View Online / Journal Homepage / Table of Contents for this issue

APPLICATION

www.rsc.org/materials | Journal of Materials Chemistry

Multifunctional magnetic nanoparticles for medical imaging applications

Chen Fang and Miqin Zhang*

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

Received 3rd February 2009, Accepted 9th April 2009

First published as an Advance Article on the web 1st June 2009
DOI: 10.1039/b902182e
Magnetic nanoparticles (MNPs) have attracted enormous research attention due to their unique
magnetic properties that enable the detection by non-invasive medical imaging modalitymagnetic
resonance imaging (MRI). By incorporating advanced features, such as specific targeting,
multimodality and therapeutic delivery, the detectability and applicability of MNPs have been
dramatically expanded. A delicate design of structure, composition and surface chemistry is essential to
achieving the desired properties in MNP systems, such as high imaging-contrast and chemical stability,
non-fouling surface, target specificity and/or multimodality. This article presents the design
fundamentals on the development of MNP systems, from discussion of material selection for
nanoparticle cores and coatings, strategies for chemical synthesis and surface modification and their
merits and limitations, to conjugation of special biomolecules for intended functions, and reviews the
recent advances in the field.

1. Introduction
The development of magnetic nanoparticles (MNPs) with
advanced features has been a major focus of research in nanomedicine.1,2 The unique magnetic properties of MNPs enable
their detectability by magnetic resonance imaging (MRI).3,4 MRI
can provide both morphological and anatomical information
with high spatial resolution and virtually no limit on penetration
depth,5,6 and its detectability can be significantly expanded by
using molecular imaging contrast agents such as MNPs.7 The
large surface-to-volume ratio of MNPs provides abundant
chemically active sites for biomolecule conjugation,8 allowing
delicate design and engineering of these MNPs for intended
functions such as long-circulating in the bloodstream,2,9 targetDepartment of Materials Science and Engineering, University of
Washington, Seattle, WA, 98195, USA. E-mail: mzhang@washington.edu
This paper is part of a J. Mater. Chem. theme issue on inorganic
nanoparticles for biological sensing, imaging, and therapeutics. Guest
editor: Jinwoo Cheon.

Chen Fang received his BS

(2001) and MS (2004) in
materials science and engineering from Shanghai Jiaotong
University. He is currently
pursuing his PhD at the
University of Washington under
the supervision of Prof. Miqin
Zhang.

6258 | J. Mater. Chem., 2009, 19, 62586266

specificity to lesion tissue,911 optical detectability,12 and therapeutic delivery.10,1315 Combining the merits of these advanced
medical imaging modalities with the breakthrough of molecular
and cell biology, molecular imaging can visualize, characterize
and quantify biological processes at a cellular and molecular
level in a non-invasive manner,16 enabling timely and accurate
diagnosis and individualized treatment of devastating diseases,
such as cancer and cardiovascular disease.17,18 The operation of
MRI is based on the mechanism of nuclear magnetic resonance
(NMR) and the relaxation of hydrogen proton spins in an
applied magnetic field.5 Two independent processes, longitudinal
relaxation (T1recovery) and transverse relaxation (T2decay),
can be acquired to generate an MR image. The contrast in MR
images, which refers to the signal differences between adjacent
regions, arises from variations in relaxation time among protons
associated with the local environment in the tissue. The clinical
application of MRI is often hampered by the low contrast
between lesions and surrounding healthy tissue in acquired
images. MRI contrast agents, with high magnetic moments,

Miqin Zhang received her PhD

in materials science from the
University of California at Berkeley in 1999. She is currently
a professor in the Department of
Materials Science and Engineering at the University of
Washington. Her research
directions include nanotechnology for cancer diagnosis and
therapy, tissue engineering for
tissue
regeneration
and
controlled drug delivery, and
cell-based sensors for toxin
detection and drug screening.
This journal is The Royal Society of Chemistry 2009

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

View Online

shorten the longitudinal and transverse relaxation time of their

surrounding protons,19 thus amplifying the signal difference
between lesions and healthy tissues. Small molecule contrast
agents, such as gadolinium diethylenetriaminepentaacetic acid
complex (Gd-DTPA), were the first-generation clinical contrast
agents,19 followed by iron oxide nanoparticle-based contrast
agents initially developed for a liver and spleen imaging.20
Recently, a number of nanoparticle-based contrast agents have
been approved for clinical use, including Lumiren for bowel
imaging, Combidex for lymph node metastases imaging.2124
A typical MNP system (Fig. 1A) is comprised of a magnetic
core that provides contrast enhancement, a polymer shell that
renders the stability and biocompatibility, and, frequently,
surface-bound or embedded molecules that endows targetspecific capability and/or multifunctionality.3,4,22 In a multifunctional system, MNPs may be further incorporated with
therapeutic payloads (chemotherapeutics or biotherapeutics),
serving as both an imaging agent and a therapeutic carrier.
Depending on the magnetic property of the core, the MNP can
either serve as either T1 or T2 contrast agent. The effectiveness
of an MNP contrast agent can be described by its longitudinal
relaxivity r1 and transverse relaxivity r2, the rate of relaxation,
or the slope of R1 (1/T1) or R2 (1/T2) versus the contrast agent
concentration. Superparamagnetic nanoparticles has very large
magnetization under applied magnetic field, which can cause
large susceptibility difference between the particles and
surrounding medium resulting in microscopic magnetic field
gradients.2 The microscopic field gradients due to the presence
of MNPs will cause pronounced T2-shortening effect, and hence
superparamagnetic nanoparticles are typically used to provide
negative contrast enhancement using T2-weighted imaging pulse

Fig. 1 Graphic illustration of the structure of a multifunctional/multimodality MNP and different types of magnetic cores. (A) The structure
of a multifunctional/multimodality MNP, with a magnetic core, a polymeric coating, and targeting ligands extended from the surface of MNP
with the aid of polymeric spacers. Therapeutic payloads (drugs and
genes) and imaging reporters (fluorophores and radionuclides) can be
either embedded in the coating, or conjugated on the surface. (B)
Schematic representation of different types of magnetic cores: Spherical
nanocrystal, core-shell nanocrystal, heterodimer nanocrystal non-crystalline nanoparticle.

This journal is The Royal Society of Chemistry 2009

sequences. The T2-shortening ability is dependent directly on

the magnet moment of nanoparticles,25 that is determined by the
composition, size, shape and surface chemistry of nanoparticles.2628 However, the negative contrast agents have their
drawbacks on T2-weighted MRI. The resulting dark signal from
the nanoparticles is often confused with the signals from pathogenic conditions, and the susceptibility artifacts distort the
background image around lesions.29,30 Alternatively, T1 contrast
agents are predominantly paramagnetic nanoparticles and
generate positive contrast enhancement via T1-weighted
sequences. Despite the fact that T1-shortening processes require
a close interaction between protons and contrast agents, which
can be hindered by the thickness of the coating on the MNPs,
several nanoparticle-based T1 contrast agents have been reported recently.13,29,3136
In the following sections, we will review the recent advances on
the development of MNP systems, including the design and
fabrication of magnetic cores and coatings, and further derivations for imaging applications.

