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Cite this: Chem. Soc. Rev., 2012, 41, 25902605
TUTORIAL REVIEW
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Mesoporous silica nanoparticles in biomedical applicationsw

Zongxi Li,a Jonathan C. Barnes,bc Aleksandr Bosoy,bc J. Fraser Stoddartbc and
Jerey I. Zink*a
Received 8th September 2011
DOI: 10.1039/c1cs15246g
This tutorial review provides an outlook on nanomaterials that are currently being used for
theranostic purposes, with a special focus on mesoporous silica nanoparticle (MSNP) based
materials. MSNPs with large surface area and pore volume can serve as ecient carriers for
various therapeutic agents. The functionalization of MSNPs with molecular, supramolecular or
polymer moieties, provides the material with great versatility while performing drug delivery
tasks, which makes the delivery process highly controllable. This emerging area at the interface of
chemistry and the life sciences oers a broad palette of opportunities for researchers with interests
ranging from solgel science, the fabrication of nanomaterials, supramolecular chemistry,
controllable drug delivery and targeted theranostics in biology and medicine.
California NanoSystems Institute and Department of Chemistry and

Biochemistry, University of California, 607 Charles E. Young
Drive East, Los Angeles, California 90095, USA.
E-mail: zink@chem.ucla.edu; Fax: +1(310)206-4638;
Tel: +1(310)825-1001
b
Department of Chemistry, Northwestern University,
2145 Sheridan Road, Evanston, Illinois 60208-3113, USA
c
NanoCentury KAIST Institute and Graduate School of EEWS
(WCU), Korea Advanced Institute of Science and Technology
(KAIST), 373-1 Guseong Dong, Yuseong Gu, Daejeon 305-701,
Republic of Korea
w Part of the nanomedicine themed issue.
Zongxi Li was born in Beijing,

China in 1988. She graduated
from Peking University, China
in 2007 with a BS in Chemistry.
She then came to the United
States and is currently pursuing
her PhD under the supervision
of Prof. Jerey I. Zink at
the University of California,
Los Angeles (UCLA). She is
a member of the California
Nanosystems Institute (CNSI)
and the UC Center for
Environmental Implications of
Nanotechnology (UC CEIN).
Zongxi Li
Her research focuses on the
functional mesoporous silica nanomaterials used for drug delivery
purposes, including the study of the physical chemical properties
of these materials, the design and synthesis of molecular
nanomachines for controllable release and the biomedical
applications of these materials as mechanized theranostic agents.
2590
Chem. Soc. Rev., 2012, 41, 25902605
1. Introduction
1.1. The magic bullet and chemistry in
theranostic nanomedicine
At the start of the 20th century, Dr Paul Ehrlich coined the
phrase magic bullet in reference to the ability of an antigen
to target side chains on the surface of cells with great
specicity.1 In the realm of cancer-based therapeutics, this
idea of a site-specic targeting moietywhether passively or
activelyis absolutely critical if an eective dose of a drug
Jonathan Barnes was born in

Louisville, Kentucky on January
13, 1982. He obtained his BS
and MS degrees in organic
chemistry in a dual-degree
program at the University of
Kentucky in 2006. After
spending a few years in the
biotech industry, he is
presently pursuing his PhD
in organic chemistry at
Northwestern University under
the supervision of Prof. J.
Fraser Stoddart investigating
the use of mechanically interJonathan C. Barnes
locked molecules (MIMs) on
the surface of mesoporous silica nanoparticles (MSNPs) for the
purposes of stimuli-responsive drug delivery. Other research
interests include the design, synthesis, and characterization of
radically-enhanced molecular recognition in MIMs. Currently, he
is a visiting pre-Doctoral Fellow at the Korea Advanced Institute of
Science and Technology (KAIST) in Daejeon, South Korea
investigating the application of MIMs in energy-storage devices.
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The Royal Society of Chemistry 2012
compound is to reach the pathological region of interest

without its damaging normal cells in surrounding healthy
tissue. Ideally, a magic bullet would consist of a nanometre-sized delivery platform that is capable of specically
targeting tumor tissue, avoiding premature fragmentation and
degradation,2 and facilitating the transfer of a more highly
concentrated drug payload across the cell membrane. This
integrated system could then undergo a controlled-release
upon activation by one or more possible stimuli, such as light,
temperature, pH, and so on. Additionally, this ideal nanomedicine would possess the meanseither extrinsically, or
Aleksandr Bosoy is a Russianborn graphic and product

designer who grew up in
Cleveland, Ohio and attended
The Ohio State University
where he obtained a Bachelor
of Science in Industrial
Design. Having worked as a
graphic artist for Ohio State,
Aleksandr was oered the
opportunity to join Professor
Stoddarts research group at
Northwestern University in
2010, and has since produced
numerous graphical abstracts,
Aleksandr Bosoy
publication
images,
and
notable journal covers that represent Stoddart group research
in a modern and exciting way. While initially unfamiliar with the
world of chemistry, he has learned a great deal from Professor
Stoddart and his fellow group members during his time with the
group, while simultaneously spreading modern design principles
throughout the scientic community with his various published
covers and graphics.
Sir Fraser Stoddart received all

(BSc, PhD, DSc) his degrees
from the University of
Edinburgh. His academic
career can be traced from
Queens University (Canada)
to the Universities of Sheeld
(197090) and Birmingham
(199097) with a sojourn at
the ICI Corporate Laboratory
from 1978 to 1981, and then
across the Pond to UCLA
in 1997. Since 2008, he has
held a Board of Trustees
Professorship in the DepartJ. Fraser Stoddart
ment of Chemistry at Northwestern University. His research has opened up a new materials
world of mechanically interlocked molecules and, in doing so,
has produced a blueprint for the subsequent growth of molecular
nanotechnology.
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intrinsicallyto track the progress of the accumulation in

the tumor tissue of, as well as the release of, the therapeutic
agent through the use of radionuclides3 or contrast agents.4
If these criteria are met, then the idea of a personalized
concurrent therapy can be realized through the use of
various types of multifunctional theranostic nanomedicines,
some of which are shown in Fig. 1. There are many dierent
types of theranostics that have been developed over the past
three decades. Of them, the most clinically vetted are multifunctional liposomes and polymeric micelles.
In this review, we will discuss briey the fundamentals of multifunctional liposomes, polymeric micelles and nanogels, and solid
nanoparticles such as gold and iron oxide-based therapeutics,
giving some recent examples of each. Also, the topic of small
interfering RNA (siRNA) gene silencing is mentioned briey,
since it serves as an alternative or additional cargo to the
traditional chemotherapeutics like doxorubicin and paclitaxel.
The main focus of this review, however, is to highlight the utility
of multi-functional mesoporous silica nanoparticles (MSNPs),
which are currently being studied in vivo, as highly robust and
tunable delivery platforms for controlled release of therapeutics.
It is important to note that chemistry is at the core of all of these
strategies starting with drugs constituted of compounds made up
of single molecules and continuing on to the targeting ligands and
defensive coatings on the surface of the particles that aid in
improving the biodistribution specicity and to prolonging the
nanomedicines lifetime in circulation. Furthermore, the introduction of supramolecular complexes and the incorporation of
mechanically interlocked molecules (MIMs) at the surface of
MSNPs allows nanoscale switches to gain precise control over
the release of cargo from these inorganicorganic mesostructured
materials. Regardless of the delivery platform chosen, the functions and properties of each scaold can be modulated, or tuned,
to adapt to the circumstances of the infection, or disease, through
Jerey I. Zink is a Distinguished

Professor of Chemistry in the
Department of Chemistry and
Biochemistry and a member of
the California Nanosystems
Institute at the University of
California
Los
Angeles
(UCLA). He received his
Bachelors of Science degree
at the University of Wisconsin
and his PhD degree at the
University of Illinois UrbanaChampaign under the supervision of Russell S. Drago.
After graduation he joined the
Jerey I. Zink
faculty at UCLA as an assistant
professor. His research interests include excited state properties of
metal-containing molecules (especially excited state distortions and
excited state mixed valence) studied by electronic and resonance
Raman spectroscopy and the time-dependent theory of spectroscopy, triboluminescence, solgel optical and biomaterials, and
nanostructured functional materials. In the latter area, he and his
research group are particularly interested in electron and energy
transfer and in molecular machines.
Chem. Soc. Rev., 2012, 41, 25902605
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Fig. 1 Various types of theranostic nanomedicines are depicted in

attack mode over a site of tumor growth in this cartoon representation. Conjugated targeting ligands are shown as circles or semi-circles.
Cargo, conjugated or housed internally, is shown as green spheres.
Purple spheres represent imbedded contrast agents. A multifunctional
(a) polymeric nanogel, (b) polymeric micelle, (c) gold nanoparticle,
(d) iron oxide nanoparticle, (e) siRNA ensconced in a liposome delivery
vector, and (f) a stimuli-responsive capped mesoporous silica nanoparticle are shown.
the use of integrated systems within the context of applicationsdriven chemistry.

