Magnetic Fe 3 O 4 @Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications

Abstract

With the development of nanotechnology, multifunctional nanoparticles have attracted great attention in the field of biomedicine in recent years. Magnetic Fe 3 O 4 @mSiO 2 composite microspheres (MMS), consist of magnetic Fe 3 O 4 cores and mesoporous silica shells, are considered as promising biomedical materials. In this review, we focused on the current advances in synthesis methods and biomedical applications of MMS. At First, we outlined different structures of MMS such as core–shell, hollow and rattle type MMS, and their structures, synthesis approaches and properties were discussed in detail. Combining with the magnetism of Fe 3 O 4 and the mesopores of mSiO 2 , MMS were wildly applied in biomedical. Then, we summarized the biomedical applications of MMS, including drug loading and release, MRI, tumour targeted therapy, hyperthermia, multimodal cancer therapies and bioseparation. At last, the great potentials of MMS as multifunctional diagnose and therapy platforms were discussed.

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Printed in the United States of America
Nanoscience and
Nanotechnology Letters
Vol. 9, 1849–1860, 2017
Magnetic Fe3O4@Mesoporous Silica Composite
Microspheres: Synthesis and Biomedical Applications
Hongcheng Yang, Pengfei Jiang, Zhu Chen, and Libo Nie∗
Hunan Key Laboratory of Biomedical Nanomaterials and Devices, Hunan University of Technology, Zhuzhou 412007, P. R. China
With the development of nanotechnology, multifunctional nanoparticles have attracted great atten-
tion in the field of biomedicine in recent years. Magnetic Fe3O4@mSiO2composite microspheres
(MMS), consist of magnetic Fe3O4cores and mesoporous silica shells, are considered as promis-
ing biomedical materials. In this review, we focused on the current advances in synthesis methods
and biomedical applications of MMS. At First, we outlined different structures of MMS such as
core–shell, hollow and rattle type MMS, and their structures, synthesis approaches and properties
were discussed in detail. Combining with the magnetism of Fe3O4and the mesopores of mSiO2,
MMS were wildly applied in biomedical. Then, we summarized the biomedical applications of MMS,
including drug loading and release, MRI, tumour targeted therapy, hyperthermia, multimodal cancer
therapies and bioseparation. At last, the great potentials of MMS as multifunctional diagnose and
therapy platforms were discussed.
Keywords: Fe3O4Nanoparticles, Mesoporous Silica, Drug Delivery System, Theranostics.
CONTENTS
1. Introduction . .......................................1849
2. MMSComposite Microspheres .........................1851
2.1. Core–ShellMMS................................1851
2.2. HollowMMS...................................1851
2.3. Rattle MMS . . . .................................1852
3. Applicationsof MMSinBiomedicalEngineering...........1853
3.1. DrugLoading andControlledRelease ................1853
3.2. TargetingDrugDeliverySystem ....................1854
3.3. MRI/ChemotherapySystem........................1855
3.4. Magnetic Hyperthermia/Chemotherapy System ......... 1855
3.5. BiosorptionandBioseparation ......................1856
4. Conclusions........................................1857
Acknowledgments ...................................1857
Referencesand Notes ................................1857
1. INTRODUCTION
As we know, Fe3O4nanoparticles with the size less
than 30 nm exhibit superparamagnetism, which is
desired in biomedical applications. Up to now, mag-
netic Fe3O4nanoparticles are widely applied in magnetic
separation, magnetic hyperthermia, magnetic resonance
imaging (MRI) and so on.1–6 Specially, drug delivery
systems (DDS) based on magnetic nanoparticles show
higher tumor accumulation efficiency with the aid of
external magnet.7Moreover, magnetic nanoparticles
can be conjugated with or encapsulated in polymers,8
noble metals,9carbon nanotubes or spheres,1011
∗Author to whom correspondence should be addressed.
quantum dots12 and mesoporous silica13 to expand their
applications.