2. Building magnetic cores

The majority of MNP systems utilize inorganic nanocrystals
as their magnetic cores. The composition of those inorganic
nanocrystals ranges from metals to alloys to metal oxides.
Noncrystalline nanoparticles, such as polymeric nanoparticles,37,38 self-assembled micelles,13 can also serve as magnetic
cores. Fig. 1B listed the most commonly used magnetic cores for
building MNP systems. The design of the magnetic cores for
MNPs requires careful and balanced consideration of materials
properties, synthesis feasibility and application requirements.
Magnetic properties, chemical stability and toxicity are the
primary focus in the design of a MNP system. Materials that
have high magnetizations (Ms) are ideal candidates for MRI
contrast agents. Common magnetic materials contain certain
transitional elements with unpaired electrons, such as Fe, Co, Ni,
Mn, Cr or Gd, and can be categorized as metals, metal alloys
metal oxides. Metals and alloys, such Fe, FeCo, are among the
magnetic materials with the highest magnetizations. However,
most of them are susceptible of oxidation and corrosion. Metal
oxides materials are generally stable, and have acceptable
magnetizations. Therefore, most MNP-based contrast agents
that have been thoroughly investigated are metal oxides. Toxicity
considerations should also be integrated into materials selection,
since elements with an inoffensive toxicity profile are most likely
accepted for clinical applications. Therefore, iron-based MNPs
are most investigated since iron has an innocuous toxicity profile,
is a basic element in human bodies and can be added to the
bodys iron store after particle degradation.39 Manganese is
another essential trace element in human bodies, but its tolerable
limit is much lower than irons. Other elements, such as Co, Ni,
Cr and Gd, are highly toxic, which necessitates proper coatings
or chelation when they are used in vivo.
Metal oxide nanocrystals were the most-investigated in the
search for MNP-based MRI contrast agents. Among those metal
oxide compounds, superparamagnetic iron oxide nanoparticles
(SPIONs), including magnetite (Fe3O4) and maghemite
(g-Fe2O3), have been a major research focus during the past
decade.22 These nanocrystalline iron oxides belong to the ferrite
J. Mater. Chem., 2009, 19, 62586266 | 6259

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

View Online

family, and have spinel structures, where the oxygen atoms form
fcc lattices and iron atoms occupy tetrahedral (Td) and octahedral (Oh) interstitial sites.40 Particularly, magnetite has an inverse
spinel structure, where the Fe2+ ions occupy Td sites and the Fe3+
ions occupy both Oh and Td sites. The spins of those ions in the
Td sites and Oh sites align antiparallel under an external magnetic
field, yielding a large total net magnetization and a ferrimagnetic
spin structure.11 Owing to their large surface-to-volume ratio,
SPIONs exhibit superparamagnetism at room temperature. The
major advantage regarding clinical applications is that iron
oxides are biocompatible and biodegradable, and have a good
chemical stability against solvent leaching. There are a number of
clinically approved SPIONs that serve as T2 contrast agents for
various MRI applications.41,42
Other types of ferrites, in which Fe2+ ions are fully or partially
replaced by other transitional metals (e.g. Mn, Co, Ni and Zn),
were also studied.11,4345 Lee et al. reported characterization and
in vivo evaluation of a series of ferrite nanocrystals (MFe2O4,
M Mn, Fe, Co, Ni).11 Among those ferrite nanocrystals,
manganese ferrite (MnFe2O4) nanocrystals demonstrated the
largest magnetization and T2 contrast enhancement. Recently,
B
arcena et al. reported the successful synthesis of zinc ferrite
nanocrystals with a mixed spinel structure.45 Those zinc ferrite
nanocrystals demonstrated better T2 contrast enhancement than
comparable magnetite nanocrystals.
In addition to the ferrites family, other transitional metal
compounds have also been evaluated as potential MRI contrast
agents. Nanocrystals of those compounds display various
magnetic properties, such as paramagnetism and antiferromagnetism, and some of them could serve as T1 contrast agents. Rare
earth elements, represented by gadolinium, have generated great
research interest because they have very high magnetic moments
and interesting optical properties for integration of other imaging
modalities.46 Synthesis of size- and shape-controlled rare earth
oxide nanocrystals has also been demonstrated.4749 Recently,
contrast agents based on rare earth fluoride50 and phosphate36
have also been synthesized. Despite the fact that some of those
nanocrystals show promising T1 contrast enhancement, few in
vivo applications have been reported. Bridot et al. reported the
synthesis and in vivo applications of a multimodal contrast agents
based on gadolinium(III) oxide (Gd2O3) nanocrystals.35 The
nanocrystals were synthesized by a nonaqueous co-precipitation
method, and coated with a polysiloxane shell. In addition to rare
earth elements, manganese-based compounds have also been
investigated. Na et al. synthesized manganese(II) oxide (MnO)
nanocrystals of different sizes,29 for tumor detection and cell
tracking.29,51 Future clinical applications of those MNPs require
rigorous surface engineering and careful toxicity evaluation.
Metal nanocrystals, including metal alloy nanocrystals, are
promising candidates for high performance contrast agents.
Since the net magnetization of metals is generally much higher
than those of metal oxides, the clinical dosages of metal-based
MNPs required for sufficient contrast enhancement would be
much lower than those of metal oxides-based MNPs. However,
the chemical instability exhibited by most metal nanocrystals is
the major hurdle limiting their application in medical imaging.
Metal nanocrystals are readily oxidized upon exposure to oxygen
or moisture, and transformed to metal oxides or hydroxides with
inferior magnetic properties,52 compromising their contrast
6260 | J. Mater. Chem., 2009, 19, 62586266

enhancement ability. Furthermore, a significant amount of free

metal ions can be released during the oxidation process, resulting
in severe toxicity.
To prevent the metallic cores from oxidization and corrosion,
compact and chemically stable shells are grown on the cores.
Noble metals53 (e.g. Au, Pt, etc.) and graphitic carbon32 have
been used as shell materials. Alternatively, crystalline oxide shells
can be created by controlled oxidation of as-synthesized metal
nanocrystals. For example, Peng et al. reported the synthesis of
Fe nanocrystals and subsequent creation of a crystalline oxide
shell utilizing an oxygen transferring agent.54 They also revealed
that amorphous oxide coating could not protect the iron core
from complete oxidation.
In some metal alloy nanocrystals, such as FePt, the interaction
between two metal elements may lead to greater chemical
stability in comparison to the single-element metallic nanocrystals. A more detailed coverage on the synthesis and surface
modification of FePt nanocrystals has been presented in a recent
review by Sun et al.55 Hydrophilic, biocompatible FePt nanocrystals have been produced,56 and their application as bifunctional imaging and therapeutic agents has also been reported.57
The FeCo nanocrystal is another type of metal alloy nanocrystals that have drawn the interest of researchers. FeCo
nanocrystals have extremely high magnetization, but are highly
susceptible to oxidation and corrosion. To solve this problem,
Seo et al. synthesized graphite shell-coated FeCo nanocrystals
with 4 nm and 7 nm core sizes.32 While the 7 nm nanocrystals
were proven to be excellent T2 contrast agents, the 4 nm nanocrystals are suitable for both T1 and T2 contrast enhancement.
The graphitic shells are chemically inert, and their near-infrared
absorbance property allows the potential use of the nanocrystals
in photothermal ablation therapeutics.
Recently, heterostructured magnetic nanocrystals have
attracted tremendous research attention. Multiple components
with distinct functionalities, such as surface plasmon resonance
and fluorescence, can be integrated in to a single heterostructured
magnetic core. The typical heterostructures include abovementioned coreshell structure, as well as heterodimers,5860 and
hollow nanoparticles.34 The formation of core-shell and heterodimer nanoparticles is typically via the seed-induced nucleation
process,58 and a comprehensive review on the synthetic mechanism of those heterostructures has been reviewed by Zeng et al.61
Noble metal-based heterostructured MNPs can serve as MR and
optical reflection dual-imaging probes,62 while semiconductorbased MNPs can serve as MR and fluorescence dual-imaging
probes.57,63 Hollow nanoparticles are derived from colloidal solid
nanocrystals via acid etching.34,64 Those hollow nanocrystals can
serve as both an imaging contrast agent and a drug carrier where
therapeutic payloads can be easily incorporated in the center
vacancy of MNPs.64 Additionally, hollow MnO nanoparticles
were found to improve T1 contrast as compared to the comparable solid MnO nanoparticles.34,64
For most inorganic magnetic nanocrystals serving for medical
imaging, the chemical synthesis methods can be divided into two
categories: co-precipitation and thermal decomposition.52
Co-precipitation methods are predominately performed in an
aqueous environment, and the process includes dissolving
precursors (metal salts) in acidified water with optional surface
coating materials, and then titrating the solution with alkaline
This journal is The Royal Society of Chemistry 2009