1.2.
Liposomes and the EPR eect
Liposomes came into the forefront of science and technology

approximately 40 years ago as a result of the serendipitous
discovery by Bangham5 when he observed that their basic
construct consists (Fig. 1e) of a phospholipid bilayer wherein
the amphiphilic building blocks align in such a way that the
hydrophilic heads face the interior and exterior of the supramolecular superstructure, while the interior of the membrane
houses the hydrophobic tails. This dual nature gives a liposome
the ability to envelope hydrophilic drugs in its interior and
hydrophobic drugs in its membrane. Unilamellar liposomes
are approximately 100200 nm in diameter and, if unprotected
in the blood, will be cleared quickly from circulation by the
mononuclear phagocyte system (MPS).5 However, the addition
of biocompatible polymers, such as polyethylene glycol (PEG)
chains onto their surface, increases the blood circulation half-life
from 30 min to 80 h, as in the case for Doxil, the commercial
stealth liposome. These stealth liposomes have prolonged
circulation times as a result of steric interference at the lipsomal
surface by the PEG chains, which prevent the tagging of the
liposome with opsonin proteins that the macrophage recognizes
for removal of the foreign body. A longer circulation time,
and hence an increased bioavailability, is quite important because
most nanocarriers operate by targeting tumors passively and
taking advantage of their leaky vasculature and poor lymphatic
drainage that occurs because of rapid and highly active tumor
angiogenesis.6 This phenomenon is commonly referred to as
the enhanced permeability and retention (EPR) eect whereby
the endothelial cells of the blood vessel walls possess large
fenestrations, or gaps, between cells as compared to normal
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Chem. Soc. Rev., 2012, 41, 25902605
healthy tissue, which have tight junctions. The EPR eect allows
small nanocarriers to extravasate the endothelial barrier and
accumulate in the tumor tissues, while leaving the healthy
surrounding tissue largely untouched.6
Taking advantage of these chinks in the armor of tumor
tissues, many advances have been made since the introduction of
the rst PEGylated (Doxil) and non-PEGylated (Myocet)
doxorubicin-encapsulated liposomes.7 Most recently Lombardi
et al.8 have been able to administer dual-loadedwith doxorubicin
and gemcitabinePEGylated-liposomes in patients with advanced
hepatocellular carcinoma in phase II clinical trials, which showed
some complete (7%) and partial (17%) responses to the treatment. In another study, Kono and coworkers9 synthesized multifunctional PEGylated-liposomes that possessed the ability to
release doxorubicin at temperatures above 40 1C in tumor-bearing
mice using thermosensitive polyether chains. The tumor accumulation was monitored by installing a gadolinium-chelating
dendrimer on the surface of the liposome and monitoring the
T1-weighted MRI signal intensity. This approach showed signicant tumor suppression where the nal tumor volume after 8 days
was less than one-fourth of the tumor volume in the control
where only mild heat was applied in the absence of a liposome.
1.3.
Polymeric micelles
Although polymeric micelles have a similar supramolecular

superstructure to liposomes in so far as the amphiphilic polymer
building blocks self-assemble to form hydrophobic pockets
and hydrophilic surfaces, micelles (Fig. 1b) possess only one
hydrophilic outer surface and the entire interior of the soft
nanoparticle is hydrophobic.9 This dierence not only allows
micelles to be smaller (10100 nm) than liposomes, but it also
means that only hydrophobic drugs can be encapsulated, leaving
any hydrophilic cargo or contrast agents to be appended to the
surface. One of the advantages of micelles being smaller is
that they can penetrate the leaky vasculature of tumors more
easily than liposomes. One of the drawbacks of being small,
however, is that micelles loading capacities are lower than those
other nanocarriers, a situation which can lead to faster release
and less tumor-site specicity. In connection with liposomes,
micelles are capable of prolonged circulation times as a result of
the commonly used PEG polymer to form the outer corona, a
practice which helps slow the rate of clearance by inhibiting
opsonization.10
Over the past few decades, considerable progress has been
made towards increasing the functionality of micelles by
exploring dierent targeting ligands that can be appended to
the surface of the soft nanoparticle with the overall goal of
increasing specicity and uptake of drugs. Moreover, the use of
PEG-folic acid conjugates, peptides, and sugars enhance the
active targeting and binding of nanocarriers to cancer cells which
overexpress the corresponding receptors.11 A recent Phase I
clinical study involving PEGylated micelles, conducted by
Nishiya and coworkers12 demonstrated the ability of cisplatinincorporated polymeric micelles to attenuate the release of the
cisplatin, thereby signicantly lowering the toxicities normally
observed when free cisplatin is administered intravenously. In
an investigation conducted by Lavasanifar and Xiong,13 a
multifunctional polymeric micelle was shown to be capable of
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co-delivering mdr1 siRNA and doxorubicin to multidrug resistant

(MDR) cancer cells in mice. Their design took advantage of active
tumor-targeting peptide ligands e.g., RGD and TAT- as well as a
near IR uorescence imaging (NIRF) probe to identify tumor
accumulation and a pH-sensitive hydrazone linkage for release of
doxorubicin. The results of this investigation showed an increased
cellular uptake and doxorubicin-related toxicity in the usually drugresistant cancer cells because of silencing of the mdr1 gene which
encodes for the drug transporter protein P-glycoprotein (P-gp).
1.4.
Polymeric nanogels
Polymeric nanogels are another type of soft polymer-based

nanoparticle which has seen considerable progress over the
past decade (Fig. 1a). These networks are dierent from
micelles and liposomes in that they consist of hydrophilic
cross-linked or self-assembled polymer networks, which have
higher loading capacities (30% wt.), greater stability, and can
be triggered to release a payload through physical expansion
in response to environmental changes in pH, ionic strength, or
temperature. Depending on the constitution of the network,
and the degree of cross-linking, nanogels range in size from
20200 nm and upon environmentally-induced swelling are
comprised of 95% water. Payloads can be encapsulated in
nanogels through various means, such as (i) physical entrapment within the polymer network, (ii) covalent conjugation to
either the interior or exterior of the soft nanoparticle, or
through (iii) controlled self-assembly through electrostatic or
van der Waals interactions. The latter means of loading can
result in a collapse of the swollen network because of charge
neutralization of the polyelectrolytic polymer that leads to a
lower osmotic pressure of the counterions in solution. Regarding
the release of a payload, nanogels possess more options in
comparison to other nanocarriers, such as liposomes and micelles.
In addition to gradual diusion of the payload, or polymer
degradation, faster release can be initiated in response to (1)
changes in pH, which changes the degree of ionization and results
in swelling or loss of interaction with the payload, (2) an increase
in ionic strength whereby a competitive binding event occurs that
displaces the payload that was bound electrostatically, or (3)
changes in temperature which cause a physical transition in a
thermoresponsive network that leads to increased porosity and
release of the cargo.
Following in the footsteps of liposomes and micelles, targeted
delivery of nanogels to specic pathological tissue can be
achieved by direct conjugation of targeting groups, such as folic
acid, that aid in binding to cells that overexpress the corresponding receptor. Recently, Bronich, Kabanov, and coworkers14
demonstrated the ecacy of in vivo delivery of the anticancer drug cisplatin by means of a folate-functionlised diblock
copolymer comprised of poly(ethylene oxide)-b-poly(methacrylic
acid) (PEG-b-PMA)that was chemically cross-linked using 1,2ethylenediamine bridgesagainst cancer xenografts in mice. In
this investigation, the cisplatin was loaded before the conjugation
of the folate molecule in order to reduce the undesirable
coordination of the a-carboxylic acid groups of folatewhich
are integral in binding to the surface receptors of the cancer
cellsto the Pt metal in the drug. In comparison to the direct
administration of free cisplatin and a non-folate-functionalised
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nanogel that contained cisplatin, the pH-responsive folatenanogel-cisplatin nanomedicine showed greater tumor accumulation and suppression of tumor growth as well as no signs
of toxicity, as evidenced by the lack of changes in the histology of
the kidney, liver, and spleen, and by normal weight gain of the
mice in the study. Additionally, the mice that were injected with
free cisplatin experienced dramatic weight loss as a result of
toxicity and simultaneously experienced less inhibition of tumor
growth in comparison to either nanogel formulation.
1.5.
Nanocarriers as a delivery platform for siRNA
The process of post-transcriptional gene silencing using