Mesoporous silica spheres (mSiO2have the advantages
of good biocompatibility and bio-degradation, easy func-
tionalization, high specific surface area and adjustable pore
size, which are the ideal support materials for the loading
of drugs and biomolecules via the interaction of hydrogen
bond, electronic adsorption or impregnation method.14–21
Moreover, the surface of mSiO2can be easily modified
with amino,22 thiol,2324 carboxylic groups25 or chelate
ligands26 to facilitate the coupling of biomolecules or
drugs.27 The drugs loaded in mSiO2can be controlled to
release by external stimulus such as pH, lights, thermo,
redox and so on.28–31 The mesoporous structure is syn-
thesized through a sol–gel process based on the assembly
of surfactant molecules and silica precursors,32 which the
diameter of nanoparticles and the size of mesopores can
be easily controlled.
To combine the advantages of Fe3O4nanoparticles
and mSiO2, Wu and colleagues33 firstly reported mag-
netic Fe3O4/mesoporous silica composite spheres in 2004.
After that, many efforts have been devoted to fabricate
the composite spheres, including: (i) Fe3O4nanoparticles
embedded in the pore channels of mSiO2,3435 (ii) Fe3O4
nanoparticles coated on the surface of mSiO2,36 and
(iii) mSiO2coated on the surfaces of Fe3O4nanoparticles.37
Obviously, parts of the mesopores are blocked by Fe3O4
nanoparticles in the former two structures, which prevents
the loading of drugs or biomolecules. The last structure,
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Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications Yang et al.
denoted as Fe3O4@mSiO2composite spheres (MMS),
can not only prevent the degration of Fe3O4nanopar-
ticles in harsh environments in vivo, but also increase
the biocompatibility and their applications in biomedical
fields because the nanoparticles are easy to modify with
functional groups.3839 To date, researchers have explored
the possibilities of MMS as nano-carriers for biomedi-
cal purposes, including drug delivery, magnetic resonance
imaging, bioseparation, multimodal therapies system and
so on.40–43
Hongcheng Yang was born in 1991. He obtained his B.S. degree from Shaoguan University.
Currently he is studying for his M.Sc. degree in Hunan University of Technology, China.
His research focused on multifunctional drug delivery systems.
Pengfei Jiang was born in 1992. He obtained his B.S. degree from Shaoguan University.
Currently he is studying for his M.Sc. degree in Hunan University of Technology, China.
His research focused on DNA detection.
Zhu Chen was born in 1986, he obtained a Ph.D. degree in applied biological medical
engineering in 2016 from Southeast University, entered Southeast University as a postdoc-
toral researcher in 2016 and was a lecturer of Hunan University of Technology since 2016.
His research interest include biomedical electronics and medical instrument development.
He published about 15 research papers in SCI journals, EI journals and Chinese journals
and 6 granted patents.
Libo Nie was born in 1973. She obtained her master degree of applied chemistry from
Hunan University in 2001, and her Ph.D. degree of biomedical engineering from Southeast
University in 2005. She worked as a post-doctoral researcher in Sun Yat-Sen University in
2006–2008. She is a professor in school of life science and chemistry of Hunan University
of Technology since 2010. Her research interests focus on biomaterials and biosensor. She
has published more than 40 papers and 1 book.
In this review, we focused on the current advances
of MMS in their synthesis and biomedical applications.
Firstly, the different structures of MMS including core–
shell, hollow and rattle MMS as well as their proper-
ties were outlined. Next, the applications of MMS in
biomedicine were summarized, which involve of drug
loading and release, MRI, tumour targeted therapy, hyper-
thermia, multimodal cancer therapies and bioseparation.
Finally, we paid special attention to discussing the
prospects of MMS in biomedical applications.
1850 Nanosci. Nanotechnol. Lett. 9, 1849–1860,2017

Yang et al. Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications
Fig. 1. Schematic illustration of core–shell Fe3O4@nSiO2@mSiO2.
Reprinted with permission from [57], Y. Wang, et al., Langmuir 29, 1273
(2013). © 2013, American Chemical Society.
2. MMS COMPOSITE MICROSPHERES
In general, the core–shell MMS are fabricated by coating
a layer of mSiO2on the surface of Fe3O4nanoparticles via
a simple sol–gel method.44 In addition, with the help of
templates,45 the hollow or rattle MMS can be structured.46
In the course of MMS formation, quantum dots,4748 noble
metal nanomaterials49 or fluorescent dyes50 can be conju-
gated on the surface or embedded in the layer of mSiO2to
obtain multifunctional MMS,51 which are widely applied
in the field of biomedicine owing to their properties of
mutimodal therapies for cancer.
