Advanced Drug Delivery Reviews 65 (2013) 732743

Contents lists available at SciVerse ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

New forms of superparamagnetic nanoparticles for

biomedical applications
Chenjie Xu a, b,, Shouheng Sun a,
a
b

Department of Chemistry, Brown University, Providence, RI 02912, USA

Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637457, Singapore

a r t i c l e

i n f o

Article history:
Accepted 3 October 2012
Available online 2 November 2012
Keywords:
Magnetic nanoparticles
Synthesis
Modication
Biomedical application
Drug delivery
Molecular imaging

a b s t r a c t
Magnetic nanoparticles (MNPs) based on iron oxide, especially magnetite (Fe3O4), have been explored as sensitive probes for magnetic resonance imaging and therapeutic applications. Such application potentials plus the
need to achieve high efciency and sensitivity have motivated the search for new forms of superparamagnetic
NPs with additional chemical and physical functionalities. This review summarizes the latest development of
high moment MNPs, multifunctional MNPs, and porous hollow MNPs for biosensing, molecular imaging, and
drug delivery applications.
2012 Elsevier B.V. All rights reserved.

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . .
Synthesis of MNPs . . . . . . . . . . . . . . . . .
2.1.
MNPs with high magnetic moment . . . . . .
2.1.1.
Structure controlled ferrite MNPs . .
2.1.2.
Metallic MNPs . . . . . . . . . . .
2.2.
Multifunctional MNPs . . . . . . . . . . . .
2.2.1.
Molecular functionalization of MNPs .
2.2.2.
Heterogeneous MNPs . . . . . . . .
2.2.3.
Core/shell MNPs . . . . . . . . . .
2.3.
Hollow MNPs . . . . . . . . . . . . . . . .
3.
Modication and functionalization of MNPs . . . . .
4.
Biomedical applications . . . . . . . . . . . . . .
4.1.
High magnetic moment MNPs for biosensing .
4.2.
Molecular imaging with multifunctional MNPs
4.2.1.
Tumor imaging . . . . . . . . . . .
4.2.2.
Cell tracking . . . . . . . . . . . .
4.3.
Drug delivery with hollow MNPs . . . . . . .
5.
Conclusion . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . .

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732
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741

1. Introduction

This review is part of the Advanced Drug Delivery Reviews theme issue on Inorganic
nanoparticle platforms.
Corresponding authors at: Department of Chemistry, Brown University, Providence, RI 02912, USA.
E-mail addresses: cjxu@ntu.edu.sg (C. Xu), ssun@brown.edu (S. Sun).
0169-409X/$ see front matter 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.addr.2012.10.008

Nanomedicine is an emerging eld that provides novel approaches

to address the ever-increasing challenges in conventional medicine [1].
Magnetic nanoparticles (MNPs), due to their comparable sizes to biological molecules and their unique physical properties, have been explored
extensively for medical applications. Among various functional MNPs

C. Xu, S. Sun / Advanced Drug Delivery Reviews 65 (2013) 732743

studied, superparamagnetic nanoparticles (NPs) are especially promising

as contrast enhancement agents for magnetic resonance imaging (MRI)
and also as a platform for drug delivery. These MNPs, represented by
magnetite (Fe3O4) NPs, are often made in sizes smaller than 20 nm in diameter and their magnetization directions are subject to thermal uctuation at room or biological temperatures. Therefore, without an external
magnetic eld, their overall magnetization value is randomized to zero.
Such uctuation in magnetization direction minimizes the magnetic interactions between any two NP in the dispersion, making the dispersion
stable in physiological solutions and facilitating NP coupling with biological agents. Once exposed to an external magnetic eld, these MNPs can
align along the eld direction, achieving magnetic saturation at a magnitude that far exceeds that from any of the known biological entities. This
unique property of MNPs allows not only the detection of the MNPcontaining biological samples, but also the manipulation of these biological samples with an external magnetic eld [2,3].
Conventional MNPs like iron oxide NPs have been demonstrated
successfully in biomedical applications both in vitro (magnetic separation, magnetic sensing/detection, and magnetic transfection) and in
vivo (MRI, targeted drug delivery, and tissue engineering). However,
limitations exist including low magnetic moment [4], low sensitivity
in MRI diagnosis [5], and low cargo capacity [6]. For example, one of
the commercial iron oxide NP products, Feridex IV, has r2 relaxivity of
98.3 mM1S 1 under normal MRI conditions, which requires ~35 mg
iron for imaging liver of an adult with 60 kg of body weight [7]. Furthermore, due to the wide distribution of both size and magnetic moment,
traditional MNPs tend to generate large magnetic eld gradients that
cause dephasing and signal loss in and around the MNP-concentrated
regions. This makes it difcult to distinguish MNP-targeted area from
other eld perturbers such as air bubbles and blood clots [8]. When
acting as drug carriers, traditional MNPs offer only one chemical surface
for drug loading and targeting-molecular conjugation, lowering the capacity of either targeting agent or drug molecular (usually less than 10%
by weight) as well as the targeting and therapeutic efciency [911]. To
overcome the limitations of mono-functional traditional MNPs, new
forms of MNPs with high magnetic moment, multifunctionality, and
high drug loading have been actively pursued [4,1215]. Here, we summarize the recent developments in the synthesis of new MNPs for sensitive biomedical applications, including spinel structured ferrite NPs
and metallic NPs with high magnetic moments, multifunctional MNPs
for controlled coupling of different biological agents, and porous hollow
MNPs with increased capacity for drug loading.
2. Synthesis of MNPs
Traditional iron oxide based MNPs are synthesized by coprecipitation of ferrous and ferric ions in alkaline media in the presence of surfactants (e.g. Dextran). In the synthesis, other metal salts
can be added to form ferrite MFe2O4. Despite the versatility of the
synthesis, iron oxide NPs made from this method do not have the
desired control on the morphology and magnetic moment. Monodisperse iron oxide NPs are now often produced by high-temperature reductive decomposition of metal salt or organometallic precursors in
organic solutions [16,17]. In this method, a burst nucleation event rst
occurs when the concentration of metal precursors quickly increases
to the critical saturation point without further formation of nuclei afterwards [18]. The remaining precursors deposit on the pre-formed nuclei,
forming NPs with narrow size distribution. The method produces not
only monodisperse ferrite NPs with high magnetic moment, but also a
series of new MNPs with multifuctionalities.
2.1. MNPs with high magnetic moment
2.1.1. Structure controlled ferrite MNPs
Ferrite MFe2O4 or MOFe2O3, with M being the common divalent
transition metal cations (Mg 2+, Fe 2+, Co 2+, Ni 2+, Cu 2+, Zn 2+) is