sequence-specic small interfering RNA (siRNA) is a powerful
tool in the realm of therapeutics. Instead of delivering only an
anti-cancer drug such as doxorubicin or paclitaxel, which may be
ineective on account of the cancers ability to develop resistance,
it is possible to target and inhibit the production of a specic
protein13 that may be involved in tumor angiogenesis or drug
resistance. siRNA consists of approximately 2125 nucleotides,
which, once in the cell, can induce gene knockdown by binding
to a complementary sequence of messenger RNA (mRNA) in the
RNA-induced silencing complex (RISC), thereby causing the
degradation of the target mRNA and a reduction of the corresponding protein. The biggest hurdles to implementing this
process as an eective therapeutic strategy are (i) the premature
degradation of free siRNA while en route to the tumor tissue, (ii)
the site-specic targeting and uptake in a particular cancer cell,
and (iii) the triggered release into the cytosol after endocytosis
has occurred. A multifunctional nanocarrier, such as the siRNAencapsulated liposome (Fig. 1e) is one example of a possible
delivery vector. The following study will shed some light on the
current chemical strategies being employed to overcome the
aforementioned issues.
A clever example of a multifunctional nanocarrier which is
capable of delivering an assortment of chemotherapeutic drugs
as well as siRNA to cancer cells through receptor-mediated
endocytosis was demonstrated by Brinker and coworkers15
who developed a novel nanoporous particle-supported lipid
bilayer, which they termed a protocell. The composition of
the nanocarrier consists of a mesoporous silica nanoparticle
core (B100150 nm) which houses the multicomponent cargos,
and a supported lipid bilayer (SLB) on the exterior, to which
targeting and fusogenic peptides, as well as PEG spacers, are
appended covalently. The loading capacity far exceeds traditional liposomes that are similar in size and endocytosis occurs
through multivalent binding to the cell surface, followed by
pH-triggered release of the cargo by way of SLB degradation
and osmotic swelling/membrane destabilization of the endosome
because of protonation of the imidazole groups in the fusogenic
peptide. The addition of a nuclear localization sequence (NLS)
allowed siRNA cargo to be transported across the nuclear
membrane and localized in the nuclei. This example is one of
many multifunctional targeting-nanocarriers currently under
investigation.11
1.6.
Gold and iron oxide nanoparticles
Metallic solid and core-shell nanoparticles oer many advantages in the ght against cancer. For example, spherical gold
Chem. Soc. Rev., 2012, 41, 25902605
2593
nanoparticles (Au NPs)like that shown in Fig. 1cpossess16 an

intrinsic surface plasmonic absorption at B520 nm at a size of
10 nm. By changing the size of the particle, or its length to form
nanorods, or by employing a silica-gold core-shell construct, the
absorption can be increased to the near IR (NIR) region. This
shift is advantageous for the purposes of photothermal therapy
because of the ability to penetrate tissue more deeply at longer
wavelengths, thereby heating tumor-localized Au NPs and killing
cancer tissues, while leaving the surrounding healthy tissues
unharmed. In the case of iron oxide nanoparticles (IONPs),
typically comprised of Fe3O4 (Fig. 1d), their superparamagnetic
core allows the theranostic nanomedicine to be tracked using
MRI on account of their negative enhancement eect on
T2-weighted sequences.17 Chemical modication on the surface
of each type of nanoparticle is similar in that protective ligands,
such as PEG,16 are tethered to the nanoparticles surfaces to
prolong the bioavailability of the nanocarrier. Other modications
include appending targeting ligands, such as folic acid, and drug
conjugated polymers18 to the surface to enhance biodistribution
and uptake as well as stimuli-responsive release of a drug17,18 or
oligonucleotide,19 respectively. The biggest dierence in the
chemistry of surface modication between the two types of
nanoparticles discussed here is that typically thiol linkers are used
to tether ligands to the surface of Au NPs as a result of the stable
Au-thiol bonds that are formed, while IONPs are typically coated
with silica to promote biocompatibility as well as to enable
chemical functionalization.16
1.7.
Mechanized mesoporous silica nanoparticles
Mechanized MSNPs (i.e. MSNPs functionalized with nanomachines) oer a wide range of functionalities and are highly
robust and modular as they can be chemically modied to t
the circumstances of almost any desired setting (Fig. 1f).
Possessing a high surface area-to-volume ratio allows for
increased surface functionalization, while still maintaining
great porosity, which allows the inorganic platform to house
appreciable amounts of cargo without destabilization of the
silica framework.11,2023 The remainder of this review will
focus on the synthesis and properties of MSNPs, as well as on
the supramolecular chemistry behind the controlled release of
cargo using nanoscale switches with the ultimate goal of demonstrating the utility of this platform in theranostic nanomedicine.
For example, the Stober process has been widely applied for the
preparation of monodispersed silica nanoparticles between
50 and 2000 nm size, using the ammonia-catalyzed hydrolysis
of tetraethylorthosilicate (TEOS) in a water-alcohol solution.25
Using micelles formed by a cationic surfactant as the
templating agent, the silicate source can be directed to
condense around the micellar template into ordered silica
structures. Mesoporous silica materials were rst synthesized
by two dierent research groups for catalytic applications.26,27
Although the materials made by the original procedures are
mainly mesoporous silica sheets with disorganized morphologies, there have been continuous eorts in making these
materials into smaller size and homogeneous morphology in
order to increase their biocompatibiliy. Grun et al. rst
prepared submicromter-scaled MCM-41 particles using a
modied Stober synthesis.28 Later on, MCM-41 silica particles
of 100 nm were obtained by using a dilute surfactant
solution.29 Mesoporous silica nanoparticles below 50 nm have
also been obtained using a double surfactant system or dialysis
process.30
In a typical synthesis of the 100 nm MCM-41 type (Fig. 2)
mesoporous silica nanoparticles, the silica source, tetraethylorthosilicate (TEOS), is added into a heated basic (pH 11)
aqueous solution of the templating surfactant, cetyltrimethylammonium bromide (CTAB). 100 nm diameter nanoparticles
(Fig. 2a) are formed through base-catalyzed solgel condensation
around the hexagonally packed micelle structures (Fig. 2b).20,23
After aging, the resulting nanoparticles are reuxed in acidic
alcohol to decrease the interactions between the surfactant and
the silica frame, and remove the templating agent from the
mesopores. X-ray diraction and electron microscopy conrm
that the hexagonal arrays of pores remain intact after the
surfactant removal process. The solvent extracted particles are
spherical in shape, roughly 100 nm in diameter, and contain
2D-hexagonally arranged pores 23 nm in diameter.
Metal or metal oxide nanocrystals around 10 nm in diameter
can be incorporated (Fig. 2c,d) into the MSNP during the particle
2. Properties of the mesoporous silica

nanoparticles (MSNPs)
2.1.
Synthesis of the MSNPs
A base-catalyzed solgel process has been employed to produce

silica nanoparticles with sizes suitable for biomedical applications. The solgel process utilizes the organosilane precursors
(TMOS, TEOS, etc.), which, by means of hydrolysis and
condensation reactions,
Hydrolysis:
OH + Si(OR)4 - Si(OR)3OH + RO
(1)
SiO + Si(OH)4 - SiOSi + OH
(2)
Condensation:
lead to the formation of a new phase (sol). The small colloidal

particles within the sol then condense into the gel phase.24
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Chem. Soc. Rev., 2012, 41, 25902605
Fig. 2 (a) SEM image of MCM-41 mesoporous silica nanoparticles;

