition of the rel-ation. This can be achieved by tuning the seed-to-precursor evant oleate complex, resulting in heterostructured metal-oxide ratio and controlling the heating pro le so that the concentra-NPs. Heterostructures based on FePt NPs and semiconducting

[76tion of the precursor stays below the homogeneous nucleation chalcogenide NPs have been systematically studied. ] The

[16]threshold throughout the synthesis process. In the growth sequential growth of CdX (X = S or Se) onto FePt NPs at a lower

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reaction temperature results in the formation

[77]of FePt/CdX core/shell NPs. However, due

to the dewetting of CdX from the FePt surface at higher reaction temperature, the core/shell FePt/CdX NPs can be converted to FePt-CdX dumbbell NPs, as shown in Figures 8 a,c. This

–MS synthesis has been extended to γ-Fe 2O3

[72](M = Zn, Cd, Hg) NPs. Note that Fe –3O4

CdSe NPs show an emission wavelength peak at 610 nm with quantum yield of about 38%. The resulting uorescent MNPs have two attractive features—superparamagnetism and uorescence—which allow them to be con-trolled using magnetic force and to be imaged

[77]using a uorescence microscope. Ag–Fe3O4

dumbbell NPs were made in a micellar structure by ultrasonication of a heteroge-neous solution of as-prepared Fe 3O4 NPs in an organic solution and AgNO 3 in water, as exhibited in Figures 8 b,d. The sonication pro-vides the energy required to form a microe-mulsion, which is stabilized by the NPs that self-assemble at the liquid/liquid interface. Fe(II) in the NPs acts as a catalytic center for

+the reduction of Ag to Ag NPs. The partial

exposure of the NPs to the aqueous phase

+and the self-catalyzed reduction of Ag and Figure 8. Schematic illustration of the synthesis of CdS–FePt heterodumbbells (a,c), and the nucleation of Ag are proposed as two factors

[76

micellar synthesis of Ag–Fe ,77] that lead to the heterodimer morphology. The 3O4 heterodumbbells (b,d). Reproduced with permission. Copyright 2004, 2005 American Chemical Society. synthesis can be readily extended to make

[77]Ag–FePt NPs as well.

Using combinations of the chemistry

described above, more exotic dumbbell NPs that contain a noble metal, MNPs, and QDs can be made. For example, PbS–Au–Fe 3O4 NPs were obtained by mixing Au–Fe NPs 3O4

with a Pb-oleate complex and elemental S. The competition between the adsorption of S onto the Au surface and reaction with the Pb-oleate to form PbS NPs led to het-erogeneous nucleation of PbS on the Au

[78surface. ]

3.3. Multicomponent Hybrid NPs

elf-assembly processes provide an approach S

to fabricating multicomponent hybrid NPs with integrated multifunctionality. By employing intermolecular forces, it is easy to prepare assembled nanostructures from various individual NPs, as illustrated in Figure 9.[79 ] Hydrophobic Fe ,CdSe/ZnS 3O4

NPs, doxorubicin (DOX), and poly( D,L-lactic-co -glycolic acid) (PLGA) were incorporated into the hydrophobic part of Pluronic F127 ((EO) ) micelles upon sonica-97(PO) 69(EO) 97

Figure9. Scheme for preparation of nanoassemblies as multifunctional nanoplatforms. tion. A mixture dispersion of hydrophobic

[79magnetite (or CdSe/ZnS) NPs, DOX, and ] Reproduced with permission. 6

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onodisperse NPs with controlled shape and sizes are usu-M

ally coated with a long-chain hydrocarbon, leading to a hydrophobic surface. To make these NPs biocompatible for biological applications, their surfaces are often functionalized by means of surfactant addition or surfactant exchange, as illustrated in Figure 11 . Surfactant addition is achieved through the adsorption of amphiphilic molecules that contain both a hydrophobic segment and a hydrophilic component. The hydrophobic segment forms a double layer structure with the original hydrocarbon chain, while hydrophilic groups

are exposed to the outside of the NPs, rendering them water

soluble. Surfactant exchange is the direct replacement of the original surfactant with a new bifunctional surfactant. This bifunctional surfactant has one functional group capable of binding to the NP surface tightly via a strong chemical bond and the second functional group at the other end has a polar character so that the NPs can be dispersed in water or be further functionalized.

