Mesoporous silica nanoparticle based nano drug delivery systems: synthesis,

controlled drug release and delivery, pharmacokinetics and biocompatibility

Qianjun He and Jianlin Shi
*
Received 9th November 2010, Accepted 11th January 2011
DOI: 10.1039/c0jm03851b
The biomedical applications of mesoporous silica nanoparticles (MSNs) as efcient drug delivery
carriers have attracted great attention in the last decade. The structure, morphology, size, and surface
properties of MSNs have been found to be facilely tunable for the purposes of drug loading, controlled
drug release and delivery, and multifuctionalization. Meanwhile, the biosafety and in vivo drug
efciency of MSN-based nano drug delivery systems (nano-DDSs), involving biocompatibility
(including cytotoxicity, blood and tissue compatibility) and pharmacokinetics (including
biodistribution, biodegradation, retention, excretion, blood circulation) are also drawing increasing
attention because of their clinical application prospects. Herein, we review the most recent research
progresses on the synthesis, controlled drug release and delivery, pharmacokinetics and
biocompatibility of MSNs.
1. Introduction
Since the discovery of MCM-41-type ordered mesoporous silica
(MS) by Mobil corporation scientists in 1992, there has been
large amount of research conducted on the controlled syntheses
and applications of MS.
1
Great endeavors have been made in the
control of particle size, pore diameter, morphology, structure,
surface properties and functionalization of MS to develop their
applications in the elds of biomedicine, catalysis, environmental
protection, optics, etc.
25
In particular, biomedical application
research on mesoporous silica nanoparticles (MSNs) has
received great attention in the last few years. MSNs have been
intensively suggested for use in controlled drug/gene release and
as delivery carriers,
615
biosensors,
14,15
bio-markers,
1620
enzyme
supporters,
21,22
etc. Meanwhile, the biological effects of MSNs at
different levels from molecule, cell, blood to organ/tissue,
State Key Laboratory of High Performance Ceramics and Superne
Microstructure, Shanghai Institute of Ceramics, Chinese Academy of
Sciences, 1295 Ding-Xi Road, Shanghai, 200050, China. E-mail: jlshi@
sunm.shcnc.ac.cn; Fax: +86 21 52413122; Tel: +86 21 52412714
Qianjun He
Qianjun He received his BSc
(2004) and MSc (2007)
respectively in Polymer and
Inorganic Material Sciences
under the supervision of Prof.
Zhiliang Huang at the Wuhan
Institute of Technology, and
obtained his PhD (2010) in
Materials Physics and Chem-
istry under the supervision of
Prof. Jianlin Shi at the Shanghai
Institute of Ceramics, Chinese
Academy of Sciences.
Currently, his research focuses
on the controlled synthesis,
biomedical applications and
biological effects of porous nanomaterials and drug scaffolds. He is
the co-author of more than 30 scientic papers and 7 patents
(2011).
Jianlin Shi
Jianlin Shi received his BSc
(1983) and PhD (1989) at the
Nanjing Institute of Technology
and the Shanghai Institute of
Ceramics, respectively. He is
a professor of the Shanghai
Institute of Ceramics and the
director of the State Key Lab of
High Performance Ceramics
and Superne Microstructure in
the Shanghai Institute of
Ceramics, Chinese Academy of
Sciences. Currently, his research
areas include mesopore-based
nano-composites and their cata-
lytic, biomedical and optical
applications. He has published over 200 scientic papers which
have been cited more than 3000 times by other scientists with an
h-index of 31 (2011).
This journal is The Royal Society of Chemistry 2011 J. Mater. Chem., 2011, 21, 58455855 | 5845
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www.rsc.org/materials FEATURE ARTICLE
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involving cytotoxicity,
2325
biodegradability,
2628
blood compati-
bility,
2932
biodistribution and excretion,
3337
are also drawing
increasing attention and have become current hot topics in MSN
biosafety research. This feature article summarizes the recent
progress made by different research groups on the development
of MSNs for controlled drug release and delivery and on the
investigations of their pharmacokinetics and biocompatibility,
including biodistribution, degradation, excretion, blood-circu-
lation lifetime, cellular uptake and cytotoxicity, blood compati-
bility, tissue compatibility, acute toxicity, etc.
2. Controlled synthesis of MSNs carriers
The control of the structure, morphology, size, and surface
properties of synthesized MSNs is important for their biomedical
applications. MSNs are generally prepared under basic, acidic or
neutral conditions. Under basic conditions, both the mophology
and nano-scaled particle size of MSNs, such as MCM-41-type
MSNs, are easily controllable.
38
However, the pore size tuning on
MSNs synthesized under basic conditions encountered great
difculties, which restricted their bio-application for the loading
and delivery of nanocrystals, quantum dots and large molecules
such as DNA, siRNA, proteins and enzymes. In this case, MSNs
possessing both nano-scaled particle size and large pore diameter
are highly desired. Under acidic conditions, in contrast, the pore
size of nonionic surfactant-templated MS, e.g. SBA-15 series
MS, is controllable in a wide range, and MS of various shapes
and surface patterns could be facilely synthesized but its particle
size can mostly be controlled only in the micrometre scale,
39
and
not so easily in the nano scale, mainly because of the difculties
in regulating the dimensions of micelles. Recently, we have
proposed a bottom-up tailoring methodology to successfully
regulate the morphologies and sizes of composite micellar
bunches with liquid crystal mesophases self-assembled from
multivalent metal ions (Zr
IV
) and nonionic surfactants (P123),
and subsequently the morphologies and dimensions of liquid
crystal-templated MSNs can also be controlled.