2.1. Core–Shell MMS
In common, core–shell MMS are structured with mag-
netic nanoparticle as the core and mesoporous silica as the
shell. For the synthesis of Fe3O4nanoparticles, solvother-
mal reaction52 and chemical co-precipitation53 are widely
adopted, which attribute to the time-saving and simple syn-
thesis process. The synthesis of core–shell MMS is usually
performed by the hydrolysis process of silica precursor
to coat on the surface of Fe3O4nanoparticles.5455 Liu
et al.56 coated a layer of mSiO2on the surface of Fe3O4
nanoparticles to fabricate core–shell MMS with the assist
of ultrasonic. Wang et al.57 synthesized core–shell MMS
by depositing a layer of dense silica (nSiO2on the surface
of the magnetic core at first, and then coating a layer of
mesoporous silica on the surface of dense silica (Fig. 1).
Moreover, the controllable shell thickness of mesoporous
silica can be obtained by adjusting the hydrolysis amount
of silica precursor.
For MMS, the magnetization saturation (Ms) value,
shell thickness and particle size are relative to a cer-
tain extent (Table I). Obviously, the size of MMS can
be adjusted by the diameter of Fe3O4nanoparticles, the
Tab l e I . The core diameter, saturation magnetization value, BET surface area, pore diameter, shell thickness and pore volume of core–shell MMS.
Core Middle MMS Shell thickness Ms of Ms value SBET DBJH VBJH
diameter (nm) layer diameter (nm) of mSiO2Fe3O4(emu/g) of MMS (emu/g) (cm2/g)(nm)(cm
3/g) Ref.
20 / 60 40 80.5 59.5 326 2.4 0.28 117
200 RF resin 600 180 / 34.5 623 5.0 0.91 177
200 nSiO2450 / 78.8 40.1 676 2.7 0.46 57
170 nSiO2250 40 80.4 40.4 404 2.7 0.68 97
200 nSiO2420 100 80.5 63.8 203 2.0 0.24 28
276 nSiO2548 200 64.7 15.3 577 3.5 0.24 54
thickness of the shells and the middle layers of the inor-
ganic or organic materials. The Ms value of core–shell
MMS decreases comparing to naked magnetic nanopar-
ticles due to the non-magnetism of mSiO2. Moreover,
the Ms of MMS is closely related to the intrinsic Ms
value of Fe3O4nanoparticles, the thickness of shell as
well as the ratio of magnetic and nonmagnetic mate-
rials. The mesopore size of mSiO2can be controlled
by adjusting the ratios of the surfactants and the pore
swelling agents in sol–gel process.58–60 The pore volume,
Brunauer-Emmett-Teller (BET) surface area and pore size
of MMS slightly decrease after the modification of func-
tional groups according to the reports.6162 In addition, the
pore order of mSiO2can be structured through changing
the hydrolysis condensation rates or optimizing the sol–gel
procedure.63 Therefore, MMS with different structures, Ms
value, particle sizes and mesopore sizes can be obtained
to meet the researchers’ requirements.
2.2. Hollow MMS
Hollow MMS are based on the core–shell structure, but
with a hollow magnetic core and a mesoporous silica
shell. It’s important that the hollow structure increases the
drug-loading capacity compared with the core–shell MMS.
To obtain the hollow structure of Fe3O4nanoparticles, Yang
et al.64 reported a facial method based on inverse miniemul-
sion polymerization using water droplets as a soft template.
However, this structure hasn’t suitable porous channels for
molecules to get in or out from the inner magnetic core.
To solve this problem, researchers developed reduction
and hard template methods to obtain hollow porous Fe3O4
nanoparticles. In Wu’s strategy,65 the hollow MMS were
fabricated by the reduction and in situ decomposition of
-FeOOH, resulting in a hollow magnetic core with large
pores on the surface (Fig. 2). In this structure, the drugs or
biomolecules are permitted to permeate into or leak out the
inner core through the pore channels, which increases the
loading capacity of drugs effectively.