(b)(d) TEM image of (b) MCM-41; (c) mixed iron-oxide and silver
encapsulated MSNPs; (d) Zn-doped iron oxide encapsulated MSNPs.
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synthesis to provide additional functionalities. To synthesize the

metal-core MSNPs, a suspension of the surfactant-coated metal
nanocrystals in organic solvent is added to a solution of the
templating surfactant (such as CTAB). The metal nanocrystals need to have a surfactant coating in order to stabilize
them in organic solvents and to facilitate their incorporation
into the hydrophobic interior of the templating micelles.
The silicate source (such as TEOS) is then introduced into the
mixture to initiate the silica condensation. This type of procedure
has been used to embed gold, silver and iron oxide (including
doped iron oxide) into the MSNPs.20,31 The metal/metal oxide
cores can provide a variety of additional functionalities to the
MSNPs, such as antimicrobial activity through dissolved metal
ions, plasmonic eects or magnetic properties including MRI
capabilities.
2.2.
Functionalisation of MSNPs and cargo loading
The ease of introducing various organic functional groups,

either through covalent bonding or electrostatic interactions,
provides high level of versatility and many mechanized
features to the mesoporous silica materials. The covalent
attachment of functional groups usually involves introducing
organic structures in the form of silanes, which can be attached
using co-condensation or post-synthetic grafting methods.32
The co-condensation method allows the hydrolysis of the
functional silanes while the particles are forming, therefore
the guest molecules are incorporated into the resulting silica
frameworks. In contrast, post-synthetic grafting introduces
the functional groups mainly to the exposed silica surface
after the MSNPs are formed, which can be performed either
before or after the surfactant removal.32 Besides covalent
attachment, functional moieties can also be introduced to
the MSNPs through electrostatic interactions. This usually
makes use of the negative charges from the free SiO groups
on the particles surface. For example, cationic polymers (such
as polyethyleneimine) can be electrostatically adsorbed onto
the silica nanoparticles to provide nucleic acid binding
properties.3335
Another crucial property that makes mesoporous silica
materials promising for drug delivery applications is their
ability to encapsulate dierent types of cargo molecules within
their pore channels. This is important because the encapsulation may protect many therapeutic agents from enzymatic
degradation. The particles are usually loaded by soaking them
in a drug solution. The drug molecules are incorporated by the
particles through adsorption. The interactions between the cargo
molecules and the particle usually include hydrogen bonding
and electrostatic interactions. The uptake capacities of the
MSNPs are correlated with the specic surface areas of the
materials.36 The loading and release eciencies of the particles
are also aected by the electrostatic interactions between the
cargo molecules and the silica surface.3739 When combined with
the functional modications on the MSNPs, the payloads are
only allowed to be released in a controllable fashion at the
targeted diseased tissues, with no premature release during their
circulation within the bloodstream. This can signicantly reduce
the adverse side eects of the drug and increases the overall
therapeutic ecacy.
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3. How to achieve controllable cargo delivery

3.1.
Control of the pore openings
Based on the above described properties of mesoporous silica

nanoparticles, the obvious way to use them as a delivery
system is to load the drugs by adsorbing them onto the
particles and then release them by dissolution inside the target
media. In this case, there is no control over the pore openings
and the resulting system performs sustained release. The rate
of the release would highly depend on the solubility of the drug
in the surrounding solvent. If the drug molecules are highly
water soluble, they would be released as soon as the particles
are suspended in an aqueous biological media, which would
not be advantageous over a solution dose of the same drug. If
the drug molecules are hydrophobic, the particles do provide
some control over the release of the drug. Once hydrophobic
drugs are loaded into the MSNPs, the release of the drugs in
an aqueous media is minimal. Only when the particles come
into contact with a hydrophobic environment, for instance
upon addition of a surfactant, the hydrophobic cargo is then
released. In vitro studies have shown that the interactions
between particles and the cell membrane phospholipids during
the particle endocytosis can cause the release of the encapsulated
hydrophobic drugs.40
MSNPs-based controlled release systems have been developed
(Fig. 3) by applying mechanical controls over the pore openings.
First, polymers that are either adsorbed or covalently bonded to
the surface of the MSNPs have served (Fig. 3b) as a mechanized
controlled release system.41 Under their close condition, the
polymer chains tightly wrap around the particle surface, each
blocking multiple pore openings. Then the polymers are induced
by certain stimuli to undergo swelling or coiling so that the pore
openings are re-exposed and cargo is released through the
unblocked pores. A second method (Fig. 3a) to achieve
controllable release is to form chemical bonds directly over the
pore openings that can later be cleaved upon stimulation.42 A
third way (Fig. 3c) to mechanically block the pores is to attach
bulky groups such as Au or CdS nanocrystals over the pore
openings.11 These bulky groups serve as gatekeepers for the
encapsulated cargo. Removal of the bulky blocking groups via
chemical methods initiates cargo release.
When bulky groups are assembled by non-covalent interactions, they become nanomachines, such as nanovalves and
snap-top machines.20 These nanomachines usually contain
a static stalk covalently attached to the particles surface and
a bulky cyclic moving component which encircles the stalk via
non-covalent interactions. The nanomachines are designed to
undergo large amplitude motions upon stimuli. The blocking and
un-blocking of the pore openings is achieved (Fig. 3d,e) by such
motions. It is worth noting that in such designs the attachment of
nanomachines may not cover all the pore openings on the
particle surface perfectly. Particles such as MCM-41 have pore
channels that are not inter-connected, which allows the washing
procedures to remove cargo from any pores that have faulty
machines. Yet another way to achieve controlled release is by
derivatizing the pore interiors of the MSNPs. One such example
is the nanoimpeller machine (Fig. 3f) that takes advantage of
the rapid cis-trans isomerization of the azobenzene groups upon
Chem. Soc. Rev., 2012, 41, 25902605
2595
motions of the gatekeeper groups, which in turn leads to the

un-blocking of the pore openings.
4. Nanoswitches, nanovalves, and nanomachines
Fig. 3 Pore opening control motifs designed for mesoporous silica

nanoparticle-based stimuli responsive delivery systems, showing pore
blocking and unblocking by (a) the formation and breaking of
covalent bonds between molecules (e.g. coumarin) attached within
the pore channels; (b) the shrinking and swelling of polymer chains
coated on the particle surface; (c) attachment and removal of bulky
groups (e.g. Au, CdS nanocrystals) over the pore openings;
(d) threading and dethreading of a cyclic torus molecule in this snaptop design consisting of a [2]rotaxane with a bulky stopper; (e) shuttling
of a cyclic molecule between two recognizing sites along a molecular stalk
towards and away from the pore opening in a supramolecular nanovalve design; (f) azobenzene molecules tethered within the pore channels
hinder the diusion of the encapsulated cargo molecules, whereas the
wagging motion resulting from the cis-trans photoisomerization of the
azobenzene propels the cargo molecules out of the mesopores.
light activation.43 The details of nanomachine operation are

discussed in section 4.
3.2.
4.1.
Nanoimpellers
In the search for dierent mechanisms of activation, the

phenomenon of azobenzene photoisomerization was
utilized43,48 to expel luminescent molecules from the nanopores of MSNPs by tethering azobenzene molecules to the
interior walls of the nanopores (Fig. 4). By exciting these
azobenzene molecules at wavelength around their isosbestic
point (400450 nm), both their trans-to-cis and cis-to-trans
Triggers for cargo release
These above mentioned mechanized controlled release systems

could have a variety of internal and external power supplies.
The rst type of stimulus is provided by chemicals. Systems
can be designed to be responsive to external chemical additions,
or to the internal chemical changes within organs and cells, such
as pH change and cytoplasmic enzymes.11,20,44 Since the addition
of chemical stimulants is not always feasible for in vitro and
in vivo experiments, the biological applications of chemical
responsive controlled release systems are limited by the types of
chemical changes existing in the cells and organisms. The second
type of stimuli is electrical, using redox reactions to trigger the
release. This can be accomplished by external means, like directly
applying electrodes, or by internal means, e.g. using the internal
reducing conditions inside cells.45,46 Light has been applied as
another external power supply for controlled release systems.42,43
The in vivo application of light stimuli is limited by the tissue
penetration ability of the stimulating light. External heating can
be used to trigger the release of the mechanized MSNPs. Heat
can also be made an internal stimulus when it is generated by
magnetic nanocrystals in an oscillating magnetic eld.31 All of
the above-described power supplies trigger the operation of the
mechanized MSNPs either by causing structural changes to
polymer coatings, or by causing molecular or supramolecular
2596
In order to deliver concentrated payloads of drugs to cancerous