4
By virtue of
introducing multivalent metal salts ZrOCl
2
, novel LLC meso-
phases of metal ionP123 composite micelles were assembled and
their morphologies and dimensions could be easily controlled
through varying the concentrations of the added multivalent
metal salts, and subsequently the morphologies and dimensions
of SBA-15-type MS were correspondingly tailored from long
nanorods of 645 245 nm to short nanorods of 360 210 nm,
even to nanoplates of 310 740 nm and subspheroidal nano-
particles of 230 nmin diameter (Fig. 1). Furthermore, rhodamine
B-co-condensed spherical SBA-15 MSNs (RhB-Cc-SBA-15NPs)
were synthesized based on the proposed bottom-up tailoring
methodology and a facile co-condensation approach.
5
With this
approach, not only could RhB-Cc-SBA-15NPs be easily
controlled to form uniform spherical nanoparticles, but also the
RhB molecules were found to be monodispersed and covalently
bonded within the pore channels. Therefore, RhB-Cc-SBA-
15NPs possessed high RhB grafting amounts (0.088
0.123 nm
2
), and exhibited high uorescence quantum yields (up
to 88.1%) and uorescence detection, and excellent photo-
stability, and presented great potential for applications in drug
delivery and uorescence probing application for use in medical
diagnosis and synchronous therapy.
On the other hand, the synthesis of MSNs under neutral
conditions is also worth noting, because some organicinorganic
hybrid MSNs, which are synthesized from organically esteried
or amidated silica precursors or have monomolecular inclusion
compounds within the pore channels, will easily hydrolyze under
either basic or acidic conditions. Under neutral conditions,
mesoporous silica can also be easily controlled in the micrometre
scale, but not in the nano scale.
40
Recently, we chose a phosphate
buffer solution (PBS) of pH 7 as the reaction medium and
nonioniccationic composite surfactants of CTAB and Brij-56 as
the composite structure-directing agent to synthesize MSNs.
3
Monodispersed MSNs with regular spherical morphology and
controllable size within a wide nano-scale range (401220 nm)
have been successfully synthesized by adding propanetriol (PT)
as co-surfactant/co-solvent, changing the reaction temperature,
or introducing a multistep silica source addition mode (Fig. 2).
Hollow MSNs (HMSNs) with a large cavity in the core have
attracted special attention for nano-medical applications because
of their unique properties such as low density, large specic
surface areas, high loading capacities and the potentially reduced
amount of carriers used. The general synthetic strategy for these
special HMSNs is the typical soft/hard templating method,
which includes the formation of uniform soft/hard templates and
their surface functionalization followed by the deposition of the
desired shell. The soft templates could be emulsion drops,
41
PVP
aggregates
42
or micellar aggregates,
43
while the hard templates
could be Fe
3
O
4
nanocrystals,
44
Au nanoparticles,
45
polystyrene
spheres
46
or carbon spheres
47
etc. Although great success for
fabricating HMSNs by various templates has been achieved,
their actual use as nano drug delivery systems (nano-DDSs)
in vivo has not been realized. The current obstacle for in vivo
applications of HMSNs is the difculty of obtaining HMSNs
with high dispersivity, controlled particle/pore sizes and shell
thickness.
Recently, a novel but simple synthetic strategy, namely the
structure difference-based selective etching process, has been
developed to prepare HMSNs by using a compositionally
homogeneous core/shell structure,
48
hopefully to satisfy
Fig. 1 Schematic illustration of the bottom-up morphological and
dimensional tailoring of SBA-15-type MSNs assembled from control-
lable LLC composite micellar bunches. Reprinted with permission from
ref. 4. Copyright 2009, Royal Society of Chemistry Publishing Company.
5846 | J. Mater. Chem., 2011, 21, 58455855 This journal is The Royal Society of Chemistry 2011
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nano-medical applications (Fig. 3A). The templating route can
be classied into two categories, the heterogeneous and the
homogenous templating routes. The general process to remove
the core part of a core/shell structure is based on the heteroge-
neous templating route, i.e., the compositional difference
between core and shell makes the selective removal of the core
possible.
49
Another process is the homogeneous templating
route, i.e., where the composition between core and shell is the
same, or almost the same, while the structures are different which
leads to different dissolution behaviors of the core and shell.
48
By
making use of the difference in condensation/densication
degrees between the St ober-based solid silica core and the
surfactant-directed mesoporous silica shell, the core part was
selectively removed and highly monodisperse HMSNs with
tunable particle/pore sizes and wall thicknesses were then
obtained (Fig. 3B). Interestingly, based on this strategy, a kind of
homogeneous rattle-type MSNs (RMSNs) with dimension-
controlled cavities between the solid silica core and the
mesoporous silica shell could also be created (Fig. 3C). The
intentionally created cavities could efciently enhance the drug
loading capacity (1222 mg doxorubicin per gram silica) and
efciency (98% for doxorubicin), which shows great advantages
for drug loading and delivery.