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

View Online

compounds.52 For example, aqueous synthesis of SPIONs can be

achieved by titrating base solutions into Fe2+/Fe3+ salts solutions.65 During the co-precipitation process, the nucleation stage
and growth stage of nanocrystals can not be easily separated,
resulting in polydisperse nanocrystals.66 The low reaction
temperature of the co-precipitation method leads to poor crystallinity of the products, resulting in low saturated magnetization.52 Nevertheless, large-scale production of nanocrystals is
feasible via co-precipitation methods. Since functional coating
materials can be added during the synthesis step, it is possible to
integrate core synthesis and coating in a single reaction (so-called
one-pot synthesis or in situ coating process, which will be
discussed in the next section) without post-synthetic surface
coating procedures.67 SPIONs coated with other hydrophilic
materials, such as dextran,68 poly(ethylene glycol) (PEG)69 and
chitosan,70 have also been synthesized in such one-pot
methods. Alternatively, a co-precipitation reaction could be
accomplished in a constrained environment. For example,
some surfactants can form water-in-oil reverse micelles, and
co-precipitation reaction can take place in those so-called
nanoreactors.71 The reverse micelle method can be used to
achieve size control of nanocrystals, but it the has drawbacks of
low yield and poor crystallinity.72
The thermal decomposition processes include dissolving metal
organic precursors in organic solvents with the assistance of
surfactants, and decomposing those precursors at elevated
temperature.52 The organic precursors are either organometallics
(e.g. metal carbonyl compounds73) or metal organic acid salts
(e.g. acetate,49 acetonacetate,44,49,74,75 oleate,43,76 etc.), and the
surfactants typically contain polar capping groups and long
hydrocarbon chains. Nanocrystals produced by thermal
decomposition methods have excellent monodispersity and
crystallinity.52 As a result, those nanocrystals exhibit superior
magnetic properties over nanocrystals of similar compositions
synthesized by co-precipitation methods. The size and shape
control of nanocrystals can be easily achieved by changing the
reaction temperature, precursor concentration, precursor to
surfactant ratio and other factors.43,73,76 Additionally, large-scale
production of nanocrystals can also be achieved with thermal
decomposition methods.43 The drawbacks of thermal decomposition methods include: highly toxic precursors in some cases,73
difficulty to achieve one-pot synthesis despite limited success.77,78
In most cases, nanocrystals produced by the thermal decomposition method are stabilized by surfactants (e.g. oleic acid), and
are only dispersible in nonpolar solvents (e.g. hexane, toluene)
or weak polar solvents (e.g. chloroform, tetrahydrofuran).
Therefore, post-synthetic processes are required to introduce
hydrophilic and biocompatible coatings on those nanocrystals,
which will be discussed in detail in the next section.
In addition to those two categories, other methods, such as
solgel reactions, flow injection syntheses, electrochemical
methods, aerosol/vapor methods and sonolysis have also been
employed to produce inorganic nanocrystals. A detailed
coverage of those methods was provided by Laurent et al.22
In addition to crystalline nanoparticles, noncrystalline nanoparticles can also serve as the magnetic cores of MNPs. Those
noncrystalline nanoparticles comprise a myriad of small paramagnetic molecules such as Gd3+, Mn2+ or other metal ions with
unpaired electrons. Those metal ions are always chelated by
This journal is The Royal Society of Chemistry 2009

small molecule ligands, which can prevent the release of free

metal ions, minimizing potential toxicity.79,80 Other imaging
reporters or therapeutic drugs can be easily incorporated during
the production of those nanoparticles, which allows them to
serve as multifunctional platforms.13
Those nanoparticles can be fabricated via hydrophobic selfassembly13 or polymerization methods.37,80 Among those metal
ions, Gd3+ is the best candidate since it has a high magnetic
moment and seven unpaired electrons, and small molecule
ligands for chelating Gd3+ have been thoroughly investigated.81
Taylor et al. reported the fabrication of Gd3+-based nanoparticles by a solgel synthesis method.80 Another element being
investigated is manganese. Nanoparticles based on manganese
complexes has been reported which shows promising T1 relaxivity.13,37 Chemotherapeutic drugs can also be embedded inside
the cores so that MNP systems can also serve as drug carriers.13
Based on those examples of success, noncrystalline nanoparticles
have great potential to achieve multimodality and multifunctionality.

3. Constructing biocompatible surface coatings

Biomedical applications require a robust MNP system to be
properly coated by hydrophilic polymers. First, surface coatings
are important to prevent MNPs from agglomeration in physiological environment. Second, coatings act as a barrier, effectively
shielding the magnetic core against the attack of chemical species
in the aqueous solution. Third, coatings provide functional
groups (e.g. amine, carboxyl) that can serve as anchor points for
further attachment of functional moieties, such as targeting
ligands, fluorescent molecules. For in vivo applications, the
coatings of MNPs strongly influence the longevity of MNPs in
the blood. Upon entering the blood circulation, MNPs are subjected to opsonization, the non-specific fouling of plasma protein
on the surface of MNPs, and subsequent uptake by reticuloendothelial system (RES). Therefore, proper coatings are required
to prevent the opsonization of MNPs, and to increase the ability
to evade RES. As a result, MNPs with long blood-circulation
time would maximize the possibility to reach target tissue.
In addition, coatings can also be tailored to improve MNPs
intracellular behaviors, therapeutic loading and release
properties.
The surface coatings also affect the relaxivity of MNPs.
Laconte et al. reported that the increased coating thickness
would dramatically decrease the R2 relaxivity of monocrystalline
iron oxide nanoparticles.82 Studies also indicated that the
hydrophobicity of surface coating, and the coordination chemistry of inner capping ligands, strongly influenced the relaxation
properties of MNPs.83,84
A diverse variety of materials have been developed and
employed as the coatings for MNPs, and most of them are
organic macromolecules, i.e., polymers. Based on different
criteria, those macromolecules can be categorized as hydrophilic
or amphiphilic polymers, neutral or charged polymers, naturally
derived or synthetic polymers, and homopolymers or copolymers. Neutral polymers contain abundant neutral and hydrophilic groups (e.g. hydroxyl, ether) which offer excellent
resistance against opsonization. The major drawback of neutral
polymers is the lack of functional groups (e.g. amine, carboxyl)
J. Mater. Chem., 2009, 19, 62586266 | 6261