In general, it is easy to obtain hollow structure using
organic polymer nanoparticles as the templates. Liu et al.66
assembled Fe3O4nanoparticles on the surface of PS
nanospheres via electrostatic interaction, and then hollow
MMS were obtained with the sol–gel process and the
extraction of PS templates (Fig. 3).67 Evidently, the size
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Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications Yang et al.
Fig. 2. The synthetic procedure of hollow nanorod MMS. Reprinted with permission from [65], H. Wu, et al., Adv. Funct. Mater. 21, 1850
(2011). © 2011, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Fig. 3. The synthetic procedure of hollow MMS. Reprinted with permission from [66], F. Liu, et al., Chem. Commun. 51, 2357 (2015). © 2015,
Royal Society of Chemistry.
Fig. 4. The synthetic procedure of rattle MMS with RF resin as the template. Reprinted with permission from [69], Q. Yue, et al., J. Mater. Chem . A
3, 5730 (2015). © 2015, Royal Society of Chemistry.
of the inner cavity can be easily adjusted by altering PS
nanospheres with different diameters.
2.3. Rattle MMS
Theoretically, there still exists space blocking in hol-
low MMS due to the direct contact of magnetic cores
and mSiO2shells, which prevents the molecules entering
or leaving the inner cavities freely. To overcome these
drawbacks, researchers developed a novel type of MMS,
so-called rattle MMS which were characterized by isolated
spaces between the magnetic cores and the mSiO2shells.
Due to the separation of the core and the shell, abun-
dant molecules can be loaded and released almost without
hindering.
One strategy to obtain rattle MMS is to use the organic
polymer (such as PS,68 RF resin69as the middle tem-
plate between magnetic core and mSiO2shell (Fig. 4).
With the assist of etching agent or calcination, the tem-
plate layer can be eliminated to obtain rattle MMS. Zhao
and co-workers70 reported a new route to structure rat-
tle MMS by hydrothermal treatment. In their method, the
dense silica was used as the middle template layer, which
was condensed by hydrothermal treatment at 170 C,
resulting in the formation of cavity between the core
and the shell (Fig. 5). The middle layer of dense sil-
ica can also be treated with alkaline etching solution,
obtaining dense silica layers with difference thicknesses
by adjusting the concentrations of alkaline solution or the
etching times.71 In addition, Zhu et al.72 applied nanocar-
bon spheres formed by hydrothermal treatment of glucose
to adsorb iron precursors. After coated with mesoporous
silica, the rattle MMS were obtained by reducing the
iron precursors into Fe3O4nanoparticles and eliminat-
ing the carbon spheres template by calcination (Fig. 6).73
Fig. 5. Scheme of the synthetic procedure of rattle MMS: (1) Coating
a dense silica on the hematite core; (2) formation of the silica-organic
by simultaneous sol–gel polymerization of TEOS and C18TMS; (3) gen-
eration of the cavity under hydrothermal conditions; (4) calcination to
remove the organic groups; (5) H2reduction to produce the magnetic.
Reprinted with permission from [70], W. Zhao, et al., Adv. Funct. Mater.
18, 2780 (2008). © 2008, WILEY-VCH Verlag GmbH & Co. KGaA,
Weinheim.
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Yang et al. Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications
Fig. 6. Schematic procedure of rattle MMS. Reprinted with permission from [73], Y. Zhu, et al., Chem. Mater. 21, 2547 (2009). © 2009, American
Chemical Society.
Zhou et al.74 also reported that Fe3O4nanoparticles were
embedded into the template of nano-CaCO3spheres, and
then the template was eliminated by acetic acid to obtain
rattle MMS. Therefore, sacrificial template method, etch-
ing or condensing the dense silica are the effective way
to yield the cavity structures of rattle MMS. Among these
structures, Fe3O4nanoparticles with dense silica coating
can isolate the molecules loaded in the cavity structure that
sensitive to magnetic nanoparticles.