On the other hand, the HMSNs can be easily multi-function-
alized to create multi-purpose nano-medical platforms for
simultaneous imaging diagnosis and drug therapy. The general
strategy for the multifunctionalization mainly focused on
embedding functional inorganic nanocrystals into the core part
of HMSNs. The functional nanocrystals could be magnetic
Fe
3
O
4
nanoparticles because of their potential to act as the
contrast agents of T
2
-weight magnetic resonance imaging (MRI),
and Au nanocrystals due to their unique optical properties such
as the surface plasma resonance enhanced light scattering and the
absorption for live cell dark-eld imaging and photothermic
therapy for cancer. The structure difference-based selective
etching process was also extended to fabricate multifunctional
heterogeneous rattle-type Fe
3
O
4
@mSiO
2
and Au@mSiO
2
nanoparticles in virtue of the easy formation of solid/meso-
porous silica layers onto the surface of inorganic nanocrystals.
50
The obtained Fe
3
O
4
@mSiO
2
nano-rattles (Fig. 4) showed the
enhanced anticancer drug loading capacity (20%) and high ef-
ciency (up to 100%) for doxorubicin, and high in vivo MRI
effectiveness.
3. Drug loading, controlled release and delivery
MSNs have been intensively suggested as drug delivery carriers
since they came to light, because they possess many unique
Fig. 2 TEM images of monodispersed MSNs with various particle sizes
of 54 nm (A), 72 nm (B), 88 nm (C), 104 nm (D) and 188 nm (E), and
particle size distributions (F) measured by the DLS method. Reprinted
with permission from ref. 3. Copyright 2009, Elsevier Ltd.
Fig. 3 (A) Schematic illustration of the formation of hollow/rattle-type
MSNs, which includes the preparation of solid core/mesoporous silica
shell nanoparticles and subsequent complete or partial removal of the
silica core; TEM images of hollow MSNs (B) and homogeneous rattle-
type MSNs (C). Reprinted with permission from ref. 48. Copyright 2009,
American Chemical Society.
This journal is The Royal Society of Chemistry 2011 J. Mater. Chem., 2011, 21, 58455855 | 5847
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properties such as tunable particle size and morphology, uniform
and tunable pore size, high surface area and pore volume, facile
surface functionalization and stable physicochemical properties.
Compared to the most general organic carriers such as lipo-
somes, micelles, viruses, capsules, etc., MSNs have the signicant
advantage of being free from various biochemical attacks and
bioerosions. In addition, MSNs have high drug loading capacity,
sustained release prole, good thermal stability, etc. Therefore,
MSNs have attracted a great deal of research attention for
various controlled release and delivery.
3.1. Effect of pore structure and pore surface modication on
drug loading and release
As a drug carrier, high drug-loading capacity is being pursued.
According to the dimensions of drug molecules, the pore size of
MSNs can be easily controlled to be just suitable to lodge as
many drug molecules as possible, the surface potential and
hydrophilicity can also be altered for attracting drug molecules
to enter the pores of MSNs by surface modication.
30,5154
A
series of hollow core/mesoporous shell structures and rattle-type
mesoporous structures have been designed to encapsulate large
amounts of drug molecules into the hollow core by several
research groups, which have extraordinarily high drug loading
capacities of more than 1 g drugs per gramMSNs.
41,42,48,5557
Very
recently, a signicant hierarchical mesoporous and hollow
structure has been obtained in our research group to simulta-
neously load two kinds of drugs of different molecular sizes and
hydrophilicity/hydrophobicity (Fig. 5A). A novel kind of core
shell dual-mesoporous structure with smaller mesopores in the
shells and ordered larger mesopores in the core has been con-
structed by a simple dual-templating method, which shows
a three-step release prole controlled by tuning the shell thick-
ness from 5 nm to 60 nm (Fig. 5B). These core/shell hierarchical
structures may provide a useful platform for multidrug-
combined therapy.
58
In addition to heightening the drug loading capacity, the
release prole of MSNs can also be controlled via adjusting their
structures and modifying their surface properties.
30,4,5
Approxi-
mately the same size between pore diameter and drug molecule
favors sustained release owing to the size connement effect,
however the loaded drug can be released at a relatively high rate
when the pore size of MSNs is much larger than that of drug
molecules used. MSNs have diversiform mesopore structures
including MCM-41, MCM-48, SBA-15, etc., and the diffusion
rate and route of drug molecules loaded in MSNs depends highly
on the mesoporous structure type of the MSNs. MCM-41-type
MSNs have short two-dimension hexagonal pore channels that
allow loaded drug molecules to directly diffuse outwards,
however drug molecules loaded in the MCM-48-type MSNs
which have a three-dimension cubic pore structure have to travel
a longer distance along the zigzagged pore channels until release.