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

View Online

for convenient bioconjugation, and chemical derivations are

often required. On the contrary, functional groups for bioconjugation are abundant in charged polymers. However, MNPs
coated with charged polymers are prone to opsonization due to
strong electrostatic interactions between the MNP surface and
plasma proteins. Typical neutral polymers include dextran and
PEG. Dextran, a branched polysaccharide comprised of glucose
subunits, is one of the most-investigated coating materials for
MNPs due to its proven biocompatibility.68 Most clinically
approved iron oxide nanoparticles are coated with dextran or its
derivatives.42,8587 PEG is a neutral, linear synthetic polyether
that can be prepared with a wide range of terminal functional
groups. PEG is nontoxic, nonimmunogenic and resistant to
protein fouling MNPs coated with PEG exhibit long bloodcirculation time.88 PEG has been widely accepted as a nanoparticle coating for biomedical applications.8992 Examples of
charged polymers include natural polymers, such as chitosan,
hyaluronic acid synthetic polymers, such as poly(acrylic acid)
(PAA), polyethyleneimine (PEI). Chitosan is a cationic polysaccharide that is nontoxic, hydrophilic, biocompatible,
bioabsorbable biodegradable. Chitosan and its derivatives have
long been used as carriers for nucleic acids and other pharmaceutical formulations.93 PEI is a synthetic cationic polymer that
comes with either linear or branched forms. Although PEI is
toxic and non-biodegradable, it has long been used for gene
delivery thanks to its ability to complex with DNA, facilitate
endosomal release via the proton sponge effect, and guide
intracellular trafficking of DNA into the nucleus.94 Numerous
copolymers have been synthesized to synergize the advantages
and overcome the disadvantages of each component. For
example, Bhattarai et al. synthesized a PEG-grafted chitosan
copolymer that has improved solubility in neutral pH, and it was
utilized as an injectable thermoreversible hydrogel.95 Veiseh et al.
demonstrated that PEG-grafted PEI copolymers can both
complex DNA to facilitate cell transfection, and exhibit lowtoxic and non-fouling profile necessary for molecular targeting.96
There are two major approaches to form the coatings of
MNPs: in situ coating (during the one-pot synthesis) and postsynthetic coating. During the in situ coating process, precursors
of magnetic cores and coating materials are dissolved in the same
reaction solution, and the nucleation of magnetic cores occurs on
the coating materials. Therefore, the magnetic cores and the
coatings of MNPs form at the same time.33,36,69,97100 In the postsynthetic coating process, first, the magnetic cores are synthesized, and optionally capped by surfactants protecting against
agglomeration. Then, the coating materials are introduced to the
surface of magnetic cores by either direct grafting,12,35,90,91 ligand
exchange,11,26,57,59,92,101104 or hydrophobic interactions.32,60,105108
Typically, two strategies have been used to link coating
materials on the surface of magnetic cores: the end-grafting
strategy and the surface-encapsulation strategy. Schematic
representations of those coating strategies are listed in Fig. 2.
End-grafting strategy utilizes a single surface-capping group on
one end of the coating molecules to connect the magnetic core
and coating molecules. The end-grafting process can be achieved
either by in situ coating or post-synthetic coating. Various
surface binding groups have been explored in the past in order to
form stable surface coatings. Initially, carboxyl groups have been
utilized to anchor coating molecules on transitional metal oxide
6262 | J. Mater. Chem., 2009, 19, 62586266

Fig. 2 Graphic illustration of different types of coating strategies for

hydrophilic MNPs: end-grafting, encapsulation by linear polymers,
encapsulation by hyperbranched polymers coating via hydrophobic
interactions.

surfaces,97,100 while thiol groups have been utilized for capping

noble metal surfaces.59,104 Recently, other high affinity surfacecapping groups have been explored to improve the stability of the
coating. Hydroxamic acid,109 phosphine oxide106 and catecholbased57,101,103,104 ligands have been reported to form stable coatings on the surfaces of various MNPs. Some surface-capping
molecules can form a cross-linked mesh on the core surface,
resulting in coatings with better chemical stability. For example,
Jun et al. reported coating of ferrites MNPs with dimercaptosuccinic acid (DMSA).26 Some of thiol groups on the DMSA
coating formed disulfide bridges to enhance stability, while
remaining free thiols were still available for further bioconjugation. Alkoxysilanes have also been studied extensively
since they can form highly stable polysiloxane shells on the
surface of metal oxide MNPs.12,35,8991,110,111 However, due to
limited amount of surface-capping groups per coating molecule,
linkages between the end-grafted coatings and magnetic cores
may easily break down, resulting in loss of coatings and
agglomeration of MNPs. Furthermore, some of those highaffinity capping groups are bulky, causing low surface density of
end-grafted polymers. As a result, the overall colloidal stability
of MNPs, as well as the availability of functional groups for
bioconjugation, could be affected.
To overcome the limitations of the end-grafting strategy,
nanoparticle cores can be fully encapsulated by a surfaceencapsulation strategy. Polymers with multiple surface-interacting groups (i.e. multidentate polymers) can be introduced as the
coatings of MNPs by either in situ or post-synthetic coating
methods. The collective effect of multidentate connections results
in stronger interactions and greater stability of the coating
compared to those coatings produced by the end-grafting
method. The first category of polymers includes linear and
partially branched polymers. The flexibility of these polymers
enables them to be wrapped around the magnetic cores. Various
polymers, including dextran,98 PAA,112 modified hyaluronic
acid113 and various copolymers,69 have been utilized as the
coatings of MNPs. The second category of polymers is hyperbranched polymers, which can form a close-packed layer of
surface coatings. Examples of those polymers include branched
PEI and other types of dendrimers. Scherer et al. developed PEIcoated MNPs for gene delivery.15 Landmark et al. have
This journal is The Royal Society of Chemistry 2009

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

View Online

developed Fe3O4 nanoparticles coated with poly(amidoamine)

(PAMAM) dendrimers.102
A special case of the surface-encapsulation strategy is formation of coatings via hydrophobic interactions. As mentioned in
the previous section, magnetic nanocrystals that are synthesized
by thermal decomposition method are often capped by hydrophobic surfactants. Those hydrophobic magnetic cores can be
coated with amphiphilic molecules, forming micelle-like structures. An amphiphilic molecule (e.g. phospholipids) consists of
both hydrophilic and hydrophobic regions. The hydrophilic
regions can interact with water by either ionic interactions
or hydrogen bonding, stabilizing MNP-containing micelles
in aqueous solutions. The hydrophobic regions are typically
long-chain hydrocarbons that can interact with hydrophobic
surfactants on the core surface. The aqueous stability of those
MNP-containing micelles can be improved by using amphiphilic
copolymers derived from PEG11,60,105,107 or polysaccharides.114
Large amphiphilic copolymers with multiple hydrophilic and
hydrophobic regions can be wrapped around the magnetic cores,
resulting in great chemical and thermal stability of MNP-containing micelles.108,115 Since the coating process via micelle
formation is independent of the chemical composition of
magnetic cores, this strategy can apply to not only MNPs, but
also other nanomaterials including quantum dots, carbon
nanotubes noble metal nanocrystals.108,114116 Some of those
micelle structures can be further modified to mimic high-density
lipoprotein (HDL), a naturally occurring nanoparticle. Those
HDL nanoparticles have demonstrated their ability to target the
expression of macrophages.116
The quality of the coatings on MNPs can be monitored by
measuring the hydrodynamic size, surface charge and other
physicochemical parameters. The hydrodynamic size of MNPs
can be obtained by dynamic light scattering (DLS), and are often
studied under various solution conditions, such as pH, ionic
strength and temperature.103,117 The surface charge of MNPs is
examined by measuring the zeta potential of MNPs. Once MNPs
are well characterized after the synthesis and coating stages,
further derivation and evaluation toward biomedical applications will begin.