3. APPLICATIONS OF MMS IN
BIOMEDICAL ENGINEERING
MMS are paid intensive attentions in biomedicine due to
their magnetism and mesoporous structure. The large BET
surface area and pore volume of mesoporous silica layer
provide enough space to load cargoes, and the magnetic
cores of Fe3O4nanoparticles have the advantages of mag-
netic separation, magnetic targeting, magnetic hyperther-
mia and magnetic resonance imaging.75–81 Used as drug
delivery system, the cell uptake of MMS can be enhanced
by external magnetic field treatment.82 In addition, the sur-
face of MMS can be easily modified by functional groups
or conjugated with biomolecules and nanomaterial, which
expands their applications in the field of biomedicine.83–86
MMS are of great potential as multifunctional platforms
for biomedical applications such as cancer therapy, drug
delivery, tumour targeted imaging, bioseparation, muti-
modal imaging and theranostic platform.87–96
3.1. Drug Loading and Controlled Release
Many drugs, especially the anti-cancer drugs such as dox-
orubicin (DOX), etoposide (VP16), camptothecin (CPT)
and paclitaxel, have nonnegligible toxic side effects to
normal cells.97–101 Encapsulation of drugs in MMS pro-
tects the drugs from leaking outside prior to reaching
tumour tissues, which reduces the side effect of toxic
drugs.102 The mechanism of drug-loading in MMS mainly
include electrostatic interaction or hydrogen bond, and the
drug release curves induced by external stimulus can be
described as Higuchi and other models based on Fickian
diffusion.103–106
Table II shows the drug loading capacities of various
types of MMS with similar pore volume and BET sur-
face area. Obviously, the drug-loading capacities of rattle
and hollow MMS are higher than that of core–shell MMS
due to the cavity structures of the former two. Further-
more, the loading capacity of hollow MMS is relatively
less than that of rattle MMS, which may be attributed to
that the Fe3O4nanoparticles in hollow MMS block parts
of the pore channels of mesoporous silica. In addition,
the loading capacity of MMS is related to the solubility
parameters of solvents according to the reports.107
The loaded drugs can release from MMS by outer stim-
ulus such as heat, pH, enzyme,lightsaswellasaltering
magnetic field (AMF).108–113 However, it’s possible that the
leakage of drugs occurs before the drugs are delivered to
tumour site, which is harmful to healthy cells and wastes
the expensive anti-cancer drugs. One way to avoid this sit-
uation is to conjugate nano-caps (or gatekeepers)114115 on
the surface of MMS to block the pores, which can prevent
the drugs from leaking and release drugs with the external
triggers to achieve a controllable drug release behavior.116
Using thermo-sensitive polymer as the gatekeepers, it is
easy to control the shrinkage of the polymer to release
drugs by altering its temperature with AMF treatment due
to the hyperthermia capacity of Fe3O4nanoparticles in
MMS. Guo et al.117 utilized P(EO-co-LLA) as the thermo-
sensitive gatekeepers and realized the controlled drug
release in MMS via AMF treatment (Fig. 7). At the same
time, P(EO-co-LLA) can also be used as pH-sensitive gate-
keepers to achieve controlled drug release by altering the
pH values of environments. Recently, An et al.118 devel-
oped a new strategy using diselenide linkers as the gate-
keepers, which can be broken by glutathione reductase
(GSH) to release the drugs from MMS. The results showed
that almost no drug released from MMS without the stimu-
lus of GSH, while up to 84% drugs released after the treat-
ment of 10 mM GSH. This “zero” release model of MMS
is of significant prospect in clinical application because of
the much higher concentration of GSH in cancer cells than
that in normal cells which can release drugs automatically
after the uptake of cancer cells. Therefore, MMS coated
Table II. Drug loading capacity of core–shell, hollow and rattle MMS.
Diameter SBET VBJH Loading capacity
Type (nm) (cm2/g) (cm3/g) of DOX (mg/g) Ref.
Core–shell 150 464 0.62 45 155
Hollow Spheroidicity 362 0.62 150 65
(length: 180 nm
diameter: 53 nm)
Rattle 119 494 0.53 385 68
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Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications Yang et al.
Fig. 7. Illustration of the preparation and controlled release process of core–shell MMS with gatekeepers. Reprinted with permission from [117],
W. Guo, et al., Dalton Trans. 43, 18056 (2014). © 2014, The Royal Society of Chemistry.
with gatekeepers can be developed to the ideal models for
drug controlled release in blood circulation and extracel-
lular environment, and the drugs release rapidly after the
uptake of cancer cells.119120
Considering that the gatekeepers prevent MMS from
further functionalizing, Shen et al.121 reported a new strat-
egy that Fe3O4nanoparticle embedded thermo-sensitive
polymer was structured inside the mSiO2shell (Fig. 8).