Moreover, both the opposite potential and the similar hydro-
philicity between MSNs and drug molecules also favor the sus-
tained release of drugs (Fig. 6). Recently, Mou
59
and our
group
30,5
changed the surface potentials of MSNs with quater-
nary ammonium groups from being negatively to being posi-
tively charged, and loaded negatively charged drugs
(sulfasalazine and salvianolic acid B used for anti-inammatory
and anti-hepatic brosis applications, respectively). Compared
to the negatively charged MSNs, the positive-charge modied
MSNs exhibited remarkably sustained release proles.
3.2. Functionalization for controlled release and targeted
delivery of drugs
To be a perfect drug carrier, MSNs are highly desired to exhibit
zero release before reaching the targeted focal zones and the
stimuli-responsive drug release character at specic sites for
Fig. 4 TEM image (A) and backscattered electron SEM image (B) of
heterogeneous rattle-type Fe
3
O
4
@mSiO
2
nanoparticles (inset of B:
purposely selected back scattered electron image of a broken nano-rattle
to reveal the hollow structure). Reprinted with permission from ref. 50.
Copyright 2010, American Chemical Society.
Fig. 5 Hollow MSNs with hierarchical mesoporous shells for loading
drugs of different molecular sizes and hydrophilicity/hydrophobicity (A),
and the coreshell dual-mesoporous MSNs with smaller mesopores in the
shells and ordered larger mesopores in the cores for a three-step release
prole controlled by the shell thickness (B). Reprinted with permission
from ref. 58. Copyright 2010, American Chemical Society.
Fig. 6 Counterpart charge modication of MSNs for negative-charge/
positive-charge drug loading and sustained release.
5848 | J. Mater. Chem., 2011, 21, 58455855 This journal is The Royal Society of Chemistry 2011
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reducing the toxic side effects of drugs. To reach this goal, great
efforts have been made worldwide to install various triggers
including temperature,
6062
redox,
6368
pH value,
6875
light,
7683
magnetism,
8486
enzyme,
87,88
ultrasound,
89
etc.
Because tumor and inammatory tissues are more acidic than
normal tissues and blood, the pH-responsive nano-DDSs based
on MSNs have been designed to achieve a site-selective
controlled release. As early as in 2005, we
69
reported a pH-
responsive nano-DDS by coating polyelectrolyte (PAH/PSS)
multilayers on hollow MSNs. In addition, MSNs can also be
functionalized with carboxylic acid/polycations, hydroxypropyl
methylcellulose phthalate, amine/poly(acrylic acid),
polyethyleneimine/cyclodextrin (PEI/CD) polypseudoroxotane,
polyethyleneimine/cyclodextrin, amine/sulfonate, poly(2-(diethy-
lamino)ethyl methacrylate), aromatic amines/b-cyclodextrin
nanovalves, diethylenetriamine, poly-(dimethyldiallylammo-
nium chloride (PDDA), etc. for pH-responsive release. Lin
6466
and Zink
86
reported a series of nano-caps as gatekeepers for
MSNs, such as CdS, Au, Fe
3
O
4
and PAMAM nanoparticles,
which were uncovered under external stimulation by redox, light
or magnetism leading to the release of loaded drugs (Fig. 7).
Zink
67,72,74,75
and Fujiwara
76
designed various nanomachines,
such as smart supramolecular nano-valves ([2]-pseudorotaxane
and [2]-rotaxane) and nano-impellers (azobenzene and
coumarin), to realize the pH-/light-responsive drug release
(Fig. 8). Recently, Bein
87
covered a kind of biotinavidin cap on
MSNs to realize the protease-responsive release. A kind of
general temperature sensitive polymer poly(N-iso-
propylacrylamide) (PNIPAM) was also coated on MSNs for
temperature-responsive release.
6062
In contrast to the common drug loading in surfactant-extracted
MSNs for nano-DDSs, it was reported
9
very recently that the
as-synthesized MSNs without the surfactant being removed
(surfactant@MSNs) demonstrated the sustained release of
surfactants inaqueous solution, whichdependedonthe surfactant
used. These surfactant@MSNs could kill cancer cells at a much
higher efciency by the release of surfactant molecules than
a common anti-cancer drugcamptothecine-post-loaded-
MSNs, especially at low MSNs concentrations in the long term.
Based on such a surfactant@MSNs system, hydrophobic drugs,
such as camptothecine, paclitexal and doxorubicin, can be
successfully loaded into the hydrophobic core part of the surfac-
tant micelle, and subsequently loaded into MSNs together with
the surfactant micelles. Such a drug@surfactant@MSNs nano-
DDS has been discovered with a signicant pH-responsive release
mechanism based on the electrostatic attraction between surfac-
tant micelles and MSNs. Cationic surfactant micelles containing
drugs are exchangeable with protons in acidic conditions but
inexchangeable in pH 7.4 normal physiological conditions,
therefore surfactant and drugs are released together at the tumor
rather than in normal tissues or the blood. The well-chosen
surfactant CTAB (cetyltrimethyl ammonium bromide) is utilized
as a sensitizer for anticancer drugs doxorubicin and camptothe-
cine to enhance the membrane penetrability and prevent the drug
efux of P-gp by an ATP-inhibiting effect in favor of the intra-
cellular continuous accumulation of released drugs within the
multi-drug resistance cells, and thus overcome the multidrug
resistance of the tumor together with anticancer drugs by
a synergistic cell cycle arrest/apoptosis-inducing effect, as depic-
ted in Fig. 9.