733

a class of materials that has spinel structure with oxygen forming

cubic close packing and Fe3+ and M2+ occupying the octahedral and
tetrahedral interstitial sites. When Fe3+ takes octahedral sites and
M2+ in tetrahedral sites, the structure is said to have a normal spinel
structure. The MFe2O4 can also adopt an inverse spinel structure in
which half of Fe3+ exchange sites with M 2+. In this inverse spinel structure, the spins in two Fe3+ located in tetrahedral and octahedral sites
are anti-ferromagnetically coupled and cancel each other. Therefore,
magnetic moments of the inverse spinel structured MFe2O4 are dependent on the un-paired d-electrons from M2+ and their overall values are
reduced by anti-ferromagnetic coupling between Fe 3+. When M is
Fe 2+, Co2+, or Ni2+, MFe2O4 NPs have an inverse spinel structure [19].
As Fe2+ has larger magnetic moment (4 B) than Co2+ (3 B) and Ni2+
(2 B), the mass magnetization of Fe3O4 (101 emu/g) is larger than that
of CoFe2O4 (99 emu/g) and NiFe2O4 (85 emu/g) [20]. When M is Mn2+,
however, nanostructured MnFe2O4 can adopt a normal spinel structure
in which Fe3+ take octahedral sites and there has no anti-ferromagnetic
coupling between Fe 3 +. The structure provides a higher mass magnetization than the inverse spinel structured MFe2O4 [20]. Furthermore, ZnFe2O4 NPs show a ferromagnetically mixed spinel state
(Zn1 xFexO4)A[Fe2 xZnO4]B [21]. Addition of ZnFe2O4 into an inverse spinel structure (e.g. Fe3O4) can signicantly increase the net magnetic moment [22]. This was demonstrated in the non-stoichiometric
ZnxFe1xOFe2O3 NPs (x= 0.14, 0.26, 0.34 and 0.76) that were synthesized by thermal decomposition of diethyl zinc and iron acetylacetonate
(Fe(acac)3) [23]. When x was controlled from 0 to 0.34, r2 values increased systematically, achieving near 3 fold enhancement from 9.5 to
34.7 mM1 s1 (measured in a 0.55 T eld). Recently the synthesis
was further improved by replacing the unstable and pyrophoric diethyl
zinc with zinc chloride, ZnCl2 and reacting ZnCl2 with Fe(acac)3 in
the presence of oleic acid, oleylamine, and octyl ether to produce
ZnxFe1 xOFe2O3 [24]. When x in ZnxFe1 xOFe2O3 NPs was from
0 to 0.1, 0.2, 0.3, and 0.4, r2 values reached from 276 to 397, 466,
568, and 687 mM 1 s 1 (measured in a 4.5 T eld) respectively.
The effect of Zn 2 + doping into MnFe2O4 NPs was also studied [24].
This led to the formation of Zn0.4Mn0.6Fe2O4 NPs with their relaxivity
reaching 860 mM 1 s 1, the highest value ever reported. Table 1
summarizes some ferrite MNPs produced recently and their magnetic data for bio-imaging applications.
2.1.2. Metallic MNPs
MNPs based on transition metals of Fe, Co and Ni have much high
magnetic moments than their oxide counterparts [25]. They are normally
prepared by thermal decomposition or reduction of organometallic precursors. For example, Fe NPs were synthesized by thermal decomposition
of Fe(CO)5 at 180 C in the presence of oleylamine in octadecene [26], or
in the presence of oleylamine and hexadecylammonium chloride in
octadecene [27], or at 170 C in the presence of polyisobutene in decalin
under N2 [28]. Similarly, Co NPs were prepared by thermal decomposition of Co2(CO)8 [2932]. Reduction of Fe[N(SiMe3)2]2 with H2 in the
presence of surfactants under 150 C led to high moment Fe nanocubes
[33]. Similarly, high-temperature reduction of [Co(3-C8H13)(4-C8H12)]
and Ni(cycloocta-1,5-diene)2 gave Co and Ni nanorods respectively
[34,35].
Magnetic alloy NPs can be produced by the combination of thermal
decomposition and reduction of metal precursors. The key to the successful synthesis is to control the reaction condition so that two different
metals can nucleate and grow into an alloy structure [3638]. For example, FeCo NPs were synthesized by reduction of Fe(acac)3 and Co(acac)2
in the presence of oleic acid, oleylamine and 1,2-hexadecanediol under a
gas mixture of 93% Ar+7% H2 at 300 C or were made by sodium borohydride reduction of ferrous and cobalt salts [39,40]. FePt (or FeAu) NPs
were synthesized by the thermal decomposition of Fe(CO)5 and the reduction of Pt(acac)2 (or AuAc3) by 1,2-hexadecanediol in the presence
of oleic acid and oleylamine [41,42]. To stabilize high moment metallic
NPs for biological applications, some robust coating strategies have

734

C. Xu, S. Sun / Advanced Drug Delivery Reviews 65 (2013) 732743

Table 1
Survey of MNPs, their surface coating, magnetic moments and their relaxivities for MRI under a permanent magnetic eld B0.
MNPs

Core material

Core diameter (nm)