established bioconjugate chemistries.118 One advantage of

nanoparticle-based imaging agents over small molecule counterparts is that much higher amount of targeting ligands can be
conjugated to nanoparticles, resulting in higher affinity towards
the molecular targets, which is known as the multivalency
effect.119,120 Targeted MRI have broad applications on diagnosis
and staging of diseases, evaluation of therapeutic outcomes, and
other applications.
While MRI is capable of providing high-resolution for preand post-operative imaging of patients, it is not appropriate for
intraoperative monitoring. To broaden the usage of the MNP
systems, MNPs are often modified to enable detection by other
imaging modalities. Those imaging modalities include optical
imaging, computed X-ray tomography (CT), and positron
emission tomography (PET).121 Veiseh et al. developed a targetspecific dual-modality MNP system.12 By attaching Cy5.5,
a near infrared (NIR) fluorophore, onto the surface of PEGcoated iron oxide nanoparticles, this dual-modality MNP
system is detectable by both MR and fluorescent imaging.
Fluorescent MNP systems also include quantum dotsMNP
heterostructures122,123 and nanocomposites.124,125 PET imaging
has a very high sensitivity, while the image has poor resolution
and provides no anatomical information. Combined with MRI,
Choi et al. reported a PET/MRI dual-modality MNP system by

4. Achieving biological functionality

The primary goal of MNPs-based MRI contrast agents is to
improve the detectability of medical imaging. This goal can be
achieved by adding target-specificity and/or multimodality
features of MNPs. In addition to detectability improvement,
multifunctional MNPs can further expand their applications on
other areas, such as therapeutics. Along with those goals, safety
is the baseline of MNPs biomedical applications, and toxicity
and biodistribution must be studied to assure their safety
prospects.
The detectability of MRI can be significantly improved by the
preferential accumulation of MNP contrast agents in the
diseased tissue. This is known as active or specific targeting,
achieved by immobilized molecules that have high affinity
toward unique signatures of malignant cells. Those molecules are
called targeting ligands, including small molecules, peptides,
proteins, antibodies and aptamers.14 Those targeting ligands can
be immobilized on the outer surface of MNPs via various
This journal is The Royal Society of Chemistry 2009

Fig. 3 (af) PET/MR images of SLNs in a rat at 1 h post injection of 124ISA-MnMEIO into the right forepaw (I nanoprobe injection site).
Coronal (a) MR and (b) PET images in which a brachial LN (white circle)
is detected. (c) The position of the brachial LN is well matched in a PET/
MR fusion image. Four small pipette tips containing Na124I solution are
used as a fiducial marker (white arrowheads) for the concordant alignment in PET/MR images. In the transverse images, axillary (red circle)
and brachial LNs (white circle) are detected in the (d) MR and (e) PET
images, and images of each node are nicely overlapped in the corresponding PET/MR fusion image (f). (g) The explanted brachial LN also
shows consistent results with in vivo images by PET and MR. Only the
LN from the right-hand side of the rat containing 124I-SA-MnMEIO
shows strong PET and dark MR images. The schematics of the rat in the
(h) coronal and (i) transverse directions show the locations of the LNs.
Reproduced with permission from John Wiley & Sons Ltd.126

J. Mater. Chem., 2009, 19, 62586266 | 6263

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

View Online

attaching 124I, a radionuclide, to the coatings of MnFe2O4based MNPs.126 Colocalized PET/MRI fusion images can be
generated as a result of the highly complementary nature of
those two modalities (Fig. 3). Other examples of dual-modality
MNP systems include optical reflection/MRI104 and X-ray/
MRI.127
The application of MNP systems can be further expanded
beyond medical imaging by incorporating multifunctionality. By
exploiting the large surface-to-volume ratio of MNP, a large
quantity of functional molecules can be immobilized into or
around the coatings of MNPs. A common example is that MNPs
can serve as vehicles for delivering therapeutic payloads, such as
conventional chemotherapeutic drugs, therapeutic peptides,
proteins and genes.10,13,15,96 For example, by conjugating chlorotoxin (CTX), a peptide that binds specifically to brain cancer
cells, and methotrexate (MTX), a chemotherapeutic drug to
PEG-coated SPIONs, Sun et al. developed an imaging/drug
delivery multifunctional system that demonstrated promising
results in vivo (Fig. 4).10 Engineering considerations of such
MNP-based nanocarriers include: adequate protection of therapeutic payloads during circulation, target-specific biodistribution, sufficient cellular internalization, controlled
payload-releasing profile, and organelle-specific delivery.128
Successful MNP-based nanocarriers can provide imaging tools
for real-time monitoring of the delivery of the therapeutic
payload.
Finally, MNP systems must minimize toxicity to assure that
they do not harm prospective patients. Attention should be
paid on the toxicity of each individual components and MNPs
as a whole system, as well as the toxicity of the byproducts
during the degradation process.129,130 The biodistribution of
MNPs is another critical aspect on the safety of MNPs applications since unfavorable biodistribution may lead to strong
side effects.130 Although there is no universal set of criteria,
standardizing preclinical characterization of nanoparticles can
help better elucidate their structureactivity relationships
(SARs).131,132

5. Summary and outlook

During the past decade, the breakthrough of nanotechnology,
molecular biology and novel therapeutics greatly accelerated the
development of MNP systems. Numerous milestones have been
achieved during the progress of MNP development. Aiming at
the solutions to future diagnostics and therapeutics, the development goal of MNP systems is to achieve higher imaging
contrast, better stability and superior biocompatibility. With
better understanding of chemistry and physics, a diverse variety
of nanoparticles, such as metal oxide/metal/alloy nanocrystals,
heterostructures and noncrystalline nanoparticles have been
developed. Improvements on the magnetic properties of MNPs
increase the ability of contrast enhancement, resulting in higher
sensitivity and less dosage for potential applications. Numerous
biocompatible coating materials have been developed. The
implementation of PEG and other non-fouling polymers as
surface coatings of MNPs has dramatically increased the blood
circulation time, offering more opportunities for MNPs to reach
their destination. Different coating strategies, such as endgrafting and surface encapsulation, have been applied along with
in situ and post-synthetic coating techniques, to maximize the
stability of MNP systems and simplify the overall procedure.
Target-specific, multimodality MNPs have helped medical
imaging to be more sensitive and accurate. Multifunctional MNP
systems can deliver therapeutics with minimized side effects,
while allowing noninvasive monitoring of therapeutic outcome.
Although much progress has been made on the fabrication of
MNPs with delicate structure and fascinating properties, it has
been difficult to precisely probe the in vivo behavior of those
MNPs, such as accumulation, degradation and clearance. Novel
characterization tools need to be developed in order to trace
MNPs inside living objects. Quantitative testing protocols are
required to reveal the correlation between the basic physicochemical properties of MNPs and their in vivo behavior. Some
fundamental issues, such as long-term toxicity, targeting efficiency, have to be addressed before the clinical entry of MNPs.
Once those problems are solved, MNPs will finally prevail,
bringing unprecedented solutions to the diagnosis, treatment and
prevention of most devastating diseases, such as cancer, cardiovascular diseases and neurological diseases.

Acknowledgements
The work was supported in part by grants (R01CA119408,
R01EB006043, and R01CA134213) from the U.S. National
Institute of Health.

References
Fig. 4 Axial cross sections displaying 9L tumors of mice before injection
of nanoparticle conjugates and 1 and 3 days post-injection. T2 map
overlays of the tumor region show decreased T2 for both NP-MTX and
NP-MTX-CTX nanoprobe conjugates 1 day after administration.
However, the reduction is more significant and uniform in tumor of
mouse receiving NP-MTX-CTX. A total of 3 days post-injection,
the tumor T2 values of the mouse receiving NP-MTX-CTX remained
at the decreased level, while those of mouse receiving NP-MTX returned
to the post-injection level suggesting clearance of NP-MTX from tumor
tissue. Reproduced with permission from Future Medicine Ltd.10

6264 | J. Mater. Chem., 2009, 19, 62586266

1 S. M. Nie, Y. Xing, G. J. Kim and J. W. Simons, Annu. Rev. Biomed.

Eng., 2007, 9, 257288.
2 Q. A. Pankhurst, J. Connolly, S. K. Jones and J. Dobson, J. Phys. D:
Appl. Phys., 2003, 36, R167R181.
3 S. Mornet, S. Vasseur, F. Grasset and E. Duguet, J. Mater. Chem.,
2004, 14, 21612175.
4 C. Sun, J. S. H. Lee and M. Q. Zhang, Adv. Drug Delivery Rev., 2008,
60, 12521265.
5 M. A. Brown and R. C. Semelka, MRI: Basic Principles and
Applications, Wiley-Liss, New York, 2003.
6 J. K. Willmann, N. van Bruggen, L. M. Dinkelborg and
S. S. Gambhir, Nat. Rev. Drug. Discovery, 2008, 7, 591607.