With AMF treatment, the temperature of the middle
polymer layer changed, which induced the shrinking or
swelling of thermo-sensitive polymer, resulting in the con-
trol release of drugs that encapsulated in polymer layer.
Although various controlled drug release strategies were
developed, the “zero” drug release before MMS arrive
tumour sites still remains the challenges, which is desired
to be addressed in clinical therapy application.
3.2. Targeting Drug Delivery System
Obviously, the magnetic cores in MMS present the ability
of magnetic targeting, which the drug-loaded nanoparticles
Fig. 8. Synthetic illustration of Fe3O4@PNIPAM/5-Fu@mSiO2-CHI/R6G nanocomposites. Reprinted with permission from [121], B. Shen, et al.,
ACS Appl. Mater. Interfaces 8, 24502 (2016). © 2016, American Chemical Society.
can be induced to the lesion site by the guidance of exter-
nal magnet. Chen et al.122 reported that the uptake of MMS
by cancer cells increased and a considerable amount of
MMS accumulation in tumor site in vivo with external
magnet treatment.123 Therefore, more MMS can targetedly
accumulated at tumour tissues with the guiding of mag-
netic field.
Compared with the passive enhanced permeability and
retention (EPR) effects,124 the active targeting approaches
are able to deliver drugs to and accumulate at tumor sites
more effectively. The effective way to realize targeting
drug delivery is to conjugate tumor targeting ligands on
the surfaces of MMS.125 The tumor targeting ligands are
able to identify the cancer cells from normal cells and
facilitate the cell uptake of MMS.126 Such ligands include
antibodies, peptides, aptamers and small molecules.127–135
An et al.118 conjugated folate acid (FA) on the surface of
MMS and incubated with HeLa cells, which showed that
more FA modified MMS gathered around the cancer cells
and exhibited faster uptake by HeLa cells. Chen et al.123
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Yang et al. Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications
also reported the targeting effect of Arg-Gly-Asp (RGD)
peptide modified MMS, which showed that a more con-
siderable amount of MMS accumulation in tumors than
that without targeted peptide functionalization. In general,
MMS are of great potential as the platforms for targeting
drug delivery system by modifying with specific ligands.
3.3. MRI/Chemotherapy System
Nowadays, theranostic systems integrate diagnosis
and therapy have attracted intensive attentions in
biomedicine.136–139 As a common diagnostic approach,
magnetic resonance imaging is perhaps one of the most
powerful imaging methods for its superiority in soft tis-
sue contrast that it is able to provide additional details
of tissue function, blood perfusion, structure and even
molecular information within the living bodies.140–143
Fe3O4nanoparticles cause field inhomogeneity perturb-
ing of the spin–spin relaxation of water protons, which
offers T2weighted imaging in vivo.144145 Basedonthe
T2contrast agents of Fe3O4nanoparticles and the drug
loading ability of mSiO2, MMS can be used as thera-
nostic systems combining MRI and chemotherapy. Chen
et al.123 reported the MRI signal of HeLa cancer cells was
significantly enhanced by increasing the concentration of
MMS. Furthermore, they used RGD modified MMS to
realize tumour targeted MR imaging, which remarkably
enhanced the accumulation of MMS at tumor sites. Simi-
larly, Zhang et al.146 reported that neural progenitor cells
labeled MMS targetedly accumulated at lesion site of
mice bearing middle cerebral artery occlusion (MCAO),
resulting in the decrease of MR signal in ischemic area,
especially in peri-focal zone of the lesion. Wu et al.65
investigated T2-weighted MR imaging of hollow MMS
in vivo (Fig. 9). The signal intensities of liver, kidneys,
and spleen were reduced to a minimum value 30 min
after the administration. According to the signal intensi-
ties, the nanocomposites tended to accumulate more in
Fig. 9. In vivo T2-weighted MR images of (a) liver, and (b) kidneys/spleen before and after intravenous administration of 2.5 mg Fe per kg body weight
of hollow MMS (30, 60, and 120 min posttreatment). Reprinted with permission from [65], H. Wu, et al., Adv. Funct. Mater. 21, 1850 (2011). © 2011,
WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
liver and spleen tissue than in kidneys. In addition, the
anticancer drugs (DOX or CPT) were effectively loaded
in MMS, which exhibited significantly higher cytotoxic-
ity than that of free drugs. These multifunctional MMS
showed special abilities in MRI/chemotherapy system
and increased the apoptosis of cancer cells owing to the
endocytosis.