Surface coating

Feridex
Resovist
Combidex
Iron oxide

Fe3O4, -Fe2O3
Fe3O4
Fe3O4
Fe3O4

Dextran
Carboxy-dextran
Dextran
DMSA

Mnferrite

MnFe2O4

Coferrite
Niferrite
Zniron oxide

CoFe2O4
NiFe2O4
Zn0Fe1OFe2O3
Zn0.14Fe0.86OFe2O3
Zn0.26Fe0.74OFe2O3
Zn0.34Fe0.66OFe2O3
Zn0.76Fe0.24OFe2O3
Zn0Fe1Fe2O4
Zn0.1Fe0.9Fe2O4
Zn0.2Fe0.8Fe2O4
Zn0.3Fe0.7Fe2O4
Zn0.4Fe0.6Fe2O4
Zn0.8Fe0.2Fe2O4
Zn0Mn1Fe2O4
Zn0.1Mn0.9Fe2O4
Zn0.2Mn0.8Fe2O4
Zn0.3Fe0.7Fe2O4
Zn0.4Fe0.6Fe2O4
Zn0.8Fe0.2Fe2O4
Fe12Co88
Fe40Co60
-Fe
Amorphous Fe
-Fe

4.96
4
5.85
4
6
9
12
6
9
12
12
12
4.6
4.5
4.5
4.9
4.5
15
15
15
15
15
15
15
15
15
15
15
15
4
7
10
15
15

(ZnxFe1x)Fe2O4

(ZnxMn1x)Fe2O4

FeCo/C
Fe
Fe
Fe

DMSA

DMSA
DMSA
DSPE-PEG

DMSA

DMSA

Phospholipid-PEG
PEG
OAm-PEG
OAm-PEG

Magnetic moment (emu/g)

45
61
25
43
80
101
68
98
110
99
85
19.8
26.8
43.1
54.1
30.0
114
126
140
152
161
115
125
140
154
166
175
137
162
215
70
90.6
164

B0 (T)

Relaxivity r2 (mM1 s1)

Reference

1.5
1.5
1.5
1.5

120
186
65
78
106
130
218
208
265
358
172
152
9.5
14.5
22.4
34.7
7.4
276
397
466
568
687
307
422
516
637
754
860
388
185
644
129
67
220

[44]
[45]
[45]
[20]

1.5

1.5
1.5
0.55

4.5

4.5

1.5
1.5
3
3

[23]

[24]

[43]
[46]
[27]

Notes: DSPE-PEG: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] (DSPE-PEG, PEG MW = 5 kD); DMSA: 2,3-dimercaptosuccinic acid;
OAm-PEG: oleylamine-,-bis(2-carboxyethyl)poly(ethylene glycol).

been applied. For example, a layer of graphitic shell was coated onto FeCo
NPs to protect their high magnetic moment from fast decay [36,43]. Crystalline Fe3O4 shell was also used to protect metallic Fe NPs as demonstrated in the Fe/Fe3O4 NPs through the controlled oxidation of the
as-synthesized Fe NPs with (CH3)3NO [26]. Metallic NPs that have been
studied as contrast agents for MRI are listed in Table 1.
2.2. Multifunctional MNPs
Iron oxide MNPs are already multifunctional. Due to their response
to external magnetic eld, they have been studied as contrast agent
for MRI and as magnetic heating element for magnetic uid hyperthermia. However, such MNPs only have one kind of chemical surface. To
couple these NPs with different biological agents and drug molecules,
MNPs with different chemical surfaces are preferred [47]. This can be
achieved through molecular functionalization of existing MNPs, design
of multi-component MNPs (heterogeneous MNPs), or co-encapsulation
of MNPs with other functional components in a matrix (core/shell
MNPs).
2.2.1. Molecular functionalization of MNPs
Conjugation of other functional molecules onto the surface of
MNPs is an easy approach to achieve multifunctionality. This strategy is cost-effective, time-efcient, and easy to adapt for other circumstances. The conjugation can be realized by conventional coupling
chemistry, click chemistry, and chelating coordination [48].
Conventional coupling chemistry uses the well-known reaction
among \NH2, \SH, and \COOH to functionalize MNPs. For example, NH2-coated MNPs can be coupled with functional molecule
containing \COOH via an amide bond formed through common

EDC/NHS or sulfo-NHS coupling chemistry. Molecule bearing \SH can

be grafted onto the NH2-coated MNPs via a heterobifunctional linker
such as succinimidyl iodoacetate, N-succinimidyl-3-(2-pyridyldithio)
propionate, or succinimidyl-4-(N-meleiminomethyl)cyclohexane-1carboxylate.
Click chemistry is a copper-catalyzed cyclo-addition of azide-alkyne
and offers an alternative strategy for quick and robust coupling of NPs
with other functional molecules [49]. The reaction can be performed in
relatively mild conditions and is highly specic. A representative example
is the functionalization of cross-linked iron oxide MNPs (CLIO) with 18F,
in which CLIO functionalized with azide moiety were reacted with
3-(2-(2-(2-[ 18F]-Fluoroethoxy)ethoxy)ethoxy)prop-1-yne ( 18F-PEG3),
producing 18F-CLIO with a decay-corrected yield of 58% [50].
Chelating coordination is often used to conjugate metal ions to MNPs.
For example, 1,4,7,10-tetraazacyclododecane-N,N,N,N-tetraacetic acid
(DOPA) pre-conjugated on Fe3O4 NPs through amide bond could
bind 64Cu for additional positron emission tomography (PET) imaging capability [51]. Dithiocarbamate-bisphosphonate, (dtbp)2, was
also studied as both surfactant for CLIO and chelating group for 64Cu
[52]. Through chelating bond formation between \COO and Pt, cisplatin could be conjugated onto the surface of AuFe3O4 dumbbell
MNPs for controlled platin delivery and release [53].
2.2.2. Heterogeneous MNPs
Heterogeneous MNPs refer to those containing two or more different
functional units within one nanostructure, such as AuFe3O4, FePtCdS,
and Fe2O3carbon nanotube MNPs. In such a heterogeneous NP structure, each NP unit exhibits its unique magnetic, optical, or electronic
properties and provides its distinct surface for selective chemical modication [5456].