In addition to the controlled release of drugs, the targeted
delivery is also vitally important to reduce toxic side effects of
drugs and enhance the drug efcacy. The passive targeting of
MSN-based nano-DDSs can be partially achieved by a so-called
enhanced permeability and retention (EPR) effect, as demon-
strated by Zink and Tamanoi,
34
and the EPR effectiveness can be
mediated by the particle size, surface potential and hydrophilicity
of MSNs. The passive targeting by external magnetic eld based
on magnetically functionalized nano-DDSs can also be consid-
ered. The active targeting can be achieved by the surface modi-
cation with targeting molecules. As to chemotherapy against
cancer, well-known targeting molecules grafted on MSNs include
folate, HER2/neu receptor antibody, arginineglycineaspartic
acid (RGD), anti-CD20 antibody, anti-EGFR antibody, etc.
9093
Fig. 7 Mesoporous silica nanoparticles have been engineered with
nanoparticles that work as gatekeepers. These nanoparticles are attached
to MSNs through stimuli-responsive linkers. This combination affords
drug delivery vehicles that release their cargo in a space- and time-
controlled fashion without premature release. Reprinted with permis-
sion from ref. 13. Copyright 2010, Wiley Publishing Company.
Fig. 8 Graphical representations of operating supramolecular nano-
valves from DB24C8/dialkylammonium-tethered porous silica particles
MCM-41 (with cross section). The nanovalves can be opened by either (a)
pH stimulation with bases or (b) competitive binding with metal/uo-
rodialkylammonium cations, to trigger the controlled release of the
luminescent probe molecules, coumarin 460 or IR 140. Reprinted with
permission from ref. 74. Copyright 2006, American Chemical Society.
This journal is The Royal Society of Chemistry 2011 J. Mater. Chem., 2011, 21, 58455855 | 5849
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3.3. Effect of particle size, morphology and modication on
transmembrane transport
The transmembrane transport ability of MSNs is the prerequisite
to delivery drugs into targeted cells. The understanding of the
endocytosis, exocytosis and intracellular transport processes of
MSNs is necessary and important to manipulate the controlled
delivery and release of drugs. For an ideal state-of-the-art MSN-
based nano-DDS it is highly desirable to have the capabilities of
transmembrane transport and escape or degradation after the
completion of the drug release. These features of MSN-based
nano-DDSs can be exploited via modication/functionalization
and tuning to the particle size and morphology of MSNs.
Lin and co-workers
94
observed the entire endocytosis process
of MSNs into A549 human lung cancer cells by a differential
interference contrast (DIC) microscopy (Fig. 10A). They
conrmed that the motion of MSNs was greatly slowed down
after the MSNs were endocytosed into cells owing to the resis-
tance from the viscous cytoplasm and the cellular cytoskeleton
networks. They further demonstrated unique endocytosis of
MSNs, which was both MSNs morphology and cell line depen-
dent. The size and aggregation tendencies were identied to be
determining factors in the endocytosis efciency and kinetics.
Furthermore, Tang et al.
95
found that the MSNs with different
aspect ratios (ARs 1, 2 and 4) could be readily internalized into
A375 human melanoma cells by nonspecic cellular uptake,
however the MSNs with higher ARs could be taken up in larger
amounts and at faster internalization rates (Fig. 10C).
Lin and co-workers
96
reported the effect of surface modica-
tion/functionalization on the transmembrane transport and
escape abilities of MSNs. They found that more negatively
charged MSNs would escape more easily from the endosomes of
HeLa cells owing to their high buffering capacity by the proton
sponge effect, however the MSNs with the higher positive x-
potentials were more easily trapped within the endosomes of
HeLa cells via the caveolae-mediated mechanism, and above
a certain threshold of surface charge, a new unrevealed charge-
dependent mechanism started to be effective for HMSC.
97
Additionally, some intact lipid bilayers (DOPC, POPC,
DMPA/DMPC) were coated on the surface of MSNs to enhance
the transmembrane transport ability of MSNs and synchro-
nously prevent the leakage of the encapsulated drugs before the
MSNs were endocytosed.
80,98
The particle size of MSNs can be modulated in a broad range
of 301000 nm and the morphology of MSNs can also be well
tailored into nanorods, nanoplates and nanospheres, allowing
the facile transmembrane delivery and the long-termintracellular
retention by virtue of the EPR effect.
35,99,100
Recently, we have
found that the endocytosis efciency was dependent on the
particle size and surface property of spherical MSNs. The MSNs
of smaller particle sizes (e.g., 190 nm, as compared to larger ones
of 1220 nm) were more easily endocytosed by MDA-MB-468
cells and consequently located within their lysosomes (Fig. 10B),
however MSNs were less endocytosed after calcination owing to
the increase of their surface hydrophobicity.
101
Mou also
conrmed the particle size dependence of the cellular uptake of
MSNs by HeLa cells, and further found that the MSNs of 50 nm
in diameter had the maximum cellular uptake efciency.
99
This
size effect in the cellular uptake was also widely present in other
nanomaterials.