This journal is The Royal Society of Chemistry 2009

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

View Online
7 T. F. Massoud and S. S. Gambhir, Genes Dev., 2003, 17, 545580.
8 S. M. Moghimi, A. C. Hunter and J. C. Murray, FASEB J., 2005, 19,
311330.
9 C. Sun, O. Veiseh, J. Gunn, C. Fang, S. Hansen, D. Lee, R. Sze,
R. G. Ellenbogen, J. Olson and M. Zhang, Small, 2008, 4, 372379.
10 C. Sun, C. Fang, Z. Stephen, O. Veiseh, S. Hansen, D. Lee,
R. G. Ellenbogen, J. Olson and M. Q. Zhang, Nanomedicine, 2008,
3, 495505.
11 H. B. Na, J. Lee, K. An, Y. I. Park, M. Park, I. S. Lee, D. Nam,
S. T. Kim, S. Kim, S. Kim, K. Lim, K. Kim, S. Kim and
T. Hyeon, Angew. Chem. Int. Ed., 2007, 46, 53975401.
12 O. Veiseh, C. Sun, J. Gunn, N. Kohler, P. Gabikian, D. Lee,
N. Bhattarai, R. Ellenbogen, R. Sze, A. Hallahan, J. Olson and
M. Q. Zhang, Nano Lett., 2005, 5, 10031008.
13 D. Pan, S. D. Caruthers, G. Hu, A. Senpan, M. J. Scott,
P. J. Gaffney, S. Wickline and G. M. Lanza, J. Am. Chem. Soc.,
2008, 130, 91869187.
14 O. Veiseh, J. Gunn and M. Zhang, Adv. Drug Delivery Rev., in press.
15 F. Scherer, M. Anton, U. Schillinger, J. Henkel, C. Bergemann,
A. Kruger, B. Gansbacher and C. Plank, Gene Ther., 2002, 9, 102109.
16 M. Rudin and R. Weissleder, Nat. Rev. Drug. Discov., 2003, 2, 123
131.
17 D. M. McDonald and P. L. Choyke, Nat. Med., 2003, 9, 713725.
18 R. Weissleder and M. J. Pittet, Nature, 2008, 452, 580589.
19 P. Caravan, J. J. Ellison, T. J. McMurry and R. B. Lauffer, Chem.
Rev., 1999, 99, 22932352.
20 M. H. M. Dias and P. C. Lauterbur, Magn. Reson. Med., 1986, 3,
328330.
21 B. Bonnemain, J. Drug. Targeting, 1998, 6, 167174.
22 S. Laurent, D. Forge, M. Port, A. Roch, C. Robic, L. V. Elst and
R. N. Muller, Chem. Rev., 2008, 108, 20642110.
23 Y. X. J. Wang, S. M. Hussain and G. P. Krestin, Eur. Radiol., 2001,
11, 23192331.
24 M. G. Harisinghani, J. Barentsz, P. F. Hahn, W. M. Deserno,
S. Tabatabaei, C. H. van de Kaa, J. de la Rosette and
R. Weissleder, N. Engl. J. Med., 2003, 348, 2491U2495.
25 S. H. Koenig and K. E. Kellar, Magn. Reson. Med., 1995, 34, 227
233.
26 Y. w. Jun, Y. M. Huh, J. s. Choi, J. H. Lee, H. T. Song, S. j. Kim,
S. Yoon, K. S. Kim, J. S. Shin, J. S. Suh and J. Cheon, J. Am.
Chem. Soc., 2005, 127, 57325733.
27 H. W. Duan, M. Kuang, X. X. Wang, Y. A. Wang, H. Mao and
S. M. Nie, J. Phys. Chem. C, 2008, 112, 81278131.
28 U. I. Tromsdorf, N. C. Bigall, M. G. Kaul, O. T. Bruns,
M. S. Nikolic, B. Mollwitz, R. A. Sperling, R. Reimer,
H. Hohenberg, W. J. Parak, S. Forster, U. Beisiegel, G. Adam and
H. Weller, Nano Lett., 2007, 7, 24222427.
29 H. B. Na, J. Lee, K. An, Y. I. Park, M. Park, I. S. Lee, D. Nam,
S. T. Kim, S. Kim, S. Kim, K. Lim, K. Kim, S. Kim and
T. Hyeon, Angew. Chem. Int. Ed., 2007, 46, 53975401.
30 J. W. M. Bulte and D. L. Kraitchman, NMR Biomed., 2004, 17, 484
499.
31 S. V. Mahajan and J. H. Dickerson, Nanotechnology, 2007, 18,
325605.
32 W. Seo, J. Lee, X. Sun, Y. Suzuki, D. Mann, Z. Liu, M. Terashima,
P. Yang, M. Mcconnell, D. Nishimura and H. Dai, Nat. Mater.,
2006, 5, 971976.
33 F. Evanics, P. R. Diamente, F. C. J. M. van Veggel, G. J. Stanisz and
R. S. Prosser, Chem. Mater., 2006, 18, 24992505.
34 K. An, S. G. Kwon, M. Park, H. B. Na, S. I. Baik, J. H. Yu, D. Kim,
J. S. Son, Y. W. Kim, I. C. Song, W. K. Moon, H. M. Park and
T. Hyeon, Nano Lett., 2008.
35 J. L. Bridot, A. C. Faure, S. Laurent, C. Riviere, C. Billotey, B. Hiba,
M. Janier, V. Josserand, J. L. Coll, L. V. Elst, R. Muller, S. Roux,
P. Perriat and O. Tillement, J. Am. Chem. Soc., 2007, 129, 5076
5084.
36 H. Hifumi, S. Yamaoka, A. Tanimoto, D. Citterio and K. Suzuki,
J. Am. Chem. Soc., 2006, 128, 1509015091.
37 K. M. Taylor, W. J. Rieter and W. Lin, J. Am. Chem. Soc., 2008, 130,
1435814359.
38 K. M. L. Taylor, A. Jin and W. B. Lin, Angew. Chem. Int. Ed., 2008,
47, 77227725.
39 R. Weissleder, D. D. Stark, B. L. Engelstad, B. R. Bacon,
C. C. Compton, D. L. White, P. Jacobs and J. Lewis, Am.
J. Roentgenol., 1989, 152, 167173.