There are various kinds of materials that can be chosen

[82]for coating NPs. Polymer coating materials of lipids,

proteins, dendrimers, gelatin, dextran, chitosan, pullulan,

PEG, poly(ethylene- co-vinylacetate),poly(vinylpyrrolidone) (PVP), PLGA, or poly(vinyl alcohol) (PVA) are often chosen for

[82 87]this purpose. Other special molecules,

such as bifunctional 2,3-dimercaptosuc-[88]cinic acids (DMSA), dopamine, [89 91] and

[92]silanes, were also investigated for use in

NP functionalization. For example, dopamine was found to be a stable anchor on the Fe 3O4

[90,91]NP surface. Silanes were employed to

exchange the hydrophobic ligands on ferrite

[92]magnetic nanostructures. The end group

of silanes, including isocyanine, acrylate, thiol, amino, and carboxylic groups, offer extensive chemistry for the modi cation of nanostructures. Dopamine and saline as sta-bilizers often need to be combined with PEG or other poly mers to offer long-term NP sta-[91,93]bilization in biological solutions. .Besides

[94][95]PEG, chitosan, alginate, dextran, [25 , 96 ] and

[97]poly(acrylic acid) (PAA) can also be used to

stabilize nano structures and offer long-term sta-bility and biocompatibility. As an amphiphilic surfactant, phospholipid –PEG can readily coat FeCo NPs having graphitic carbon shells by means of hydrophobic interactions ( Fig. 12). [98 ] The carbon-coated FeCo NPs, which are super-paramagnetic with a high magnetic moment,

Figure 10. a) Schematic diagram of the synthesis of core–satellite DySiO ) NPs. b–d) showed not only ultrahigh R1 and R2 relax-2–(Fe 3O4 TEM images of b) rhodamine-doped silica (DySiO ), c) iron oxide (F ), and d) core–satellite ivities but also high aqueous solubility and 2 e3O4

[8biocompatibility. DySiO )n NPs. Reproduced with permission. 1 ] 2–(Fe 3O4

7

PLGA in methylene chloride was poured into an aqueous solu-tion containing Pluronic F127 and the solution was subjected

to ultrasonication using a probe-type sonicator. After that the organic solvent was evaporated at room temperature by mechan-ical stirring and subsequently washed with deionized water for several times, PLGA NPs incorporating inorganic NPs and DOX were obtained. The positively charged, poly( L -lysine) domain of poly( L -lysine)-poly(ethylene glycol)-folate (PLL-PEG-FOL) was adsorbed on the NP surface through electrostatic interactions with the negatively charged surface of the PLGA NPs derived from the terminal carboxylate groups of the PLGA chain. This platform is composed of four components. First, biodegradable PLGA NPs are used as a matrix for loading and subsequent controlled release of hydrophobic therapeutic agents into cells. Second, two kinds of inorganic NPs (Fe 3O4 and CdSe/ZnS) are incorporated into the PLGA matrix: MNPs can be employed for both magnetically guided delivery and as a T2 magnetic reso-nance imaging (MRI) contrast agent, and semiconductor NPs are incorporated into the polymer particles for optical imaging. Third, DOX is a therapeutic agent for cancers. Finally, cancer-targeting folates conjugated to the PLGA NPs by PEG groups can be used to target KB cancer cells that have over-expressed folate receptors on their cell surfaces. Similarly, uorescent magnetic nanohybrids (FMNHs) conjugated with Cetuximab

[80]were also made.

Self-assembly processes can be further enhanced by direct

chemical linkage to form hybrid NPs. An example is the

self-assembly of dye-doped silica mixed with MNPs, as shown in Figure 10 . The integrated structures can be used for simulta-[81]neous optical and magnetic imaging.