102
In addition, Tamanoi and co-workers also
ratiocinated that the internalized MSNs could fast escape from
endo-lysosomal vesicles into the cytoplasm and resist the lyso-
somal degradation, and therefore protect the loaded drugs from
bioerosion.
103
4. Pharmacokinetics of MSNs
The pharmacokinetics of nanomaterials is closely related to the
in vivo toxicity, biocompatibility and delivery efciency, and
therefore is vitally essential for the understanding, interpretation
and assessment of safety and drug efciency. There is an urgent
Fig. 9 Comparison of drug loading and release between conventional
and novel surfactant-mediated nano-DDSs respectively constructed by
the post-loading and in situ-loading routes. The novel nano-DDSs can
responsively deliver water-insoluble anticancer drugs and surfactant as
a sensitizer together into tumor cells, even into their nuclei, where the
surfactant can enhance the membrane permeability and prevent the drug
efux of P-gp by an ATP-inhibiting effect in favor of the intracellular
continuous accumulation of released drugs within the multi-drug resis-
tance cells.
Fig. 10 (A) Endocytosis process of a MSN into an A549 living human
lung cancer cell, the MSN had gone inside the cell after 27 min; (B) the
intracellular localizations of spherical MSNs (red RhB label) with
different particle sizes within lysosomes (green label) of MDA-MB-468
cells; and (C) MSNs (green FITC label) with different shapes and aspect
ratios: ARs 1 (NS100), ARs 2 (NSR240), ARs 4 (NLR450).
Reprinted with permission from: ref. 94. Copyright 2008, Springer-Ver-
lag; ref. 101. Copyright 2009, Wiley Publishing Company; ref. 95.
Copyright 2010, Elsevier Ltd.
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necessity to investigate the pharmacokinetics, toxicity and
biocompatibility of MSNs before use as nano-DDSs. Recently,
the pharmacokinetics studies on MSNs, involving bio-
distribution, biodegradation, retention, excretion and blood
circulation, are drawing great attention.
4.1. Biodegradation
Very recently, we
26
investigated the in vitro degradation behavior of
MSNs in simulated body uid (SBF), and discovered a three-stage
degradation behavior of surfactant-extracted MSNs on two time-
scales, including an extraordinarily fast bulk degradation stage on
the hour-scale and a decelerated degradation stage blocked by the
formation of a calcium/magnesium silicate layer followed by
a maintained slow diffusion stage on the day-scale, which was
distinctly different from the poor degradation behavior of calcined
MSNs and amorphous non-mesoporous silica (Fig. 11), most
probably owing to the enhanced completion of the OSiO
network after calcination and the low surface area, respectively.
Bothlowspecic surface areaandhighinitial concentrationresulted
in the reduction of the MSNs degradation percentage and the
prolonging of the MSNs degradation process, which could be well
understood by kinetic simulation and calculation in combination
withexperimental data. Noticeably, the surfactant-extractedMSNs
can degrade almost completely after a 15-day immersion at 0.1 mg
mL
1
in SBF. Bein
27
has also conrmed the degradability of
MSNs and the blocking effect of apatite precipitates, and found the
faster and slower degradation kinetics of the phenyl-functionalized
MSNs and the PEGylated MSNs, respectively, as compared to the
unfunctionalized MSNs. On the other hand, the degradation of
nanostructured mesoporous silica can be inhibited by the incorpo-
ration of a phosphorus component into the silica network for bone
regeneration applications.
28
4.2. Biodistribution, retention and excretion
Further, the in vivo biodistribution and urinary excretion of
spherical MSNs have been evaluated very recently in normal
ICR mice via tail vein injection, and the effects of the particle size
and PEGylation have been investigated.
33
The results indicated
that both MSNs and PEGylated MSNs of different particle sizes
(80360 nm) were distributed mainly in the liver and spleen, with
a minority in the lungs and very few in the kidneys and heart.
33,36
The PEGylated MSNs of smaller particle size escaped more
easily from capture by liver, spleen and lung tissues, possessed
longer blood-circulation lifetime, and were more slowly bio-
degraded and correspondingly had lower excreted amounts of
degradation products in the urine, as compared with MSNs of
smaller particle size without PEGylation. Similarly, it was also
reported very recently that great numbers of MSNs (100
130 nm) injected through tail vein were captured by liver and
spleen of nude mice bearing subcutaneous tumors, however
surprisingly there was a greater amount of MSNs distributed in
tumors and the slightly enhanced accumulation in tumors
occurred after targeting conjugation with folate. The 95%
degradation products could be safely excreted out of body
through urine and faeces 4 days after the tail vein injection of
MSNs.
34
Furthermore, the surface potential of MSNs could remarkably
impact their pharmacokinetics. Mou and co-workers
37
indicated
that amine-functionalized MSNs with a highly positive charge
(+34.4 mV at pH 7.4) surprisingly underwent rapid transport
from the liver into the gastrointestinal tract and subsequent hep-
atobiliary elimination into faeces, without detectable renal
excretion, within 30 min of tail-vein injection to male nude mice;
however the MSNs with a highly negative charge (17.6 mVat pH
7.4) remained sequestered withinthe liver for more than3 months.