This journal is The Royal Society of Chemistry 2009

40 U. Schwertmann and R. M. Cornell, The Iron Oxides: Structure,

Properties, Reactions, Occurrences and Uses, Wiley-VCH,
Weinheim, 2003.
41 S. Mornet, S. Vasseur, F. Grasset and E. Duguet, J. Mater. Chem.,
2004, 14, 21612175.
42 S. Laurent, D. Forge, M. Port, A. Roch, C. Robic, L. V. Elst and
R. N. Muller, Chem. Rev., 2008, 108, 20642110.
43 J. Park, K. An, Y. Hwang, J. Park, H. Noh, J. Kim, J. Park,
N. Hwang and T. Hyeon, Nat. Mater., 2004, 3, 891895.
44 S. Sun, H. Zeng, D. B. Robinson, S. Raoux, P. M. Rice, S. X. Wang
and G. Li, J. Am. Chem. Soc., 2004, 126, 273279.
45 C. Barcena, A. Sra, G. Chaubey, C. Khemtong, J. Liu and J. Gao,
Chem. Commun., 2008, 2224.
46 S. Heer, K. Kompe, H. U. Gudel and M. Haase, Adv. Mater., 2004,
16, 2102.
47 Y. C. Cao, J. Am. Chem. Soc., 2004, 126, 74567457.
48 R. Si, Y. Zhang, L. You and C. Yan, Angew. Chem. Int. Ed., 2005,
44, 32563260.
49 R. Si, Y. Zhang, H. Zhou, L. Sun and C. Yan, Chem. Mater., 2007,
1827.
50 F. Evanics, P. R. Diamente, F. C. J. M. van Veggel, G. J. Stanisz and
R. S. Prosser, Chem. Mater., 2006, 24992505.
51 A. Gilad, P. Walczak, M. Mcmahon, H. B. Na, J. Lee, K. An,
T. Hyeon, P. Van Zijl and J. Bulte, Magn. Reson. Med., 2008, 60,
17.
52 A. H. Lu, E. L. Salabas and F. Schuth, Angew. Chem. Int. Ed., 2007,
46, 12221244.
53 J. I. Park and J. Cheon, J. Am. Chem. Soc., 2001, 123, 57435746.
54 S. Peng, C. Wang, J. Xie and S. Sun, J. Am. Chem. Soc., 2006, 128,
1067610677.
55 S. H. Sun, Adv. Mater., 2006, 18, 393403.
56 R. Hong, N. O. Fischer, T. Emrick and V. M. Rotello, Chem.
Mater., 2005, 17, 46174621.
57 J. Gao, G. Liang, J. S. Cheung, Y. Pan, Y. Kuang, F. Zhao,
B. Zhang, X. Zhang, E. X. Wu and B. Xu, J. Am. Chem. Soc.,
2008, 130, 1182811833.
58 A. Figuerola, A. Fiore, R. Di Corato, A. Falqui, C. Giannini,
E. Micotti, A. Lascialfari, M. Corti, R. Cingolani, T. Pellegrino,
P. D. Cozzoli and L. Manna, J. Am. Chem. Soc., 2008, 130, 14771487.
59 J. Choi, Y. Jun, S. I. Yeon, H. C. Kim, J. S. Shin and J. Cheon,
J. Am. Chem. Soc., 2006, 128, 1598215983.
60 S. H. Choi, H. B. Na, Y. I. Park, K. An, S. G. Kwon, Y. Jang,
M. H. Park, J. Moon, J. S. Son, I. C. Song, W. K. Moon and
T. Hyeon, J. Am. Chem. Soc., 2008, 130, 1557315580.
61 H. Zeng and S. H. Sun, Adv. Funct. Mater., 2008, 18, 391400.
62 C. Xu, J. Xie, D. Ho, C. Wang, N. Kohler, E. G. Walsh,
J. R. Morgan, Y. E. Chin and S. Sun, Angew. Chem. Int. Ed.,
2008, 47, 173176.
63 J. Gao, B. Zhang, Y. Gao, Y. Pan, X. Zhang and B. Xu, J. Am.
Chem. Soc., 2007, 129, 1192811935.
64 J. S. Shin, R. Anisur, M. Ko, G. Im, L. Lee and D. Lee, Angew.
Chem. Int. Ed., 2009, 48, 321324.
65 Y. Zhang, C. Sun, N. Kohler and M. Q. Zhang, Biomed.
Microdevices, 2004, 6, 3340.
66 J. Park, J. Joo, S. G. Kwon, Y. Jang and T. Hyeon, Angew. Chem.
Int. Ed., 2007, 46, 46304660.
67 L. Josephson, C. H. Tung, A. Moore and R. Weissleder,
Bioconjugate Chem., 1999, 10, 186191.
68 T. Shen, R. Weissleder, M. Papisov, A. Bogdanov and T. J. Brady,
Magn. Reson. Med., 1993, 29, 599604.
69 J. F. Lutz, S. Stiller, A. Hoth, L. Kaufner, U. Pison and R. Cartier,
Biomacromolecules, 2006, 7, 31323138.
70 H. S. Lee, E. H. Kim, H. P. Shao and B. K. Kwak, J. Mag. Magn.
Mater., 2005, 293, 102105.
71 M. P. Pileni, Nat. Mater., 2003, 2, 145150.
72 D. Ingert and M. P. Pileni, Adv. Funct. Mater., 2001, 11, 136139.
73 J. Park, E. Lee, N. M. Hwang, M. Kang, S. C. Kim, Y. Hwang,
J. G. Park, H. J. Noh, J. Kim, J. H. Park and T. Hyeon, Angew.
Chem. Int. Ed., 2005, 44, 28722877.
74 A. M. Smith and S. Nie, Angew. Chem. Int. Ed., 2008, 47, 99169921.
75 S. Sun and H. Zeng, J. Am. Chem. Soc., 2002, 124, 82048205.
76 N. R. Jana, Y. F. Chen and X. G. Peng, Chem. Mater., 2004, 3931
3935.
77 Z. Li, L. Wei, M. Y. Gao and H. Lei, Adv. Mater., 2005, 17,
1001, +.