Besides MRI and chemotherapy, other functions such as
fluorescent imaging, dark-field optical and infrared thermal
imaging can also be integrated in MMS to achieve multi-
modal imaging and therapy, which is of great potential in
clinic applications.147148
3.4. Magnetic Hyperthermia/Chemotherapy System
According to the reports, the temperature of 42–46 C
induces the apoptosis of tumour cells without side
effects.149150 The magnetic hyperthermia of Fe3O4
nanoparticles, which utilizes the heat generated from the
magnetic nanoparticles promoted by AMF treatment, may
be attributed to the Neél and Brownian relaxations, fric-
tion in viscous suspension or hysteresis loss of mag-
netic nanoparticles.151152 Now, magnetic hyperthermia is
becoming more and more clinically acceptable, which
benefits from the substantial technical improvements in
achieving selected increase of temperatures in superficial
and deep-seated poorly accessible tumors.153154 Tao a nd
co-workers155 reported that MMS with a saturation mag-
netization of 4.2 emu/g can raise the temperature up to
6.6/15.5 C with the AMF intensity of 180 Gauss and
the frequency of 238/409 kHz, respectively. Obviously, the
temperature of MMS can be controlled by the saturation
magnetization of MMS or altering the intensity and the
treatment time of AMF.156
Besides magnetic hyperthermia, MMS can simul-
taneously carry out chemotherapy because of their
drug-loading capacity, which is named multimodal
therapies.157158 This strategy of multimodal therapies is
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Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications Yang et al.
more effective than magnetic hyperthermia or chemother-
apy individually due to the synergistic effect.159 Yao
et al.160 reported that the viability of breast cancer cells
incubated with MMS was 15% treated by AMF individu-
ally, while the viability decreased to 5% when that treated
with AMF and chemotherapy simultaneously. Guo et al.117
found that DOX-loaded MMS exhibited 71.5% apopto-
sis of cancer cells, while the cell apoptosis was enhanced
to 93.7% with the addition of AMF stimuli. It is obvi-
ous that the therapy efficiency of MMS was improved
by the incorporation of chemotherapy and hyperthermia
therapy.
Furthermore, MMS display the ability to combine var-
ious therapies and imaging modes into one system such
as photothermal therapy,161 MRI-guided cancer therapy,162
photodynamics therapy (PDT)163 to achieve the excellent
effect in cancer diagnosis and therapy.
3.5. Biosorption and Bioseparation
Compared with centrifugal separation, magnetic separation
is relatively gentle and nondestructive, which is appropri-
ate for the separation and enrichment of biomolecules such
as DNA, protein, enzyme etc.164–166 Biomolecules can be
adsorbed or loaded into the pore channels of MMS by
electrostatic adsorption or covalent attachment, which is
easy to remove from the mixtures by an external magnetic
separation.167–171
For the loading of biomolecules, the negative charge
on the surface of MMS can be changed into positive
charge by connecting with functional groups,172 which
facilitates the adsorption of negative charged biomolecules
through electrostatic interaction. In addition, MMS can be
functionalized with nanoparticles or certain groups that
Fig. 10. The flow chart of the enrichment process for glycopeptides by using Fe3O4@mSiO2-IDA nanomaterials. Reprinted with permission
from [180], N. Sun, et al., Anal. Chem. 89, 1764 (2017). © 2017, American Chemical Society.