C. Xu, S. Sun / Advanced Drug Delivery Reviews 65 (2013) 732743

AuFe3O4 dumbbell-like MNPs were prepared through seedmediated growth in which Au NPs were used as seeds and Fe3O4 MNPs
were grown on Au by decomposition of Fe(CO)5 followed by oxidation
of Fe [53,57]. These dumbbell-like MNPs preserve the optical property
of Au NPs (plasmonic absorption at ~530 nm) and magnetic property
of Fe3O4 MNPs (saturation magnetic moment at 80 emu/g). The synthesis has been extended to prepare noble metalmetal oxide dumbbell
MNPs with Fe3O4 MNPs grown over the noble metal (Au, Ag, Pt, or
AuAg) NPs (Fig. 1A) [58]. In these dumbbell MNPs, the size of noble
metal NPs was controlled in pre-synthesis and the size of Fe3O4 MNPs
was tuned through the concentration of Fe(CO)5 during the reaction.
Alternatively, noble metal could be grown on the pre-synthesized
MNPs [5961]. For example, AgFe3O4 MNPs or Ag-hollow Fe3O4
MNPs were made by controlled nucleation of Ag on the pre-formed
Fe3O4 MNPs or hollow Fe3O4 MNPs [59,62]. In the synthesis, the
as-prepared MNPs dispersed in organic solution and AgNO3 dissolved
in water were mixed and agitated by ultrasonication. The sonication
provided the energy required for the formation of a micro emulsion
with Fe3O4 MNPs assembling at the liquid/liquid interface (Fig. 1B).
Fe(II) ions on MNPs acted as a catalytic center for the reduction of
Ag + and nucleation/growth of Ag NPs. The partial exposure of MNPs
to the aqueous phase caused the formation of AgFe3O4 MNPs, which
showed the typical plasmonic absorption of Ag NPs and magnetic behavior of Fe3O4 MNPs. Slightly different from this two-phase reaction,
hollow Fe3O4Ag MNPs were prepared (Fig. 1C) [60]. The synthesis
started from Fe MNPs coated with amorphous iron oxide, followed by
the reduction of Ag on the shell by oleylamine. As iron oxide shell was
amorphous, the mechanical stress caused by the lattice mismatch between iron oxide and Ag was minimized, which led to a low interfacial
energy between iron oxide and Ag. Following the Ag deposition, Fe
MNPs were oxidized to the hollow Fe3O4 MNPs through the Kirkendall
effect [63].
In addition to the noble metalmetal oxide heterogeneous MNPs,
semiconductormetal alloy, semiconductormetal oxide MNPs, and carbon nanotubemetal oxide complex have also been reported [47,64,65].

735

For example, FePtCdS and FePtCdSe MNPs were fabricated through

two-stage reaction (Fig. 1D) [66,67]. First, an amorphous CdS or CdSe
layer was grown on the surface of FePt at a low reaction temperature to
achieve a core/shell structure. Subsequently, the temperature was raised
to crystallize the CdS/CdSe phase. Because of the difference in phase transition temperatures between FePt and CdS/CdSe, the CdS/CdSe components melt and induced their dewetting from FePt cores, resulting in
the heterodimeric MNPs. In the case of carbon nanotubeiron oxide
(CNTIO), the CNT nucleated from CO catalytically on iron clusters [68].
The resulted CNTFe was oxidized in air to CNTIO.
We should note that the presence of heterojunction between different
components modies the material properties at both sides. This is caused
by many factors including surface reconstruction around the junction, lattice mismatch-induced crystal strain, and electron interaction/transfer
across the interface, which are still under intensive investigation. In
some cases, the original properties are affected negatively. For example,
the quantum yield of Fe3O4CdSe MNPs was only 38% compared with
their single-core counterparts (CdSe) [69]. In AuFe3O4 MNPs, along the
increase of Au core's size (0 to 3 to 8 nm), the r2 relaxivity of the Fe3O4
core deteriorates (121 to 114 to 105 s1 mM1) [70]. In another hand,
the original properties could be enhanced. For example, the incorporation
of Ag core (13.5 nm) onto Fe3O4 MNPs (710 nm) increased the coercivity of the MNPs from 300 Oe (Fe3O4) to 500 Oe (AgFe3O4), and also
changed their magnetic properties from superparamagnetic (Fe3O4) to
ferromagnetic (AgFe3O4) at room temperature [71]. In AgCoFe2O4
MNPs, their magneto-optical Faraday rotation was enhanced by nearly
an order of magnitude at 633 nm compared to the monomer (CoFe2O4
MNPs) [61]. Table 2 lists some common heterogeneous MNPs studied
for biomedical applications.
2.2.3. Core/shell MNPs
Multifunctional MNPs can be further prepared by encapsulating
MNPs into a robust matrix to form a core/shell structure. There have
been a number of examples reporting on the synthesis of core/shell
MNPs using gold, silica, zinc oxide [75], polymer [76], or liposomes

Fig. 1. A) Schematic illustration of the growth of metal-oxides dumbbell MNPs on pre-made noble metal NPs and high-resolution transmission electron microscope (HRTEM) images of a) AuFe3O4, b) AgFe3O4, and c) AuAgFe3O4 MNPs. Reproduced with permission from reference [58]. B) Schematic illustration of the growth of Ag-hollow Fe3O4 dumbbell
MNPs in aqueous phase. Reproduced with permission from reference [62]. C) Schematic illustration of the growth of Ag-hollow Fe3O4 dumbbell MNPs in organic phase. Reproduced
with permission from reference [60]. D) Schematic illustration of the growth of FePtCdS dumbbell MNPs. Reproduced with permission from reference [66].