J. Mater. Chem., 2009, 19, 62586266 | 6265

Downloaded by Pennsylvania State University on 24 May 2012

Published on 01 June 2009 on http://pubs.rsc.org | doi:10.1039/B902182E

View Online
78 A. H. Latham and M. E. Williams, Acc. Chem. Res., 2008, 41, 411
420.
79 P. Caravan, J. J. Ellison, T. J. McMurry and R. B. Lauffer, Chem.
Rev., 1999, 99, 22932352.
80 K. M. L. Taylor, A. Jin and W. B. Lin, Angew. Chem. Int. Ed., 2008,
47, 77227725.
81 S. Aime, M. Botta, M. Fasano and E. Terreno, Chem. Soc. Rev.,
1998, 27, 1929.
82 L. E. W. LaConte, N. Nitin, O. Zurkiya, D. Caruntu,
C. J. OConnor, X. P. Hu and G. Bao, J. Magn. Reson. Imaging,
2007, 26, 16341641.
83 H. W. Duan, M. Kuang, X. X. Wang, Y. A. Wang, H. Mao and
S. M. Nie, J. Phys. Chem. C, 2008, 112, 81278131.
84 U. I. Tromsdorf, N. C. Bigall, M. G. Kaul, O. T. Bruns,
M. S. Nikolic, B. Mollwitz, R. A. Sperling, R. Reimer,
H. Hohenberg, W. J. Parak, S. Forster, U. Beisiegel, G. Adam and
H. Weller, Nano Lett., 2007, 7, 24222427.
85 B. Bonnemain, J. Drug Targeting, 1998, 6, 167174.
86 Y. X. J. Wang, S. M. Hussain and G. P. Krestin, Eur. Radiol., 2001,
11, 23192331.
87 M. G. Harisinghani, J. Barentsz, P. F. Hahn, W. M. Deserno,
S. Tabatabaei, C. H. van de Kaa, J. de la Rosette and
R. Weissleder, New Engl. J. Med., 2003, 348, 2491U2495.
88 N. Kohler, C. Sun, A. Fichtenholtz, J. Gunn, C. Fang and
M. Q. Zhang, Small, 2006, 2, 785792.
89 Y. Zhang, N. Kohler and M. Q. Zhang, Biomaterials, 2002, 23,
15531561.
90 Y. Zhang, C. Sun, N. Kohler and M. Q. Zhang, Biomed.
Microdevices, 2004, 6, 3340.
91 N. Kohler, G. E. Fryxell and M. Q. Zhang, J. Am. Chem. Soc., 2004,
126, 72067211.
92 C. Fang, N. Bhattarai, C. Sun and M. Zhang, Small, 2009, DOI:
10.1002/smll.200801647.
93 M. Kumar, R. A. A. Muzzarelli, C. Muzzarelli, H. Sashiwa and
A. J. Domb, Chem. Rev., 2004, 104, 60176084.
94 R. Kircheis, L. Wightman and E. Wagner, Adv. Drug Delivery Rev.,
2001, 53, 341358.
95 N. Bhattarai, F. A. Matsen and M. Zhang, Macromol. Biosci., 2005,
5, 107111.
96 O. Veiseh, F. M. Kievit, J. W. Gunn, B. D. Ratner and M. Q. Zhang,
Biomaterials, 2009, 30, 649657.
97 Z. Li, L. Wei, M. Y. Gao and H. Lei, Adv. Mater., 2005, 17, 1001
1005.
98 T. Shen, R. Weissleder, M. Papisov, A. Bogdanov and T. J. Brady,
Magn. Reson. Med., 1993, 29, 599604.
99 A. M. Smith and S. Nie, Angew. Chem. Int. Ed., 2008, 47, 99169921.
100 F. Q. Hu, L. Wei, Z. Zhou, Y. L. Ran, Z. Li and M. Y. Gao, Adv.
Mater., 2006, 18, 2553.
101 R. Hong, N. O. Fischer, T. Emrick and V. M. Rotello, Chem.
Mater., 2005, 17, 46174621.
102 K. J. Landmark, S. DiMaggio, J. Ward, C. Kelly, S. Vogt, S. Hong,
A. Kotlyar, A. Myc, T. P. Thomas, J. E. Penner-Hahn, J. R. Baker,
M. M. B. Holl and B. G. Orr, ACS Nano, 2008, 773783.
103 J. Xie, C. Xu, N. Kohler, Y. Hou and S. Sun, Adv. Mater., 2007, 19,
31633166.
104 C. Xu, J. Xie, D. Ho, C. Wang, N. Kohler, E. G. Walsh,
J. R. Morgan, Y. E. Chin and S. Sun, Angew. Chem. Int. Ed.,
2008, 47, 173176.
105 C. B
arcena, A. Sra, G. Chaubey, C. Khemtong, J. Liu and J. Gao,
Chem. Commun., 2008, 2224.

6266 | J. Mater. Chem., 2009, 19, 62586266

106 N. H. Na, I. S. Lee, H. Seo, Y. Il Park, J. H. Lee, S. W. Kim and

T. Hyeon, Chem. Commun., 2007, 51675169.
107 J. S. Shin, R. Anisur, M. Ko, G. Im, L. Lee and D. Lee, Angew.
Chem. Int. Ed., 2009, 48, 321324.
108 W. W. Yu, E. Chang, J. C. Falkner, J. Y. Zhang, A. M. Al-Somali,
C. M. Sayes, J. Johns, R. Drezek and V. L. Colvin, J. Am. Chem.
Soc., 2007, 129, 28712879.
109 M. Kim, Y. F. Chen, Y. C. Liu and X. G. Peng, Adv. Mater., 2005,
17, 1429.
110 N. R. Jana, C. Earhart and J. Y. Ying, Chem. Mater., 2007, 19,
50745082.
111 R. De Palma, S. Peeters, M. J. Van Bael, H. Van den Rul,
K. Bonroy, W. Laureyn, J. Mullens, G. Borghs and G. Maes,
Chem. Mater., 2007, 19, 18211831.
112 T. R. Zhang, J. P. Ge, Y. P. Hu and Y. D. Yin, Nano Lett., 2007, 7,
32033207.
113 Y. H. Lee, H. Lee, Y. B. Kim, J. Y. Kim, T. Hyeon, H. Park,
P. B. Messersmith and T. G. Park, Adv. Mater., 2008, 20, 4154.
114 A. P. Goodwin, S. M. Tabakman, K. Welsher, S. P. Sherlock,
G. Prencipe and H. Dai, J. Am. Chem. Soc., 2009, 131, 289296.
115 C. A. J. Lin, R. A. Sperling, J. K. Li, T. Y. Yang, P. Y. Li,
M. Zanella, W. H. Chang and W. G. J. Parak, Small, 2008, 4,
334341.
116 D. P. Cormode, T. Skajaa, M. M. van Schooneveld, R. Koole,
P. Jarzyna, M. E. Lobatto, C. Calcagno, A. Barazza,
R. E. Gordon, P. Zanzonico, E. A. Fisher, Z. A. Fayad and
W. J. Mulder, Nano Lett., 2008, 8, 37153723.
117 H. Wu, H. Zhu, J. Zhuang, S. Yang, C. Liu and Y. C. Cao, Angew.
Chem. Int. Ed., 2008, 47, 37303734.
118 G. T. Hermanson, Bioconjugate Techiques, Academic Press,
Amsterdam, The Netherlands, 2008.
119 R. Weissleder, K. Kelly, E. Y. Sun, T. Shtatland and L. Josephson,
Nat. Biotechnol., 2005, 23, 14181423.
120 X. Montet, M. Funovics, K. Montet-Abou, R. Weissleder and
L. Josephson, J. Med. Chem., 2006, 49, 60876093.
121 W. B. Cai and X. Y. Chen, Small, 2007, 3, 18401854.
122 J. Gao, G. Liang, J. S. Cheung, Y. Pan, Y. Kuang, F. Zhao,
B. Zhang, X. Zhang, E. X. Wu and B. Xu, J. Am. Chem. Soc.,
2008, 130, 1182811833.
123 J. Gao, B. Zhang, Y. Gao, Y. Pan, X. Zhang and B. Xu, J. Am.
Chem. Soc., 2007, 129, 1192811935.
124 S. A. Corr, Y. P. Rakovich and Y. K. Gunko, Nanoscale Res. Lett.,
2008, 3, 87104.
125 A. Quarta, R. Di Corato, L. Manna, A. Ragusa and T. Pellegrino,
IEEE Trans. Nanobiosci., 2007, 6, 298308.
126 J. S. Choi, J. C. Park, H. Nah, S. Woo, J. Oh, K. M. Kim,
G. J. Cheon, Y. Chang, J. Yoo and J. Cheon, Angew. Chem. Int.
Ed., 2008, 47, 62596262.
127 A. Galperin and S. Margel, J. Biomed. Mater. Res. Part B, 2007,
83B, 490498.
128 D. Peer, J. M. Karp, S. Hong, O. C. FaroKhzad, R. Margalit and
R. Langer, Nat. Nanotechnol., 2007, 2, 751760.
129 N. Lewinski, V. Colvin and R. Drezek, Small, 2008, 4, 2649.
130 K. R. Vega-Villa, J. K. Takemoto, J. A. Yanez, C. M. Remsberg,
M. L. Forrest and N. M. Davies, Adv. Drug Delivery Rev., 2008,
60, 929938.
131 A. K. Patri, M. A. Dobrovolskaia, S. T. Stern and S. E. McNeil, in
Nanotechnology for Cancer Therapy, ed. M. M. Amiji, CRC Press,
Boca Raton, FL, 2007.
132 M. C. Garnett and P. Kallinteri, Occup. Med., 2006, 56, 307311.

This journal is The Royal Society of Chemistry 2009