5. Biocompatibility of MSNs
5.1. Interaction with cells and cytotoxicity
Present studies indicate that MSNs can easily be internalized into
most normal and cancer cells without apparent deleterious
effects on cellular growth, proliferation and differentiation,
although the proliferation and cycle progression of MSN-treated
A375 human malignant melanoma cells could be accelerated in
vitro and the in vivo tumor growth was surprisingly stimulated
due to the decreased level of endogenous reactive oxygen species
(ROS).
104
Souid and co-workers
25
conrmed that the cellular
respiration inhibition to HL-60 (myeloid) and Jurkat (lymphoid)
cells was both concentration- and time-dependent, and the SBA-
15-type MSNs inhibited cellular respiration at 25500 mg mL
1
,
however MCM-41-type MSNs had no noticeable effect on
respiration rate due to the limited access to cellular mitochon-
dria. In spite of the negligible cytotoxicity of MSNs, we
23
noticed
that MSNs with residual toxic surfactants such as CTAB which
remained in the pore channels would exhibit remarkably
magnied cytotoxicity. MSNs used as nano-DDSs would be
always desired to be non-cytotoxic, therefore it is necessary to
completely remove toxic surfactants from the pore channels of
MSNs prior to the drug loading.
5.2. Blood compatibility
Vein injection is an important administration approach, by which
drugs can efciently be delivered to targeted cells and tissues. In
this case, good blood compatibility is the prerequisite for drug
Fig. 11 Degradation behaviors of surfactant-extracted MSNs (solid
dotted lines), surfactant-calcined MSNs (B) and amorphous non-mes-
oporous silica (P) in SBF. Reprinted with permission from ref. 26.
Copyright 2010, Elsevier Ltd.
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loaded MSNs to be administrated through the vein injection,
including hemolysis, coagulation, nonspecic protein binding,
phagocytosis, blood platelet number and function, blood
corpuscle number, leucocytic function, enzymatic activity,
immunoreaction, etc. Recently, we
29,30
evaluated the blood
compatibility of MSNs by investigating their hemolysis, coagula-
tion, nonspecic protein binding and phagocytosis. The levels of
prothrombin time (PT), activated partial thromboplastin time
(APTT) and brinogen (Fib) were measured to evaluate the coag-
ulationbehavior of MSNs. The results indicatedthat neither APTT,
PTnor Fib values of the SBA-15-type MSNs exceeded their normal
ranges in a broad concentration range of 50500 mg mL
1
,
suggesting that the SBA-15-type MSNs could not activate the
intrinsic, extrinsic and common coagulation pathways. At low
MSN concentrations of less than 100 mg mL
1
, the hemolysis
activity of the MSNs was conrmed to be almost invisible by Lin.
31
However, we have found that at a high MSNconcentrations of 500
mgmL
1
, MSNs hadremarkableHRBCs hemolysis (14.2%), THP-1
phagocytosis (8.6%) and nonspecic HSA adsorbance (18.7%).
Fortunately, the PEGylation to MSNs with the optimal PEG
molecular weight of 10 k and the corresponding optimal PEGchain
density of 0.75 wt% could signicantly decrease these values to as
low as 0.9%, 0.1% and 2.5%, respectively.
29
5.3. Tissue compatibility
Since they were designed for the sustained release of drugs,
MSNs are expected to stay at the targeted sites for a considerably
long term. Therefore, the tissue compatibility of MSNs needs to
be considered for biosafety. Recently, the tissue compatibility of
MSNs was investigated by histopathological evaluation.
33
No
pathological abnormality could be observed in both gross and
microscopic histological examinations of various tissues
including heart, liver, spleen, lung and kidney in one month after
vein injection into mice, suggesting that the MSNs had not
caused signicant tissue toxicity and inammation though they
had not completely degraded. Through intraperitoneal injection
with MSNs twice a week for two months, Zink and Tamanoi
34
also conrmed that neither gross nor histopathological abnor-
maliteis could be observed in the major organs of mice, such as in
the liver, spleen, kidneys, heart, intestines, stomach, muscles or
lungs. Furthermore, at a high vein-injection dose of 50 mg kg
1
per day (total of ve doses with twice per week for 14 days), the
acute toxicity of MSNs was almost negligible compared with the
blank control according to the monitoring of the body-weight
change, the visible and/or palpable dermal infection, the presence
of ascites, the grooming or the impaired mobility. At an
extremely high dose of 1200 mg kg
1
, no mouse survived after
intraperitoneal or intravenous injection of MCM-41-type or
SBA-15-type MSNs, however the subcutaneous injection did not
cause death at an equally high administration dose and doses of
up to 200 mg kg
1
, which was high enough for drug loading and
delivery owing to their high drug loading capacities, was always
safe by both intraperitoneal and intravenous injection.