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C. Xu, S. Sun / Advanced Drug Delivery Reviews 65 (2013) 732743

[77] as the matrix. The robust shell not only protects the magnetic
cores, but also prevents the direct contact of magnetic core with
other sensitive biological agents. Here, we focus on the gold and silica
encapsulation.
Gold (Au) encapsulation is advantageous in term of their stability, biocompatibility, and convenience for further functionalization
[78]. The Au shell could be deposited on Fe3O4 MNPs through gradually reducing HAuCl4 on Fe3O4 MNPs by oleylamine [79]. After initial coating, the surface of MNPs was treated with sodium citrate
and cetyltrimethylammonium bromide (CTAB) for the dispersion in
aqueous solution. Such aqueous-soluble MNPs then served as seeds
to grow multiple layers of Au or Ag on the surface. The change of
shell thickness allowed the tuning of plasmonic properties of the
core/shell MNPs to be either red-shifted (to 560 nm with more Au
coating) or blue-shifted (to 501 nm with more Ag coating). Au
shell could also be formed over MNPs by simultaneously activating
MNPs and Au NPs in a hot solution [80]. Specically, Au NPs (2 nm)
coated with alkanethiolate were mixed with MNPs protected with
oleylamine/oleate. At an elevated temperature (149 C), alkanethiolate
bonding to Au was weakened and small Au attached to MNPs, forming a
core/shell structure with thiolate re-capturing the enlarged Au surface.
Compared with the direct deposition of Au shell on MNPs, this
thermally-driven procedure is time-efcient, cost-effective, and
easy to apply to control the shell thickness. More recently, Au shell
was grown on poly-L-histidine coated iron oxide NPs in an aqueous
phase [81]. The core/shell structure showed both strong absorption
in near infra-red spectrum and sensitive MRI response, allowing for
multimodality imaging.
Silica coating is another popular choice to make MNPs stable
and multifunctional. By simply hydrolyzing silica precursors
(e.g. tetraethylorthosilicate (TEOS)) under the basic solution, a uniform
and thickness-controllable silica shell can be obtained. Silica formed
through this approach (Solgel approach) is usually amorphous and
has strong afnity to MNPs [8284]. For example, quantum dots (QDs)
and iron oxide NPs had been co-encapsulated inside the silica NPs to preserve magnetic property of iron oxide NPs and optical property of QDs
[85], enabling the magnetic manipulation with real-time uorescence
microscope imaging [86]. This silica shell can also act as a carrier for

anticancer drugs (e.g. paclitaxel) and uorescent molecules (e.g. uorescein isothiocyanate (FITC)) [87]. By simply mixing FITC modied
aminopropyltriethyoxysilane with silica precursor (TEOS) during the encapsulation step, FITC was incorporated onto the surface of MNPs. The
anticancer drugs were inserted into the porous silica matrix through
soaking MNPs in a concentrated drug solution in dimethylsulfoxide
(DMSO).
These modications as discussed above can allow MNPs to have exotic properties such as plasmonic resonance and enhanced chemostability.
However, it should be noted that these are achieved at the price of increased distance between the superparamagnetic core and biological environment (water molecules mostly), which might subsequently result
in reduced sensitivity in MRI. The issues have been discussed more thoroughly in a recent review by Hyeon et al. [88].
2.3. Hollow MNPs
As a potential drug-delivery tool, MNPs offer the possibility of
being directed toward a specic target and eventually remaining localized by means of an applied magnetic eld. Research on the synthesis and modication of MNPs has enabled the further studies on
MNP biocompatibility, chemical stability, uniformity, and controllable
circulation in vivo. And emerging reports also provide solid evidence
for the effectiveness of the MNP-based delivery system. However,
limited by the high density of the inorganic core and the necessary
coating for MNP stabilization, a drug in the conjugates can only occupy a very small mass percentage [6]. One solution is to use hollow
MNPs that have a magnetic shell and void core. In this case, drugs
can be loaded both outside and inside of the MNPs. Considering the
biocompatibility requirements, the ideal candidates are Fe3O4 hollow
MNPs (HMNPs) [63,89], Fe hollow nanoframe [90], MnxFe3 xO4 hollow nanotube [91], Fe3O4/ZnS HMNPs [92], and porous Fe3O4 or
Fe3O4SiO2 double layer hollow nanorods [93,94].
Fe3O4 HMNPs were synthesized through controlled oxidation of
core/shell structured Fe/Fe3O4 MNPs by an oxygen transfer agent
(CH3)3NO (Fig. 2A) [63]. Core/shell Fe/Fe3O4 MNPs were obtained
by high-temperature solution-phase decomposition of Fe(CO)5 and
air oxidation of the amorphous Fe MNPs at room temperature [26].

Table 2
Heterogeneous MNPs studied for potential biomedical applications.
Name

Functional components

Size of components (nm)

Biomedical applications

Reference

AuFe3O4

Au
Fe3O4
Ag
Fe3O4
AuAg
Fe3O4
Ag
CoFe2O4
Ag
Hollow Fe3O4
Cu
Hollow Fe3O4
TiO2

3, 5, 6, 8
12, 18, 20, 25
215, 13.5
9, 12, 13
6
10
6
14
48, 4
510, 12
17
17
Length: 5070; 18
Thickness: 56
5.6, 11.38.1
24
4
4.6
8
Diameter: 1
25
10
6
3
5
3
68

Optical imaging, MRI, magnetic manipulation, and platin delivery

[53,58,70]

Two photon uorescence imaging, and magnetic manipulation

[58,71,72]

AgFe3O4
AuAgFe3O4
AgCoFe2O4
Ag-hollow Fe3O4
Cu-hollow Fe3O4
TiO2-Fe2O3

CdSeFe3O4
XS (X=Zn, Cd, Hg)-Fe2O3
Carbon nanotubeFe2O3
FePtAu
FePtCdS
FePtCdSe

-Fe2O3
CdSe
Fe3O4
XS (X = Zn, Cd, Hg)
-Fe2O3
Carbon nanotube
Fe2O3
Au
FePt
FePt
CdS
FePt
CdSe

[58]
[61]
[60,62]
[60]
Magnetically induced hyperthermia; magnetic induced targeting;
and photodynamic therapy

[64,73]

Fluorescent imaging and magnetic manipulation

[69]
[65]

MRI and near infra-red mapping

[68]

Biological detection, MRI, and optical signal enhancing

[74]
[67]