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4. Surface Functionalization of NPs

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review can serve as multifunctional probes for sensitive imaging

[104]applications. These MFMNPs are also effective carriers for

a larger payload of drug molecules for improving therapeutic

[105,106]ef ciency. 5.1.1. MRI Probes

MRI is an extremely useful diagnostic tool for medical sci-

[104ence. , 107 ] According to different relaxation pathways, MRI images can be classi ed as T1 (longitudinal relaxation time)- or T2 (transverse relaxation time)-weighted images. MRI contrast agents can help to clarify images and to allow better interpreta-[108tion. ] Commonly, paramagnetic complexes, such as Gd-DTPA (gadolinium diethylene triamine pentaacetic acid), are used as T1 contrast agents and MNPs are selected as T2 contrast agents. The

[109acting mechanism of T2 contrast agents is as follows. ] Under

an applied magnetic eld B0 , a magnetic moment is induced in superparamagnetic NPs, which perturbs magnetic relaxation processes of the water protons around them, shortening the spin–spin relaxation time T2. Such changes result in darkening of the corresponding area in T2-weighted MR images. The degree of the T2 contrast effect is typically represented by the spin–spin R2 relaxivity (R2 = 1/T2), where higher values of R2 result in a greater contrast effect. The relaxivity coef cient r2, which is obtained as the gradient of the plot of R2 versus the molarity of magnetic atoms, is a standardized contrast enhancement indicator. Figure 11. Strategies for NP surface modi cation.

Metal oxide MNPs can provide a strong contrast effect in

[104T2-weighted images. ] Metal alloy MNPs, such as FeCo and

[109FePt, also serve as MRI contrast agents. ] A signi cant chal-5. Biomedical Applications of MFMNPs lenge associated with the application of these MNPs is their

behavior in vivo. All of these MNPs are almost nonspeci cally

[110]5.1. Molecular Imaging taken up by the reticuloendothelial system (RES), including

[111the liver, spleen, and lymph nodes, ] making their detection

Molecular imaging refers to the characterization and measure- not very effective. The next generation of NP-based MRI con-ment of biological processes at the cellular and/or molecular trast agents should incorporate novel nanocrystalline cores,

[99level, , 100 ] its modalities include optical bioluminescence, optical coating materials, and functional ligands to improve their detec-[112 uorescence, ultrasound, MRI, magnetic resonance spectros-tion and speci c delivery/targeting. ] copy (MRS), single-photon-emission computed tomography It is important that nanostructures accumulate around the

(SPECT), and positron emission tomography (PET). Since no target tissue in biomedical applications. This is achieved by func-single imaging modality can provide complete information tionalizing the surface of nanostructures with targeting agents. about a subject’s structure and function, using multiple imaging The special interactions between targeting agents and receptors modalities that combine two or more imaging techniques has allow accumulation of the nanostructures near speci c tissue.

[101 103]been an attractive goal. The MFMNPs summarized in this MNPs have been modi ed with many different kinds of tar-geting molecules, for example, EGF (epi-[113dermal growth factor), ] Herceptin,[114 ]

[115and CEA (carcinoembryonic antigen), ] for

active detection of tumors. In a recent test, MnFe NPs were coupled with Herceptin, 2O4

an antibody speci cally binding to the over-expressed HER2/neu marker on the surface of

[116breast and ovarian cancer cells. ] Figure 13

shows the color-coded MR image of a mouse implanted with the cancer cell line NIH3T6.7 and treated with 50 mg of NP–Herceptin. It can be seen that the tumor treated with the MnFe –Herceptin NPs shows color changes 2O4

from red to blue in the color-coded MR images Figs. 13a–c ). In contrast, those treated with Figure 12. FeCo NPs with graphitic carbon shells for biomedical applications. Reproduced with (

[98]

permission. Copyright 2006 Nature Publishing Group.

the Fe –Herceptin NPs at the same dosage 3O4 8

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5.1.2. MRI/Optical Imaging Probes

[117 ptical imaging has been a popular imaging modality. O , 118 ] Organic dyes are normally employed to offer uorescent fea-[119]tures. Fluorescein isothiocyanate (FITC), DiI (a hydrophobic

[120]and lipophilic cyanine dye), and cy5.5 (another cyanine

[121]dye) are commonly conjugated with magnetic nanostruc-tures for combining both optical and MRI modalities into

[122,123]one nanostructure. In fabricating dual probes, MNPs

coated with dextran can be further linked with HIV-Tat peptide

[124](a membrane translocation signal peptide) and FITC. MNPs

were also modi ed with PEG-modi ed phospholipids with

[125]Texas Red and Tat peptide attached to the PEG chains. Iron

oxide MNPs coated with bifunctional PEGs were conjugated with Cy5.5 and chlorotoxin, a MMP2 (matrix metalloproteinase 2)

[126]-targeting peptide was aslo used.