35
6. Outlook
This review highlights some recent exciting progresses in the
synthesis, controlled release and delivery of drugs,
pharmacokinetics and biocompatibility of MSNs. The advanced
synthetic strategies have been developed to control the particle
size, pore structure, hollow and hierarchical mesoporous struc-
ture, morphology, and surface properties of MSNs. Many
intelligent nano-DDSs based on MSNs for controlled drug
release and delivery properties have been constructed. These
smart nano-DDSs can be delivered into targeted organs or cells
and release drugs in some controlled fashion by virtue of various
internal and external triggers, such as pH, specic antibodies,
external ultrasonic/electric/magnetic/light irradiation, etc., which
is encouraging and shows great promise in biomedical applica-
tions. However, there are still a great many challenges, especially
the in vivo-applicable stimuli-responsive mechanisms, which need
to be understood and investigated more comprehensively and
thoroughly, such as the in vivo target specicity, the in vivo
stimuli-responsive manoeuvrability, the real-time monitoring of
the in vivo responsive release process, etc. We conceive that, the
precise pH-response mechanism, i.e., the near zero-release in
blood or body uid at pH7.27.5, but the sustained/controlled
release at local focuses, such as tumors where pH values are
weakly acidic, should receive much attention. Besides, some new
intelligent nano-DDSs based on near infrared and ultrasound
triggers should be paid special attention in view of their efcient
tissue penetrability. The multifunctionalization of MSNs by
integrating the imaging diagnostic function with the drug
delivery is currently under extensive investigation, which is
desired to realize synchronous diagnosis and therapy.
105,106
In addition to the controlled release at specic sites, the passive
or active targeting of nano-DDSs, respectively by EPR effect,
external eld guidance or recognition of the focuses, is equally
important. The passive targeting of MSNs based on the EPR
effect
34
has been found to be effective to a certain extent, and
more passive targeting methods such as external magnetic elds
were proposed several years ago as demonstrated by the manu-
facture of a magnetic core/mesporous shell structure,
107,108
however, the practical application in animals did not prove the
effectiveness of this approach as expected. More importantly, the
active targeting by specic chemical bonding or other kinds of
conjunction between specially designed molecules or enzymes
has been suggested for decades, unfortunately, the effective tar-
geting of MSN-based nano-DDSs has not been well explored to
date, although some preliminary approaches such as folic acid
grafting have been proposed. MSNs were even PEGylated and
grafted with different kinds of antibodies
90
targeting specic
antigens, however, the capture by organs such as liver and spleen,
was still inevitably present,
33
which would do harm to these
organs and shorten the blood circulation time as well, and would
nally affect the targeting efciency. Therefore, more efforts
should be made to nd more effective ways to prolong the blood-
circulation time and render the nano-DDSs able to nd the
in vivo targeted locations.
Gene therapy is drawing increasing attention from both biol-
ogists and materials chemists. In recent years, MSNs have been
used to load plasmid RNA (1 kbp1000 kbp, a straight length of
340 nm340 mm) and siRNA(21 bp25 bp, a straight length of 7
8.5 nm), but both plasmid RNA and siRNA were loaded only on
the external surface of MSNs which were generally pre-modied
with a polycation such as PEI.
5254,66
Therefore, there are two
main disadvantages: that PEI is highly cytotoxic creating
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a potential safety issue, and that RNA cannot be adequately
protected from enzymatic cleavage by MSNs which would effect
the gene transfection efciency. One of the most probable solu-
tions is to synthesize MSNs with large enough pore channels to
contain siRNA within the pore system, followed by reversing the
negative charge on the internal surface via the grafting of a large
number of positively charged groups, which needs further
research.
The pharmacokinetics and biocompatibility of MSNs are the
prerequisite factors for future practical applications, and have
attracted great attention in recent years and some primary data
have been obtained. However, there are still many unsettled
questions which need to be answered, such as the pharmacoki-
netics and pharmacodynamics of drug loaded MSNs, the acute
and chronic toxicities, the genotoxicity, the reproductive toxicity,
the long-term in vivo degradation and tissue compatibility of
MSNs, etc. Up to now, however, these questions are still unan-
swered in the absence of extensive and systematic preclinical
study and only limited data are available as references for clinical
research on MSN-based nano-DDSs. Therefore, more efforts
should be made to this eld, and we are among those endeav-
oring to make progress on this subject. We expect that primary
clinical research will be done in the near future.
Meanwhile, the drug encapsulation efciency of MSNs and the
bioaccessibility of loaded drugs also have to be considered.
Different administration routes such as intravenous injection,
intraperitoneal injection and oral administration are options to
improve the bioaccessibility for specic diseases. The advanced
technologies of biofunctionalized lipid coating and the
synchronal in situ multidrug loading will open up a the possibility
for MSN-based nano-DDSs to inhibit tumor metastasis and
diminish the multidrug resistance of cancer cells. Finally, the
scaled production of the MSN carriers and the MSN-based
nano-DDSs will also become important for the nal possible
biomedical applications.
A simple research and development road-map for the
biomedicine applications of MSN-based nano-DDSs can be
portrayed as shown in Fig. 12, expecting a vital breakthrough to
be achieved in the future in the clinic applications of MSN-based
nano-DDSs for the diagnosis and threatment of cancers.
Acknowledgements
We gratefully acknowledge nancial support from the National
Nature Science Foundation of China (Grant Nos. 50823007 and
50972154), the Science and Technology Commission of Shanghai
(Grant No. 10430712800), the CASKJCX Project (Grant No.
KJCX2-YW-210) and the Science Foundation for Youth Scholar
of State Key Laboratory of High Performance Ceramics and
Superne Microstructures (Grant No. SKL201001).
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