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During the controlled oxidation process, Fe diffuses outward at a

faster rate than oxygen from (CH3)3NO does inward, which produces the Fe3O4 at the metaloxide interface rather than the interior of the core (Kirkendall effect). With different mechanism (acid
etching vs. Kirkendall effect), Fe3O4 NPs can evolve from solid
MNPs to uniform HMNPs under the continuous heating in the presence of trioctylphosphine oxide (TOPO) and alkylphosphonic acid
(Fig. 2B) [89]. In the heating process, alkylphosphonic acid coordinated to the metal cations on the surface of MNPs and formed
ironphosphonate complexes. The Fe hollow nanoframes were produced from the thermal decomposition of Fe(II)stearate complex
in the presence of sodium oleate and oleic acid (Fig. 2C) [90]. Recently, corrosion-aided Ostwald Ripening was used to prepare
two-component HMNPs, Fe3O4/ZnS HMNPs (Fig. 2D) [92]. In this
synthesis, FeS NPs were prepared rst and then dispersed in the
aqueous mixture containing Zn(acac)2, poly(vinylpyrrolidone), ammonium nitrate, and glycol. After reacting at 150 C for 10 h, the
superparamagnetic uorescent Fe3O4/ZnS HMNPs were obtained. Porous Fe3O4 hollow nanorods were prepared a wrapbakepeel process
from akagenite (beta-FeOOH) nanorods (Fig. 2E) [93]. In this synthesis,
-FeOOH nanorods were prepared as a template to deposit a layer of silica precursor, followed by calcinations in air and reduction under the
hydrogen/argon ow to transform the inner iron oxide to Fe3O4. The silica removal provided porous hollow Fe3O4 nanorods [93]. Without silica
removal, it became Fe3O4SiO2 double layer hollow nanorods [94].

737

3. Modication and functionalization of MNPs

For MNPs, the main forces affecting their stability in solution are
attractive van der Waals forces, repulsive double layer, and steric
interactions [95]. Such forces have been extensively discussed in
the literature [96,97] and are out of scope of this review. There are
various kinds of materials that can act as dispersants for MNPs.
The commonly chosen ones include 2,3-dimercaptosuccinic acids,
catechol derivatives, dendrimers, polysaccharides, cellulose, chitosan, PEG, and PVP (more details could be found in a recent review
by Reimhult et al. [98]). They can be grafted onto the surface of
MNPs through either ligand addition or ligand exchange [2]. Ligand
addition does not need to remove the original protecting ligands
and usually generates core/shell or layer-by-layer structure [99].
MNPs modied in this strategy usually have better dispersibility
and chemical stability, as demonstrated in FePt NP stabilization
and dispersion by using surfactant addition with DSPE-PEG as dispersants [100]. The second method, surfactant exchange replaces
the original surfactants with the dispersants (e.g. catechol derivatives [101]) that have stronger afnity to the surface of iron oxide
MNPs. This has been shown in the functionalization of Fe MNPs
[26], Fe3O4 HMNPs [13], and AuFe3O4 MNPs [70] with a catechol
derivative, dopamine. The strong coordination bond between Fe
and catechol enables the replacement of the original surfactants,
producing stable MNP dispersions in water.

Fig. 2. Transmission electron microscope (TEM) image of A) 13 nm Fe3O4 HMNPs. Reproduced with permission from reference [63]. B) 21 nm sized Fe nanoframe. Reproduced with
permission from reference [90]. C) Cubic -Fe2O3. Reproduced with permission from reference [89]. D) Fe3O4/ZnS HMNPs. Reproduced with permission from reference [92].
E) Wrapbakepeel process to obtain nanocapsules from akagenite. Reproduced with permission from reference [93].

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C. Xu, S. Sun / Advanced Drug Delivery Reviews 65 (2013) 732743

After modication, hydrodynamic diameter and surface charge

(zeta potential) of the MNPs need to be characterized because the
size and charge of MNPs can impact their uptake by cells and their
distribution in organs [102,103]. Previous studies have indicated
that when MNPs with a hydrodynamic diameter larger than 200 nm
are delivered into the circulation through systematic administration,
they are easily sequestered by the reticuloendothelial system (RES)
of the spleen and liver. But if the size is less than 10 nm, they are subject to rapid renal clearance [104]. Therefore, to ensure maximal NP
circulation, the optimum hydrodynamic diameter is believed to be
between 10 and 200 nm. Villanueva et al. showed that the charge
and nature of surface functionalizing molecules on MNPs affected
their response to cancer cells [105]. In four different charged carbohydrates including dextran (neutral), aminodextran (positive), heparin
(negative), and dimercaptosuccinic acid or DMSA (negative), cells had
effective uptake of aminodextran-MNPs, minimal uptake of neutralcharged dextran coated MNPs, low uptake of DMSA-coated MNPs, and
concentration dependent uptake of heparin coated MNPs. In addition,
the surface charge also inuenced the location of MNPs after cellular internalization. Schweiger et al. found that negatively charged MNPs were
rstly in endosomes and lately in lysosomes whereas positively charged
MNPs were exclusively inside lysosomes [106]. As early as 1996, Chouly
et al. have demonstrated that surface charge inuenced the capacity of
MNPs to be opsonized right after injection and so changed their phagocytosis. They found that the negatively charged MNPs enhanced liver
uptake greater than neutral MNPs [107].
4. Biomedical applications
4.1. High magnetic moment MNPs for biosensing
Rapid and sensitive measurement of clinically relevant biomarkers,
pathogens, and cells in biological samples (e.g. blood or urine) is priceless
for early detection/screening of disease like cancer, and for real-time
monitoring of personal responses to treatments [108]. Diagnostic magnetic resonance (DMR) based on MNPs has recently received considerable attention because of its low magnetic background from biological
samples, which enables the sensitive identication of small percentage
of biomarkers from the ocean of background entities [109]. One important parameter in these assays is signal-to-noise ratio or sensitivity,
which relates directly to magnetic properties of MNPs. MNPs with high
magnetic moment are ideal candidates to meet this need.
DMR measures the transverse relaxation rate (R2) of water molecules
in biological samples in which target molecules or cells of interest are labeled with MNPs [110]. There are two forms of DMR assays depending on
the size of the targets [108]. For molecule targets smaller than that of
MNPs, molecular targets are used as cross-linking agents to assemble
MNPs into clusters, thus effecting a corresponding decrease in T2. Alternatively, enzymatic cleavage or competitive binding of molecular targets
disassembles pre-formed clusters to cause an increase in T2, which is
called reverse switching. For large biological structures like cancer cells
or bacteria, targeted MNPs tag the surface markers to impact their magnetic moment. The change of 1/T2 is proportional to the number of
cells/bacteria MNPs bind, and also indicative of the abundance of relevant
surface biomarkers. Lee and Weissleder et al. utilized MnFe2O4 MNPs to
label cancer cells from ne-needle-aspirates (FNA) to allow the quantication and proling of cancer cells with DMR-2 system developed in their
group [111]. Thanks for the high magnetic moment of MnFe2O4 MNPs,
they could detect as less as 2 HER2/neu positive cancer cells with only
1 L sample and 15 min frames (Fig. 3A and B). While with traditional
iron oxide MNPs, the sensitivity is 1000 cells with the requirement of
10 L sample. With the same DMR device, the same group demonstrated
that another type of MNPs with high magnetic moment, Fe MNPs could
be conjugated with antibodies for tuberculosis detection [112]. In the
assay, the biological samples were incubated with Fe MNPs and then separated from the unbound Fe MNPs before DMR diagnosis. With these