Because of its chemical stability and biocompatibility, silica

[127 132]has also been widely used in biomedicine. Mesoporous

silica is a kind of alternative material for drug delivery because porous structures allow the diffusion of drugs into and out of the

[130]structure. By the addition of functional organic molecules,

[127]such as dyes, nanoscale silica can be made into multifunc-tional nanostructures. For example, optically active iron oxide/

3+silica MFMNPs were made by the copolymerization of an Eu

complex, free (3-aminopropyl) triethoxysilane (APS) and tetrae-thyl orthosilicate (TEOS) in the presence of PVP-stabilized Fe 3O4NPs. Similarly, FITC was incorporated into the iron oxide/silica

[127]system. Most recently, another kind of optical/MRI probe was

fabricated by coating with PAA and by grafting a near infrared (NIR) dye in the PAA matrix ( Fig. 14). [133 ] Such IR and MRI dual

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Figure13. Color maps of T2-weighted MR images of a mouse implanted with the cancer cell line NIH3T6.7 at different time points after injection of MnFe –Herceptin (a–c) and Fe –Herceptin (d–f) conjugates. 2O4 3O4

[116]Adapted from, with permission from Nature Publishing Group.

have no apparent change in the color-coded MR images ( Figs.

13 d–f), indicating the high MR sensitivity of MnFe 2O4–Herceptin conjugates. An even higher MRI sensitivity can be achieved by using high moment superparamagnetic NPs.

Figure 14. Multimodality imaging probe. a) Schematic representation of the synthesis of theranostics and multifunctional iron oxide NPs. b–d) Assess-ment of iron oxide NP cellular uptake via confocal laser-scanning microscopy using lung carcinoma A549 cells. b) No internalization was observed in cells treated with carboxylated iron oxide NPs, as no DiI uorescence was observed in the cytoplasm. c) Enhanced internalization was observed upon incubation with the folate-immobilized iron oxide NPs. d) Cells incubated with paclitaxel (Taxol) and DiI co-encapsulating folate-functionalized iron

[ 133 ]oxide NPs induced cell death. Reproduced with permission.

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10

computed tomography (CT) imaging as a result of their biocom-[49patibility and their high electron density. , 138 , 139 ] The density of

3gold (19.32 g cm ) is much higher than that of commercial CT

3 probe iodine (4.9 g cm ). Therefore, nanoscale gold can serve as 5.1.3. MRI/PET Probes [140an excellent contrast probe for CT imaging. , 141 ] In this regard,

Positron emission tomography (PET) is a useful imaging MnFe /silica/Au should be a powerful bimodal contrast 2O4

[142modality that uses the signals emitted by positron-emitting agent for both MRI and CT imaging. , 143 ]

[134]radiotracers to construct images. A series of positron-1118124emitting elements, including C, F, 64Cu, 68 Ga, and I, are

5.2. MFMNPs for Drug Delivery commonly used as tracers in PET imaging. PET, as an extraor-dinarily sensitive imaging modality, has comparatively low reso-lution, while MRI gives high anatomical spatial resolution. By With the rapid development of nanotechnology, NP-based

combining both of them, it is possible to get both highly sensi-drug carriers have been emerging as effective tools for drug

tive and high-resolution images. delivery in cancer therapy. There have been many different

64To combine PET with MRI in one probe, a Cu complex kinds of macromolecular structures designed for drug delivery

[144 146]can be grafted onto dextran in the dextran coating of MNPs via systems, such as micelles, liposomes,[146 ] NPs,[147 , 148 ]

[135[149][150]a chelating bifunctional ligand (p-SCNBz-DOTA). ] PET/MRI dendrimers and polymers. In these systems, the drug

probes with targeting capabilities were also fabricated by cou-is entrapped, attached, adsorbed, or encapsulated into or onto