can selectively linked biomolecules via chemical bonds,
which can separate the specific biomolecules from the
mixtures.173174 Another aspect has to be considered is
the matching of the pore size of MMS and the size of
biomolecules.175 When the size of biomolecules is smaller
than the size of mesopores, the biomolecules can be loaded
in the pore channels of MMS. However, the biomolecules
with large size are excluded outside of the mesopores,
which is so-called size-exclusion effect.176 According to
Yue’s report,177 the trypsin with the molecule size of
4.0 nm was successfully immobilized in the core–shell
MMS with a 9.0 nm mesoporous size, which exhibited a
high loading capacity of 97 g/mg. Hu et al.178 reported
that the loading capacity of immunoglobulin G (IgG) in
MMS with a pore sizes of 14.4 nm reached to 51 mg/g,
while that in MMS with a pore sizes of 3.27 nm decreased
to 41 mg/g. Therefore, the biomolecules can immobilize
in pore channels and the large one can be excluded by
size-exclusion effect of MMS.
To improve the bioseparation effects of MMS,
researchers make great efforts on selective enrichment
of biomolecules.179 One effective way is to connect the
specific functional groups on the pore wall of MMS to rec-
ognize the biomolecules. Sun et al.180 selectively enriched
N-linked glycopeptides using iminodiacetic acid (IDA)
functionalized MMS, which 424 glycopeptides assigned to
140 glycoproteins were separated with only 2 L human
serum (Fig. 10). Zhao et al.181 applied MMS functionalized
with perfluoroalkyl to selectively enrich fluorous deriva-
tized N-linked glycans. Based on the size-exclusion effect
and magnetic separation, 22 N-linked glycans were suc-
cessfully separated from the chicken ovalbumin digest at a
concentration of 0.5 g/L. The results showed that MMS
1856 Nanosci. Nanotechnol. Lett. 9, 1849–1860,2017

Yang et al. Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications
were prospective as the platforms for bioseparation and
purification.182
4. CONCLUSIONS
In summary, MMS consisting of magnetic cores and
mesoporous shells are usually structured as core–shell,
hollow and rattle type. The size, pore diameter, shell thick-
ness and saturation magnetization of MMS can be con-
trolled by adjusting the preparation parameters. Because
of the magnetism of Fe3O4nanoparticles and the meso-
pores of mSiO2, MMS are wildly applied in the field of
biomedicine such as drug delivery system, theranostic sys-
tems, multimodal therapies and bioseparation.
In this review, we highlighted the research advances of
MMS in biomedical applications. As a drug delivery sys-
tem, the rattle and hollow MMS generally possess higher
loading capacities than that of core–shell MMS. With the
coating of smart gatekeepers on MMS, the drug release
can be controlled by external stimulus such as heat, pH and
magnetic field. Induced by external magnet or modified
with specific ligands, MMS can targetedly deliver drugs
to lesion sites, resulting in more effective uptake by can-
cer cells. Also, MMS combining MRI and chemotherapy
are promising as the platform of theranostics. Based on
the magnetic hyperthermal effect, MRI of Fe3O4nanopar-
ticles and multifunctional mesoporous silica, MMS can
be used to structure multimodal therapies system incor-
porating hyperthermia and chemotherapy as well as the
multimodal imaging, which exhibits more effective in can-
cer treatment owing to the synergistic effect and imaging-
guided therapies.
However, the development of MMS still remains the
challenges for the further application in biomedicine.
As an ideal drug carrier, it is crucial that the carri-
ers possess high drug-loading capacity and “zero” drug
release before reaching the lesion site, which is one of
the challenges for MMS to realize entirely control of
drug release. Accompanying with the development of drug
delivery system, multimodal therapies are promising ten-
dency in clinic application. Base on MMS, it’s prospec-
tive to develop the platforms of multimodal imaging and
therapies by incorporating with functional nanoparticles
in MMS. It’s predictable that MMS are of great poten-
tial in biomedical applications such as targeted drug deliv-
ery system, multimodal therapies and bioseparation and
purification.
Acknowledgments: Writing of this review was
supported by the National Key Technology R&D Program
(2015BAD05B02), Research and Innovative Experi-
ment Program for College Students in Hunan Province
(201711535035) and Natural Science Foundation of
Hunan Province (2016JJ3053).
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Received: 8 October 2017. Accepted: 22 November 2017.
1860 Nanosci. Nanotechnol. Lett. 9, 1849–1860,2017