tissues, a robust drug delivery platform that possesses the ability to
control the release of the drug precisely upon activation by an
external stimulus is required. In the case of MSNPs, an appreciable
amount of cargo can be stored, but without the proper machinery
or capping mechanism, the delivery of the cargo is limited by
premature diusional loss of the payload. The challenge of capping
MSNPs pores can be solved through the use of non-covalent
chemistry and binding of caps through hydrogen bonding,
donoracceptor, and ion-dipole interactions. More specically,
the ability of a nanoparticle to release its cargo in a controlled
manner can be achieved by using supramolecular inclusion
complexes known as [2]pseudorotaxanes, by using mechanically
interlocked molecules47 (MIMs)such bistable [2]rotaxanesas
molecular switches/valves that can operate as on/o states, and
by using molecular machines that are capable of doing workas
in the case of azobenzene nanoimpellers.43
Chem. Soc. Rev., 2012, 41, 25902605
Fig. 4 Light-activated cis/trans isomerization of azobenzenes tethered

to the wall of the nanopores in MSNPs. (a) The particles are loaded
with luminescent cargo. (b) Photo-induced wagging of the azobenzene
molecule expels the cargo.
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isomerization can be activated, driving the wagging motions of

the untethered portion of the azobenzene molecules. This
sweeping motion physically expels the cargo from the conned
nanopores of the nanoparticles, thereby acting as sort of a
nanoimpeller. The general load-and-release mechanism
begins with loading the cargo by immersing the azobenzenefunctionalized nanoparticles in 1 mM solutions of the luminescent probese.g. Coumarin 540A and Rhodamine
6Gfor several hours, followed by washing the nanoparticles
thoroughly to ensure no dye is left on the surface of the
nanoparticles. Next, the nanoparticles are irradiated with
B400450 nm light and the uorescence intensity of the cargo
molecules is monitored. Very little leakage occurs before
irradiation, because of the crowded network of anchored
azobenzene molecules that block the nanopores, preventing
outward diusion of the cargo. On irradiation, however, the
nanoparticles show a controlled and steady release of the
probes with time. A control experiment was performed wherein the nanoparticles were irradiated at 647 nm. No release of
cargo was observed because azobenzene does not absorb at
this particular wavelength.
4.2.
Supramolecular nanovalves
Supramolecular nanovalves were rst designed in hope of

controlling the cargo release from the MSNPs using large
amplitude supramolecular motions. The concept of a supramolecular nanovalve includes using an immobilized stalk
molecule covalently attached to the silica matrix and a mobile
cyclic molecule as the capping agent. The bulky cyclic molecule (e.g. cyclodextrins, cucurbit[6]uril, cyclobis(paraquatp-phenylene), crown ethers) that encircles the stalk binds to
the recognition site on the stalk via non-covalent interactions.
This whole assembly serves as the gatekeeper for the pore
openings. More importantly, the binding between the cyclic
cap and the stalk is reversible, as the binding constant between
the two can be weakened under certain conditions, causing
large amplitude sliding motions of the cap, which in turn leads
to the unblocking of the pore openings. Therefore, this
supramolecular assembly can be made into to a nanovalve
machine operated by a variety of stimuli (such as chemical,
electrical, light, heat etc.).
The simplest supramolecular nanovalve involves a molecular
stalk with only one binding site for the cap. In the closed state
of the nanovalve, the cyclic capping molecule binds to the stalk,
whereas the dissociation and removal of the cap causes the valve
to open. Historically the earliest established supramolecular
nanovalve49 took advantage of the redox- and photo-responsive
threading and dethreading between a p-electron rich stalk, 1,5-bis2-(2-(2-hydroxyethoxy)ethoxy)ethoxynaphthalene (BHEEEN)
tethered to the surface of a silica matrixand a p-electron poor
ring cyclobis(paraquat-p-phenylene) (CBPQT4+) that encircles
BHEEEN to form a [2]pseudorotaxane, where the pseudo
nomenclature refers to the lack of a stopper on the untethered
portion of the stalk. The donoracceptor interaction, as well as
the CH O interactions between the PEG chain of BHEEEN
and the electropositive hydrogen atoms a to the nitrogen in
the CBPQT4+ ring are disrupted by the reduction of the
CBPQT4+ ring to the bisradical dication CBPQT2 +, causing it
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to decomplex from the BHEEEN stalk, presumably as a result

of the electronic repulsion between the now more electron rich
CBPQT2 + and electron-rich BHEEEN. Controlled release of
the Ir(ppy)3 cargo was achieved on both MCM-41 particles and
silica thin lms assembled with the above described nanovalves,
triggered either by adding a chemical reducing agent,
NaCNBH3, or by the photochemical reaction upon irradiating
the nanoparticles in MeCN at 365 nm. However, this earliest
system has the drawback of requiring organic media and lacks
biocompatibility. Later on, similar designs using the single-site
binding between the stalk and a/b-cyclodextrin rings were
designed, using acid as the trigger for release in aqueous media.
The in vitro application of one such system will be discussed in
section 5.2.2.
One of the most elaborate nanovalve systems was designed
to be fully reversible, which involves the cyclic cap shuttling
between two recognition sites along the stalk, and a bulky
stopper group at the end of the stalk, preventing the cap from
sliding o.50 A switchable bistable [2]rotaxane with two
electron-rich recognition units in the dumbbell was used, with
the electron-poor CBPQT4+ ring as the shuttling compound
that caps and uncaps the nanopores in a controlled fashion.
The two recognition units in the rod section of the dumbbell
component are tetrathiofulvalene (TTF) and 1,5-dioxynaphthalene (DNP). Although both units are electron-rich,
Fig. 5 A load-and-release mechanism using a reversible bistable

[2]rotaxane nanovalve appended to the surface of a mesoporous silica
nanoparticle (MSNP). (a) The tetracationic cyclophane CBPQT4+
resides on the TTF unit in the ground state. (b) The particle is loaded
with a luminescent cargo or a drug, by way of diusion. (c) The cargo
is trapped when the TTF unit is oxidized to TTF2+ using the chemical
oxidant Fe(ClO4)3 and the CBPQT4+ ring shuttles to the DNP unit.
(d) The cargo is released upon reduction of the TTF2+ unit to TTF
with the mild reductant ascorbic acid and the shuttling of CBPQT
back to the TTF unit.
Chem. Soc. Rev., 2012, 41, 25902605
2597
the CBPQT4+ ring prefers to reside (Fig. 5a) on the TTF unit
rather than the DNP unit by an order of magnitude. The design
of this integrated system was such that the TTF unit is positioned
farther away from the opening of the nanopores than the DNP
unit. The mesoporous nanoparticles could be loaded (Fig. 5b)
with a luminescent compoundIr(ppy)3 or rhodamine B
(RhB)while the bistable [2]rotaxane was in its ground state.
Once the nanoparticle is loaded, the cargo is trapped (Fig. 5c) in
the pores by the addition of the oxidant Fe(ClO4)3, which
oxidizes the TTF unit to TTF2+ dication, forcing the movement
of the CBPQT4+ ring to the DNP unit as a result of the
Coulombic repulsion between the TTF2+ dication and the
tetracationic CBPQT4+ ring, thereby capping the pore. Finally,
the cargo is released (Fig. 5d) on the addition of the mild
reductant, ascorbic acid, which reduces the TTF2+ dication back
to the neutral TTF unit, initiating the movement of the ring back
to the TTF unit and allowing the cargo to diuse out of the
nanoparticle, as monitored by the increase in emission intensity
associated with the cargo. This process was demonstrated to be
reversible by taking a batch of nanoparticles that had already
undergone one load-and-release cycle and reloading them with
RhB and repeating the steps a, b, c, and d in Fig. 5. A similar
increase in uorescence intensity was observed upon activation of
the nanovalve with ascorbic acid. A detailed review of many
other supramolecular nanovalves powered by redox, pH, light,
etc. has been published.20
4.3.
Snap-top machine
The operating principle of the snap-top machine is based on

a cyclic capping molecule encircling a stalk immobilized on the
silica matrix, similar to the nanovalves, except that the cyclic
cap has minimal interaction with the stalk. The cap molecules
are held in place, instead, by a bulky group blocking the distal
end of the stalk. This stopper group on the top can snap
o of the stalk upon stimulation, allowing the dethreading of