64[151pling Cu and cyclic arginine-glycine-aspartic acid (RGD) pep-nano-matrices. ] A number of studies have demonstrated

[136]tides to poly(aspartic acid) (PASP) in PASP-coated MNPs. The the advantages of using MNPs for drug delivery. MNPs conju-PET/MRI dual probe has been demonstrated as an in vivo dual-gated with methotrexate (MTX), a therapeutic drug, can target

[152,153]modality imaging agent in a sentinel lymph node (SLN) model cancer cells that overexpress folate receptors. Such NPs

[137]biological subject. In the synthesis, serum albumin (SA)-show higher internalization by cancer cells than healthy cells

124coated MnFe was applied as the MRI probe and I, a PET do. MTX can be released from the NPs by lower environ-2O4

radionuclide, was conjugated to the tyrosine residue in SA. In the mental pH and intracellular enzymes to induce apoptosis of in vivo experiment, two different types of LNs were clearly identi-cancer cells.

ed and accurately localized in a PET/MR fusion image ( Fig. 15). Recently, various novel MFMNPs have been designed for

simultaneous drug delivery and molecular imaging. For example, dumbbell-like Au-Fe 3O4 NPs were made to bind covalently 5.1.4. MRI/CT Probes [13,154]with cisplatin complexes, a kind of therapeutic drug that

[155,156] Noble-metal NPs such as gold and silver NPs have attracted binds strongly to DNA and interrupts DNA transcription,

Figure 16 . These dumbbell-like Au-Fe NPs can signi cant attention owing to their potential applications in as shown in 3O4

modality probes offer much-needed deep tissue imaging at great

sensitivity.

Figure 15. a) Preparation of 124 I-SA-MnMEIO (where MnMEIO is Mn-doped magnetism-engineered iron oxide). b) MR (left) and PET images (right)

124I, 124124 I-SA-MnMEIO, and SA-MnMEIO at various concentrations. I-SA-MnMEIO clearly exhibits the dual characteristics of PET and MRI. of free

[137]Reproduced with permission.

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Fe 3O4 porous hollow NPs (PHNPs) were also demonstrated to be an ef cient carrier for targeted delivery and controlled release of cis-[157platin ( Fig. 17 b). ] Cisplatin was loaded into

the core of the NPs by diffusion. After coupling with Herceptin, the cisplatin-loaded hollow NPs provided ef cient delivery of cisplatin to HER2-positive breast cancer cells (SK-BR-3). Different drugs can be delivered using

[158various kinds of strategies. , 159 ] Fluorescent

[80magnetic nanohybrids (FMNHs), ] which

were stabilized by pyrene-labeled poly(ε-caprolactone)- b -poly(methacrylic acid) copol-ymer (Py-PCL- b -PMAA), were explored for simultaneous cancer-targeted MRI or optical imaging and magnetically-guided drug Figure 16. a) Schematic illustration of surface functionalization of the Au–Fe 3O4nanoparticles.

b, c) TEM images of the 8–20-nm Au –Fe O particles before (b) and after (c) surface modi ca-delivery. This platform is composed of Fe 343O4tion. Reproduced with permission.[13 ] or CdSe/ZnS with DOX embedded in a bio-degradable PLGA polymer matrix. PEG-folate was coated on the surface of the polymer NPs

serve as a multifunctional platform for target-speci c cis-for active targeting of cancer cells. Most recently, a lipophilic platin delivery. The release of the therapeutic cisplatin under near infrared (NIR) dye and an anticancer drug (Taxol) were low-pH conditions renders the NP conjugates more toxic to incorporated into the polymeric matrix of PAA-coated MNPs for the targeted tumor cells than free cisplatin. In this structure, combined optical imaging/MRI detection and targeted cancer

[133a cisplatin complex was conjugated to the Au side by reacting therapy. ]