high magnetic moment MNPs, as few as 20 CFUs (colony-forming

units) could be detected in 1 mL of sputum sample in less than 30 min
(Fig. 3C and D).
4.2. Molecular imaging with multifunctional MNPs
Molecular imaging is a biomedical research discipline dealing with
visualization, characterization, and quantication of biological processes at the cellular and sub-cellular levels. The images produced
through molecular imaging (usually non-invasive) would help reect
cellular and molecular pathways and mechanism of disease in the
subjects. Existing imaging techniques include MRI, PET/SPECT, optical
imaging (uorescence, bioluminescence, and optical coherence), CT,
ultrasound etc., and each of them has their own advantages and disadvantages. For example, MNP based MRI is advantageous for the
higher spatial resolution (10100 m), but suffers from the lower
sensitivity, the high background coming from eld disturber, and
long acquisition time/high cost [113,114]. On the other side, PET are
super sensitive (10 1110 12 M) with low background, and optical
imaging is time/cost efcient which facilitates rapid testing of biologic hypotheses and proofs-of-principle in living experimental models.
Therefore, using multifunctional MNPs that combine the advantages
of two or more imaging modalities is becoming an attractive strategy
in molecular imaging. Here we will describe some representative examples in tumor imaging and cell tracking.
4.2.1. Tumor imaging
To diagnose tumor malignancy early and accurately in clinics, it is
necessary to apply two or more imaging modalities [115]. The emergence of multifunctional MNPs fullls this need and would minimize
the cost in clinical practices.
AuFe3O4 dumbbell MNPs (Fig. 4A) have been studied for both MRI
and optical imaging of EGFR-positive breast cancer cells (Fig. 4B and C).
Au NPs are optically active and have been used in a variety of optical imaging based on light-scattering, two-photo luminescence and surfaceenhanced Raman scattering [116]. Au NPs also present enhanced light
reection between 500 nm and 800 nm [70]. The combination of Au
and Fe3O4 in the dumbbell MNPs allows the integration of reection imaging and MRI, which could potentially be used as dual contrast agents
for MRI diagnosis before surgery and metastasis mapping during surgery. Recently, Chen et al. reported a triple functional imaging probe
for PET/NIFR/MRI [117]. They modied Fe3O4 MNPs with human serum
albumin (HSA) and functionalized HASFe3O4-NPs with 64Cu-DOTA and
Cy5.5 (Fig. 4D). In this case, they obtained a novel reporter that had a
high spatial resolution (MRI), good signal-to-noise ratio (PET), and convenience for both in vivo and ex vivo analysis (near infrared uorescence
(NIRF)). In a subcutaneous U87MG xenograft mouse model, Chen demonstrated the triple-imaging-capabilities of this contrast agent through
examining the preferred accumulation in tumor after 18 h circulation
time (Fig. 4EG).
4.2.2. Cell tracking
Another exciting application of multifunctional MNPs is to qualitatively and quantitatively monitor transplanted cells in the exogenous
cell therapy, which utilizes transplanted cells, in particular stem and
progenitor cells, to replace or regenerate damaged or diseased tissue
[118]. The understanding of cell distribution and engraftment tracking in cell therapy will facilitate prediction of treatment efcacy, reveal optimal transplantation conditions including cell dose, delivery
route, and timing of injections, and ultimately improve patient treatment [119,120].
Stelter et al. showed that an aminosilane coated MNPs could be functionalized with the uorescent dye (uorescein) and the positronemitting radioisotope (gallium-68) [121]. Hepatogenic HuH7 cells labeled with these MNPs were intravenously administered and could be
followed through the sensitive -ray measurements. Their results

C. Xu, S. Sun / Advanced Drug Delivery Reviews 65 (2013) 732743

739

Fig. 3. A) TEM and HRTEM (insert) images of 16 nm MnFe2O4 MNPs. B) Human breast cancer cells (BT474) were labeled with anti-Her2 CLIO and MnFe2O4 MNPs. The change in R2
(R2 = 1/T2) varied linearly with cell counts, and the detection sensitivity was 10 better using the more magnetic MnFe2O4 MNPs. Reproduced with permission from reference
[111]. C) Fe MNPs or Cannonballs (CBs) that have an iron core (11 nm) passivated with a thin ferrite shell (2.5 nm). D) Comparison of detection sensitivity. First, a microuidic
chip without a membrane lter was used to determine the intrinsic mass-detection limits. The bacteria were targeted either with CBBCG (MNPs conjugated with monocolonal
antibody of bacillus CalmetteGuerin, a surrogate for tuberculosis) or CLIOBCG. With CBBCG, they achieved a mass-detection limit of approximate 6 CFU (1 L detection volume),
much lower than that of approximate 100 CFU for CLIOBCG. When CBBCG-targeted samples (100 L) were ltered, the concentration limit was further reduced to approximate
60 CFU/mL. Reproduced with permission from reference [112].

revealed the predominant localization of the labeled cells in the lungs

2 h after injection and the even distribution throughout the animals'
body 48 h later. Nahrendorf et al. designed a PET-MRI-uorescence
trimodality contrast agent through chelating 64Cu onto the dextranated
and DTPA-modied magnetouorescent MNPs [122]. This platform was
used to image the macrophages and to identify the atherosclerotic lesions in an Apolipoprotein E deciency (apoE/) mouse model. The
combination of PET, MRI and uorescence combined the individual advantages of each imaging modality. After in vivo distribution of MNPs,
all imaged apoE/ mice showed a robust PET signal in the aortic root
and arch, which showed signicant differences between accumulated
dose in excised aortas and carotids in apoE/ versus wild-type mice.