the cyclic cap, thus unblocking the pore openings. The rst
snap-top machine, reported by our group, involved the use
of enzymatic cleavage of ester bonds between the stopper and
the rest of the stalk.51 In this example, MSNPs were loaded
with RhB dye and the polyethylene glycol stalks were then
threaded with a-CD rings which block the nanopores of the
nanoparticle, preventing the premature release of RhB molecules.
Next, the [2]rotaxane formation was completed by stoppering the
[2]pseudorotaxane with an ester-linked adamantyl group using
standard copper-catalysed 1,3-dipolar cycloaddition chemistry.
Upon treatment with Porcine Liver Esterase, the ester linkages
were cleaved, releasing the adamantyl stoppers and allowing the
cargo to diuse out from the nanopores, as evidenced by
luminescence spectroscopy.
Expanding on this design motif, our group has demonstrated (Fig. 6a) a redox-responsive snap-top machine.45 In
this case, the disulde bonds between the stopper and the
rest of the stalk can be cleaved o by adding reducing agents
(Fig. 6b). The system uses either CB[6] or a-CD as its capping
molecule. This type of modular, integrated system could
potentially prove to be useful in a biological setting, specically by taking advantage of the glutathione concentrations
found inside cells, which would eect cleavage of the disulde
bond. It is worth noting that having the cleavable group
outside the cyclic cap molecule is important in the design of
the snap-top machines, ensuring that these groups are
accessible to active bio-macromolecules (enzymes).
4.4.
Nanopistons
Another protocol52 that uses the recognition motif of b-CD

rings and pH-responsive stalks was advanced in 2010. It
involves a reversal of roles where the b-CD rings are tethered
to the surfaces of the nanoparticles and the stalks are held in
Fig. 6 (a) A loaded snap-top nanocarrier comprised of a [2]rotaxane on the surface of a MSNP. The particle is loaded with luminescent cargo and
the polyethylene glycol stalk is threaded with an a-CD followed by stoppering using a disulde-adamantyl derivative. (b) Upon activation with
2-mercaptoethanol, the disulde bond is cleaved and leads to the release of the a-CD cap and the cargo.
2598
Chem. Soc. Rev., 2012, 41, 25902605
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place by means of supramolecular interactions. This motif was

likened to nanopistons since the b-CD rings are bound
covalently to the surface of the nanoparticles while the stalks
(pistons) are free to move as soon as the molecular recognition
is decreased by lowering the pH. This allows the release of
cargo molecules with sizes smaller than the cavity of the b-CD
rings (e.g. 2,6-naphthalenedisulfonic acid dianions). The
nanopiston idea was extended based on the fact that if the
tethered b-CD rings are not bound permanently to the surfaces
of the nanoparticles, they could be cleaved o the surface of the
MSNPs, allowing larger cargo to be released. In this case, the
b-CD rings were attached to the particle surface by imine bonds,
so that they can be hydrolysed upon acidication (pH r 6). The
controlled release of the encapsulated RhB molecules was monitored. With this technology it should be possible to achieve size
selectivity for the drugs being delivered, as well as trigger the
release of two drugs using dierent stimuli.
5. Applications of mesoporous silica nanoparticles

in nanomedicine
5.1.
Applications of the non-mechanized MSNPs
5.1.1. Cellular uptake and biocompatibility of MSNPs.

Before MSNPs can be eectively applied as drug delivery
systems, their cellular uptake and cytotoxicity properties have
to be investigated. The cellular uptake of the MSNPs can be
studied by attaching uorescent dye molecules to the nanoparticles, enabling the visualization of the MSNPs by uorescence and confocol microscopy. Fluorescent dye molecules,
such as uorescein isothiocyanate (FITC) and Rhodamine B
isothiocyanate (RITC), can be bonded to the surface of the
particles by co-condensation.40 Cellular uptake of the MSNPs
and their good biocompatibility was conrmed with both
healthy and cancer cell lines.40,53,54 No cytotoxicity is observed
up to 100 mg mL 1 for non-modied 100 nm MSNPs,31,35,5456
which is well above the eective particle concentrations
required for most therapeutic treatments. Several research
groups have demonstrated that cell uptake and cellular toxicity of the MSNPs depend on the particles size, shape, surface
charge and functional groups.11,23
Cell staining experiments in conjunction with the uorescently labeled MSNPs allow the study of the cellular uptake
mechanisms and the particle location inside the cells. Small
MSNPs (o 200300 nm) are normally taken up by cells via
endocytotic pathways, which could end up taking various
routes such as the clathrin-dependent, caveolin-dependent,
receptor-mediated or the clathrin and caveolin independent
mechanism, depending on the shape, size and surface functionalization of the nanoparticles. The endocytic mechanisms for
MSNPs have been summarized in recent reviews.11,23 The
endocytotic process consists of the particle interacting with
the cell surface, cell membrane invagination and pinching o
(Fig. 7). The nanoparticles upon uptake are located inside the
endocytic vescicles which fuse with the early endosomes and
then to the sorting endosomes. The remaining fraction of the
early endosomes then matures into late endosomes before
fusing with the acidic lysosomes. The MSNPs end up inside
these acidic (pH B4.5) organelles in cells. It has also been
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Fig. 7 Illustration of the receptor-mediated endocytosis of multifunctional mesoporous silica nanoparticles and intracellular drug
release. (a) Cell surface receptors recognizing the targeting groups
on the MSNP surface; (b) cell surface invagination and pinching
during particle intake; (c) internalized MSNP within an early endosome; (d) intracellular drug release from the MSNPs.
shown that nanoparticles with surface groups that can be

protonated facilitate the proton sponge eect, which leads
to the endosomal escape of the uptaken particles.33 This
enables the membrane impermeable cargoes such as hydrophilic drugs, DNA and siRNA molecules to be released from
the membrane-bounded endosomes and travel to their
eective sites.
5.1.2. In vitro delivery of hydrophobic anti-cancer drugs.
One practical application of the MSNPs takes advantage of
the large pore capacity of the mesoporous silica materials to
improve the delivery of various hydrophobic anti-cancer drugs
within the bloodstream. This is of great importance because
the eectiveness of such drugs may be hampered by their low
solubility in water. In other cases, the intravenous administration of such drugs requires a media containing large
amount of organic solvents, such as DMSO, higher than the
amount that is potentially safe for the recipient.
Mesoporous silica nanoparticles have been proven to be a
great candidate for solving the above mentioned problems.
First of all, the abundance of silanol groups on the surface of
MSNPs makes them hydrophilic and thus dispersible in aqueous
environments. Secondly, unlike many non-porous materials,
including hard (e.g. gold, iron oxide and cadmium sulde) and
soft nanoparticles (e.g. dendrimers, proteins and polymer beads),
mesoporous materials have very large internal surface areas and
pore capacities for the incorporation of cargo molecules. Once
incorporated in the pores, the cargo molecules do not escape into
water by dissolving in an aqueous environment. This reduces the
Chem. Soc. Rev., 2012, 41, 25902605
2599
leakiness of the delivery system, allowing more drugs to reach

their therapeutic target. Last but not least, the silica particles can
be easily functionalized with various groups to gain more control
over the holding and releasing of the cargo molecules. The
in vitro and in vivo applications of non-mechanized MSNPs for
delivering hydrophobic anti-cancer drugs will be reviewed in this
section. The in vitro drug delivery systems using mechanized
MSNPs are discribed in section 5.2.
The properties of MSNPs as carriers for the hydrophobic
drug Ibuprofen have been extensively studied.36,38,57 The
interactions between the cargo Ibuprofen molecules and the
silica nanoparticles are mainly attributed to the interactions
between the carboxylic acid group on Ibuprofen and the
silanol groups in the silica matrix. The loading capacity and
the release rate of Ibuprofen in these mesoporous silica
materials are aected by the surface area, pore diameter and
surface functionalization of these materials.5860
The in vitro applications of non-gated MSNPs to deliver
hydrophobic anti-cancer drugs, namely camptothecin (CPT)
and paclitaxel (Taxol), to human cancer cells have been
studied.40,61 A suspension of the CPT-loaded MSNPs in PBS
was added to a human pancreatic cancer cell culture PANC-1.
The uptake of the MSNPs by the cancer cells was conrmed by
the uorescence from the FITC labeled particles within the
cells. Cell-growth inhibition assays were carried out for three
pancreatic cancer-cell lines (PANC-1, Capan-1 ad AsPc-1), a
colon cancer-cell line (SW 480), and a stomach cancer-cell line
(MKN 45). As shown in Fig. 8, the cytotoxic ecacy of the
CPT-loaded MSNPs on these various cancer cell lines is
similar to that of the DMSO dissolved CPT, and is much
higher than the cytotoxicity of the PBS suspension of CPT.
The mechanism of cell death was investigated by double
staining the cells with propidium iodide and Hoechst 33342.
The cells incubated with the CPT-loaded MSNPs and with
CPT in DMSO showed nuclear fragmentation and chromatin
condensation (Fig. 8), which indicates that the CPT-loaded
MSNPs induce apoptotic cell death. By contrast, the cells
treated with 10% DMSO were stained red by propidium
iodide, indicating necrosis of those cells. The apoptotic pathway induced by the CPT-loaded MSNPs was also conrmed
by a DNA fragmentation assay and Western-blot.
5.1.3. Cell targeting increases the cellular uptake of
MSNPs. One very important factor to consider while designing
in vivo drug delivery vehicles is the targeting of diseased organs or
tissues. This is especially true in cancer therapies, where
un-targeted drug delivery systems not only require much higher
amounts of the drug to achieve the same therapeutic eect, but
may also cause adverse side eects to healthy tissues. Most
strategies used for cell targeting depend on chemically modifying
the MSNPs with moieties that selectively bind cell surface
receptors to trigger receptor-mediated endocytosis. Such moieties
include small nutrient molecules such as mannose or folic acid,
bio-oligomers like peptides, and bio-macromolecules such as
proteins and antibodies. All of the above mentioned designs take
advantage of the overexpression of cellular receptors for these
moieties due to the special metabolic and nutritional demands of
certain types of cancer cells. The functionalization of the MSNPs
with folate groups, which are specic for various human cancer
2600
Chem. Soc. Rev., 2012, 41, 25902605
Fig. 8 Apoptosis induced by CPT-loaded uorescent MSNPs.