Au-S-CH 2CH 2N(CH 2COOH) 2 with cisplatin. Herceptin (HER2-speci c antibody) was coated onto Fe 3O4 through PEG3000-5.3. MFMNPs for Gene Delivery CONH-Herceptin for targeting abilities. The speci city and ef cacy of the cisplatin-Au-Fe -Herceptin NPs was examined 3O4

with Sk-Br3 cells (HER2-positive breast cancer cells) and MCF-7 With the development of DNA technology, especially recom-cells (HER2-negative breast cancer cells), as shown in Figure 17a.bination technology, gene therapy, which transfers DNA or

The cisplatin-Au-Fe -Herceptin NPs target and kill HER2-RNA into target cells, has become a novel approach for disease 3O4

[160positive cancer cells (Sk-Br3 cells) more effectively ( Figs. 17 c,d). therapy. ] However, nding effective transfection methods is a

major objective in gene therapy research due to rapid degradation of DNA and RNA by enzymes and their poor diffusion across cell

[161membranes. , 162 ]

There are numerous gene delivery methods,

such as microinjection, electroporation, micro-particle bombardment, calcium phosphate

[163co-precipitation, and liposome technology. ]

NP-based gene delivery systems are potentially more effective and active. For example, MNPs coated with adeno-associated virus (AAV) can encode green uorescent protein (GFP) by

[164using a cleavable heparin sulfate linker. ]

In addition, MNPs coated with polyami-doamine (PAMAM) dendrimers and the cati-onic polymer polyethyleneimine (PEI) have

[165been tested as a gene delivery system. , 166 ]

However, PEI is highly toxic to cells as it easily

[167disrupts cell membrane function. , 168 ] Its

toxicity can be reduced by grafting PEG to

[169PEI. ] The MFMNPs are made of MNPs and

Figure 17. a) Schematic illustration of dumbbell-like Au-Fe NPs coupled with Herceptin a copolymer of PEI and PEG, allowing ef 3O4 cient and a cisplatin complex for target-speci c cisplatin delivery. b) Schematic illustration of simul-loading and the protection of nucleic acids. All taneous surfactant exchange and cisplatin loading into a porous hollow NP (PHNP) and func-tionalization of this PHNP with Herceptin. c,d) Re ection images of Sk-Br3 (c) and MCF-7 these studies show that this NP method can

potentially be used to advanced gene delivery cells (d) after incubation with the same concentration of cisplatin-Au-Fe 3O4-Herceptin NPs.

[ 154 ,157 ]and therapy. Reproduced with permission.

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6. Concluding Remarks and Perspective

ultifunctional magnetic nanoparticles (MFMNPs) are impor-M

tant emerging platforms for multimodality imaging probes. The multifunctional surfaces of MFMNPs allow rational conjuga-tions of biological and drug molecules of interest. These recent rapid developments in the synthesis and surface modi cation of MFMNPs have enabled the use of these NPs for more effec-tive diagnosis and therapy. Next-generation molecular probes fusing multiple uorescent dyes, drugs, and multiple MNPs into a single nanoprobe should provide superior uorescence, enhanced MRI contrast, and targeted drug delivery capabilities. Before these MFMNPs can be used practically as probes

for diagnostic and therapeutic applications, numerous chal-lenges need to be met. They should be tested thoroughly for their biocompability and biodistribution. Their targeting capa-bilities need to be enhanced. Once their diagnostic and thera-peutic purposes are achieved, these NPs should be eliminated by biological systems without any other detrimental effects. The long-term effects of these NPs and their conjugates on biolog-ical systems should also be studied. Despite these numerous challenges, MFMNPs are considered the most promising tools to achieve the desired sensitivity and ef cacy required for future medical diagnostics and therapeutics. Extensive research efforts are needed and any one speci c solution to biocompat-ibility, biodistribution, and bioelimination with enhanced diag-nostic/therapy abilities may lead to an exciting breakthrough in nanomedicine. Acknowledgements

e gratefully acknowledge the support of the National Basic Research W

Program of China (2010CB934601), NSFC (20941003, 90922033), the Doctoral Program of the Education Ministry of China (20090001120010), the Beijing Outstanding Talent Program (2009D013001000013), and the New Star Program of the Beijing Committee of Science and Technology (2008B02). Work at Brown University was supported by NIH/NCI 1R21CA12859 and a Brown imaging fund.

Received: January 22, 2010

Revised: March 16, 2010

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