4.3. Drug delivery with hollow MNPs

Targeted drug delivery is a Holy Grail in chemotherapy. In an ideal
targeted drug delivery, the drug carrier selectively delivers drug molecules to the diseased site without a concurrent increase in their intensity in healthy tissues. In the late 1970s, Widder and Senyi proposed the
idea of using MNPs to carry drugs to specic sites such as solid tumor,
where high-eld magnets were positioned [123,124]. Following their
early studies, the efcacy of this approach was demonstrated in numerous small animal studies and even resulted in a small number of clinical
trials [125]. However, despite these efforts and achievements, this technique has yet to develop into a workable clinical application. One of the
reasons is the low payload capacity of existing MNPs [6] because payload (i.e. drugs) can only be attached on the surface or embedded in
the double-layer coating around MNPs. To address this issue, one of
the solutions is to utilize hollow MNPs discussed in Section 2.3, in

which drugs could be loaded both inside their hollow core and on the
surface.
Our group investigated this hypothesis through utilizing Fe3O4
HMNPs to deliver cisplatin (one of traditional chemotherapeutics)
to HER2/neu positive cancer cells [13]. We noticed the shell of
Fe3O4 HMNPs (Figs. 2A and 5A) was polycrystalline and its crystallinity could be further improved by prolonged heating in solution
containing oleic acid. With the crystal domain growing larger in
the shell structure, the crystal boundaries in the polycrystalline
structure opened up, resulting in the porous shell with 3 nm pore
size (Fig. 5B). The open pores facilitated the diffusion of cisplatin
into the cavity of Fe3O4 HMNPs during the ligand exchange process
(Fig. 5C). More specically, we carried out the loading by mixing
oleylamine/oleate-coated Fe3O4 HMNPs with cisplatin and replacing surfactant (i.e. dopamine-PEG) in chloroform/DMF followed by
solvent evaporation to maximize cisplatin loading. Through this
method, we could improve the cisplatin percentage on the nal conjugate from 4.82% of Fe3O4 MNPs to 24.8% of Fe3O4 HMNPs.
This high payload capacity of hollow MNPs has also been conrmed by
other groups. With porous Mn3O4 HMNPs, Lee et al. improved the loading
amount of a hydrophobic anticancer agent (doxorubicin), where they
mixed the water-dispersible porous Mn3O4 HMNPs with doxorubicin in
CH3OH/CH3Cl and evaporated the organic solvent [126]. They found
that the amount of doxorubicin incorporated into the porous Mn3O4
HMNPs was 3.5 times higher than that on the solid Mn3O4 MNPs under
the same NP concentration. The nal doxorubicin percentage in Mn3O4
HMNPs was approximately 14% while that in Mn3O4 MNPs was approximately 4%. Shi et al. tested the hollow core, magnetic, and mesoporous
double-shell MNPs (Fe3O4/SiO2 in Fig. 2E) as carriers for water-insoluble
anticancer drugs (docetaxel or camptothecin) [94]. The drugs were

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C. Xu, S. Sun / Advanced Drug Delivery Reviews 65 (2013) 732743

Fig. 4. A) TEM image of 820 nm AuFe3O4 dumbbell MNPs. Scale bar is 20 nm. B) T2-weighted MRI images of i) 20-nm Fe3O4, ii) 320-nm AuFe3O4, iii) 820-nm AuFe3O4 MNPs,
and iv) A 431 cells labeled with 820-nm AuFe3O4 MNPs. Reproduced with permission from reference [70]. C) Reection images of the A431 cells labeled with 820-nm AuFe3O4
MNPs. D) Schematic illustration of the multi-functional HSAFe3O4-NPs. E) Representative in vivo NIRF images of mouse injected with HSAFe3O4-NPs. Images were acquired 1 h,
4 h and 18 h post injection. F) In vivo PET imaging results of mouse injected with HSAFe3O4-NPs. Images were acquired 1 h, 4 h and 18 h post injection. G) MRI images acquired
before and 18 h post injection. Reproduced with permission from reference [117].

loaded through soaking the MNPs in a concentrated drug/DMSO solution. After purication, the drugs represented 1514% (mass percentage)
of the nal products. In comparison, for solid silica encapsulated Fe3O4
MNPs, the drug percentage was only 13% [87].

5. Conclusion
In this paper, we have summarized recent efforts in designing new
platforms of MNPs to address the problems met in the biomedical

Fig. 5. HRTEM images of A) Fe3O4 HMNP and B) Fe3O4 porous HMNP. C) Schematic illustration of simultaneous surfactant exchange and cisplatin loading into a Fe3O4 porous HMNP
and functionalization with Herceptin.
Reproduced with permission from reference [13].

C. Xu, S. Sun / Advanced Drug Delivery Reviews 65 (2013) 732743

application of traditional MNPs. To improve the magnetic moment, other

metal ions are chosen to dope into the spinel structure of ferrite. High
magnetic moment metallic MNPs are further synthesized and stabilized.
To improve the sensitivity and accuracy of MRI, other NP components responsible for different imaging modalities are also combined into one
MNP unit. To improve therapeutic efcacy, hollow MNPs are designed
so that more drug can be loaded both inside and outside the NPs.
These multifunctional MNPs have shown great advantages over the traditional MNPs in disease diagnosis, cancer imaging, cell tracking and
drug delivery. Once their biodistribution and metabolism are better understood, these new forms of MNPs will serve as sensitive probes and
platforms for highly efcient diagnostic and therapeutic applications.
Acknowledgments
This work was supported in part by Nanyang Technological University Start-Up Grant to XCJ and Brown Imaging Fund to SS.
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