PANC-1 cells were incubated for 24 h with (A) CPT-loaded MSNPs,
(B) CPT in DMSO, (C) MSNPs, or (D) 10% DMSO and were then
stained with propidium iodide/Hoechst 33342. (E) Cell-growth inhibition
assay. m: nonloaded MSNPs in PBS; : CPT in PBS; J: CPT in
DMSO;E: CPT-loaded MSNPs in PBS. The concentration of MSNOs is
shown on top of each gure, while the concentration of CPT in DMSO,
in PBS, or loaded in MSNPs, is shown under each gure.
cell lines that overexpress the a-folate receptors, was reported by

several research groups.21,62,63 MSNPs functionalized with a
monoclonal antibody have been used for selective targeting of
breast cancer cells.64
A recent study demonstrated the use of transferrin and cyclicRGD peptides as targeting moieties on MSNPs to achieve the
selectivity between normal and cancer cells, and between primary
and metastatic cancer cells.65 Transferrin-modied MSNPs
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display enhancement in particle uptake by Panc-1 pancreatic

cancer cells, which overexpress the transferrin receptors on their
plasma membrane. No enhancement of the particle uptake by
normal HFF cells was observed because these cells do not
overexpress the transferrin receptors. Plasmid transfection of
the transferrin receptor into the normal HFF cells results in an
increase in particle endocytosis, thus conrming the receptormediated endocytic pathway. Similarly, the selectivity between
the primary cancer cells (BT-549) and metastatic cancer cells
(MDA-MB 435) is achieved by covalently modifying the MSNPs
with a synthetic cyclic-RGD peptide (arginine-glycine-asparic
acid) that interacts with the anb3 integrin receptors overexpressed by the metastatic cancer cells (shown in Fig. 9a). Such
targeting strategies for MSNPs are being tested in vivo and
preliminary results have shown an improvement of the tumor
suppression potency obtained by surface modifying MSNPs with
folic acid.66 The details of this study will be further discussed in
Section 3.1.2.
5.1.4. In vitro siRNA delivery by MSNPs. MSNPs controlled
by polymers can be used for delivering nucleic acids, such as
DNAs and siRNA for gene therapy purposes. The advantage of
using MSNP-based gene delivery systems is that they allow both
the binding of nucleic acid molecules on the outer surface of the
particles and the incorporation of small therapeutic agents inside
the pore channels, enabling the dual delivery of nucleic acids
and drugs.
One way of using MSNPs as a DNA delivery vehicle involves
the surface grafting of second generation (G2) PAMAM
dendrimers.53 A plasmid DNA (pEGFPC1) that codes for an
enhanced green uorescence protein forms a complex with the
G2-PAMAM dendrimers on the MSNPs, which prevents the
Fig. 9 (a) Fluorescence microscopy images of particles taken up by a

metastatic cancer cell line MDA-MB 435, showing the enhancement of
cellular uptake for the RGD-MSNPs (lower) compared to the particles
without any targeting group (upper). Green/yellow uorescence
indicates the FITC-labeled MSNPs. (b) Fluorescence microscropy
images showing GFP knockdown by the siRNA transferred by PEI
(10 kD)-coated MSNPs in stable transfected GFP-HEPA cells. (c)
Fluorescence microscopy images showing the synergistic increase in
cellular and nuclear Dox levels in KB-V1 cells achieved by the
simultaneous delivery of Dox and Pgp siRNA by PEI (10 kD)-coated
MSNPs. Red uorescence indicates the locations of the Dox drug.
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enzymatic cleavage of the DNA and facilitates its entry into

the cells.
Polyethyleneimine (PEI) coated MSNPs have also been used
to deliver siRNA and DNA constructs.33,34 In these studies,
PEI binds to the surface of the MSNPs via electrostatic
interactions. The cellular uptake of the PEI-coated MSNPs
is considerably enhanced compared to unmodied MSNPs.
The positively charged PEI binds siRNA or DNA electrostatically, enhances the particle uptake into cells, and facilitates the endosomal escape of the nucleotide being delivered.
High molecular weight PEI increases the toxicity of the
PEI-coated MSNPs for cells, but also causes a higher siRNA
and DNA delivery ecacy. 10 kD are chosen to be the optimal
PEI length as a result of balancing the gene delivery ecacy
and toxicity of PEI. Fig. 9b shows the confocol microscopy
results of GFP knockdown in GFP-HEPA cells using PEI
(10 kD)-coated MSNPs. It also demonstrates that the PEI
coating on the particle surface does not aect the particles
ability to encapsulate and release drug molecules, providing a
dual delivery system.
In a dual delivery design using the PEI-coated MSNPs, an
additive or synergistic eect in cell killing was demonstrated.
PEI-coated MSNPs that deliver a siRNA to overcome the
drug resistance of a cancer cell line and simultaneously release
encapsulated anti-cancer drugs achieved a high cell killing
eciency.35 One mechanism for multiple drug resistance
(MDR) in cancer cells is the overexpression of drug eux
transporters such as P-glycoprotein (Pgp) protein, which
contributes to the formation of a drug eux pump that
prevents the intracellular buildup of chemotherapeutic agents.
When the PEI-coated MSNPs were used, the co-delivery of a
chemotherapeutic agent doxorubicin (Dox) and the Pgp siRNA
which shuts down the Pgp expression to a drug-resistant
cancer cell line (KB-V1 cells) resulted in a signicantly higher
intracellular and intranuclear drug concentration, and thus
improved cell killing (Fig. 9c).
5.1.5. In vivo delivery of anti-cancer drugs for tumor shrinking.
Multiple studies of the in vivo toxicity, biodistribution and
clearance of the silica nanoparticles in animal models have been
reported.56,67 100 nm MSNPs of hollow and MCM-41 types
have shown very good long-term (> 1 month) biocompatibility
in mice.56 The in vivo toxicity of MSNP is related to the injection
method. The particles size and surface functional groups and
charges have a large impact on the biodistribution and pharmacokinetics.68,69 For instance, positively charged MSNPs have a
much faster clearance rate than negatively charged ones. PEG
coated MSNPs show signicantly increased in vivo circulation
time, due to the ability of PEG to prevent the phagocytes from
removing the MSNPs. Therefore less PEG-coated MSNPs are
trapped in the liver and spleen. The in vivo degradation and
urinary excretion of MSNPs have also been observed in
several cases.
MSNPs deliver anticancer drugs into human xenografts in
mice and suppress the tumor growth.56 Nude mice with
established xenografts of human breast cancer cell MCF-7
received intraperitoneal injections when the tumor diameter
reached 3 mm. CPT was loaded into the mesopores of the
MSNPs. The incorporation of CPT into the mesopores of
Chem. Soc. Rev., 2012, 41, 25902605
2601
Fig. 10 Representative images of mice from dierent treatment

groups demonstrating the in vivo antitumor eects of the CPT-loaded
MSNPs. Nude mice with xenografts of human beast cancer cell MCF7 were treated with either saline solution as a control, unloaded
MSNPs, free CPT drug, CPT-loaded MSNPs, and CPT loaded
folate-MSNPs twice a week until the end of the experiment (68 days).
Red arrows indicate the location of the subcutaneous tumors.
MSNPs enabled the resulting drug to be suspended in aqueous

solution. The tumor shrinking eciency of the CPT-loaded
MSNPs was compared with that of the free CPT in DMSO.
After a month of treatment, the group of mice receiving the drugloaded MSNPs demonstrated a signicantly faster decline of the
tumor size, and no obvious subcutaneous tumors were visible at
the end of the treatment (Fig. 10).
In another study, the engineered MSNPs with PEI-PEG
copolymer coating were used for delivering Dox on a KB-31
(a Dox-sensitive HeLa squamous carcinoma cell line) xenografted tumor model.70 The drug loaded MSNPs were compared to free Dox or empty particles in terms of their ability to
induce apoptosis and inhibit tumor growth. When comparing
the eect on tumor size, doxorubicin loaded MSNPs showed a
signicantly higher rate of tumor shrinkage than the free drug.
The PEI-PEG copolymer coating serves to improve the
biodistribution of the MSNPs, by preventing the capture of
the nanoparticles by the mononuclear phagocytic cells in the
reticuloendothelial system (RES) of the liver and spleen. These
results are encouraging from the perspective of moving the
MSNPs platform into clinical trials.
5.2.
Applications of the mechanized MSNPs
5.2.1. In vitro drug delivery with nanoimpellors. The operation

of the nanoimpellers in water was described in section 4.1. To test
the ability of the nanoimpellers to release drug molecules inside
cancer cells upon light activation, the azobenzene derivatized
particles were loaded with CPT, and in vitro studies were carried
out on two human cancer cell lines (PANC-1 and SW480).55 The
cells were incubated with the particles modied with nanoimpellers
in the dark. When the cells were irradiated at 413 nm (0.1 W cm 2),
CPT induced cell apoptosis was observed. Cell death increased with
increasing activation time (Fig. 11ad). Excitation of PI-loaded
2602
Chem. Soc. Rev., 2012, 41, 25902605
Fig. 11 Light-triggered in vitro delivery of the anticancer drug camptothecin (CPT) inside PANC-1 cancer cells to induce apoptosis. CPTloaded nanoimpeller-controlled MSNPs were incubated with cancer cells
and illuminated for 1 (a), 3 (b), 5 (c), or 10 min (d). (e): In vitro
cytotoxicity assay. 5000 PANC-1 or SW480 cancer cells were incubated
with dierent concentrations of CPT-loaded or unloaded particles. After
incubation for 72 h following the light excitation, the numbers of
surviving cells were counted and the viability is shown as the percentage
of the viable cell number in treated wells compared to untreated wells.
LAMS refers to cells treated with 10 or 100 mg mL 1 nanoimpellercontrolled MSNPs. CPT refers to whether the CPT was loaded (+) or
absent ( ) in the LAMS. Light refers to whether the cells were exposed to
blue light (wavelength 413 nm) for 0, 1, 3, 5, or 10 min, followed by
incubation for 72 h.
particles at 0.01, 0.1 and 0.2 W cm 2 was tested, with higher

activation intensity causing increased staining.
5.2.2. In vitro drug delivery with pH-sensitive nanovalves.
The design features of the MSNPs functionalized with the
pH-sensitive supramolecular nanovalves and their operation
This journal is
under abiotic conditions were introduced in section 4.2. By

ne-tuning the pKa of the stalks on the nanovalves, the
mechanized MSNPs can be adjusted to be activated by
endosomal acidication. In this section, a MSNP gated by a
pH-sensitive nanovalve that operated autonomously inside
living cells will be discussed.37
The pH-sensitive supramolecular nanovalves with the
N-methylbenzimidazole stalks have the ability to bind the
b-CD strongly at pH 7.4 (Fig. 12a), trapping dye or drug
molecules inside the mesopores of the MSNPs. Upon entering
an acidifying endosomal compartment at pH o 6, the stalks
become protonated and b-CD cap dissociates, allowing the
cargo molecules to be released from the MSNPs. The nanovalve functionalized MSNPs were loaded with Hoechst 33342
to cause nuclear staining in human dierentiated myeloid cells
(THP-1), or loaded with anti-cancer drug doxorubicin to
induce cell apoptosis in squamous carcinoma (KB-31) cells.
The cellular uptake of the particles by the THP-1 and KB-31
cell lines was conrmed by confocal microscopy using FITC
labeled MSNPs. The lysosomal pH values of the THP-1 and
KB-31 cells are about 4.6 and 5.2 respectively, well below the
operating pH of the acid-responsive nanovalve. When
the Hoechst-loaded, FITC-labeled MSNPs are taken up by the
THP-1 cells, the blue uorescence from Hoechst is co-localized
with the MSNPs in the perinuclear regions, indicating that the
Fig. 12 In vitro delivery of anticancer drug Doxorubicin by

the MSNPs functionalized with the acid-responsive supramolecular
nanovalves. (a) Scheme of the attachment of the acid-responsive
nanovalves to the surface of the MSNPs. (b) Confocal images
of KB-31 cells incubated with MSNP containing doxorubicin drug
for the indicated times. (c) Doxorubicin-loaded MSNPs, tted
with pH nanovalves, inhibited KB-31 viability eciently as determined by a MTS assay. Doxorubicin-induced cytotoxicity was
partially inhibited by NH4Cl treatment, which prevents the lysosomal
acidication.
This journal is
Hoechst is well retained in the MSNPs during the endocytosis.

As monitored by confocol microscopy, the Hoechst dyes start
to be released after 6 h of incubation and stain the nuclei of
THP-1. Similarly, when testing the Dox release in KB-31, the
red uorescence of Dox rst co-localize with the MSNPs in the
perinuclear region, and then slowly release to the nucleus,
followed by Dox induced cell apoptosis (Fig. 12). This demonstrates the in vitro operation of the pH-sensitive nanovalves,
and the successful autonomous delivery of anti-cancer drug
intracellularly using the mechanized MSNPs.
5.2.3. In vitro drug delivery activated by oscillating

magnetic eld. External control of nanovalves by a noninvasive tissue-penetrating stimulus is a major challenge.
An attractive method utilizes an oscillating magnetic eld.
Local internal heating of the iron oxide core of MSNP was
used to activate the nanovalves on the particle surface. The
in vitro delivery of Dox using this material has been achieved
in a breast cancer cell line MDA-MB-231.31 The Doxloaded iron oxide nanocrystalcore MSNPs were assembled
with a nanovalve that remains closed at physiological
temperature and opens when heated. When the loaded particles were taken up by the cells, minimal drug release was
observed, indicating that the drug molecules are kept within
the particles during the endocytosis. Local heating opens the
nanovalves only when an oscillating eld is applied and
allows the encapsulated Dox to be released (Fig. 13). These
experiments open the door to the highly desired type of drug
delivery; non-invasive, and with spatially selective external
control of the time of administration and the dose of anticancer drugs.
Fig. 13 Scheme of the dye-loaded magnetic-core MSNPs functionalized with nanovalves that respond to internal heating caused by an
oscillating magnetic eld.
Chem. Soc. Rev., 2012, 41, 25902605
2603
Conclusions
Mesoporous silica nanoparticles with large surface area and pore
volume can be functionalized into versatile theranostic agents. In
this tutorial review, we have focused on the recent development
of controllable drug delivery systems based on mesoporous silica
nanoparticles. The synthesis, functionalization and cargo loading
methods for the nanoparticles were described. The common ways
of controlling the pore openings include attaching molecular,
supramolecular and polymer moieties to the silica matrix. The
release of the encapsulated cargo from a mechanized silica
nanoparticle can be triggered by a variety of internal and external
stimuli. These materials are promising candidates for designing
targetable, on-command types of delivery platforms. Both
in vitro and in vivo delivery of therapeutic agents by using these
materials have been achieved. The mechanized materials and
methods of activating release of therapeutic agents described in
this review are just the tip of the iceberg. Many other types of
porous materials, methods of controlling molecules to and from
the pores, and stimuli for activating the systems can be imagined.
It is the authors hope that the ideas described in this article
stimulate new discoveries in this area that may be benecial to
human health.
Acknowledgements
(1) The research was supported by the US Public Health Service
Grant RO1 CA133697 and by the National Center for Nano
Technology Research at KACST in Saudi Arabiawe thank
Dr Turki S. Al-Saud and Dr Mohamed B. Al-Fageeh for their
support of this research.
(2) We acknowledge support from the World Class University
(WCU) Program (R-31-2008-000-10055-0) in Korea.
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