The application of mesoporous silica nanoparticle family in cancer [624026]

Accepted Manuscript

Title: The application of mesoporous silica nanoparticle family in cancer
theranostics

Author: Yin Feng, Nishtha Panwar, Danny Jian Hang Tng, Swee Chuan Tjin,
Kuan Wang, Ken-Tye Yong

PII: S0010-8545(16)30108-4
DOI: http://dx.doi.org/doi: 10.1016/j.ccr.2016.04.019
Reference: CCR 112248

To appear in: Coordination Chemistry Reviews

Received date: 14-3-2016
Revised date: 29-4-2016
Accepted date: 30-4-2016

Please cite this article as: Yin Feng, Nishtha Panwar, Danny Jian Hang Tng, Swee Chuan Tjin,
Kuan Wang, Ken-Tye Yong , The application of mesoporous silica nanoparticle family in cancer
theranostics, Coordination Chemistry Reviews (2016 ), http://dx.doi.org/doi:
10.1016/j.ccr.2016.04.019.

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The Application of Mesoporous Silica Nanoparticle Family in Cancer Theranostics

Yin Fenga,c#, Nishtha Panwara#, Danny Jian Hang Tnga, Swee Chuan Tjina, Kuan Wangb,d, and
Ken-Tye Yonga

a School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore,
639798
bNanomedicine Program and Institute of Biological Chemistry, Academia Sinica, Nankang,
Taipei 115, Taiwan
cLaboratory of Chemical Genomics, School of Chemical Biology & Biotechnology, Peking
University Shenzhen Graduate School, Shenzhen 518055, China
dCollege of Biomedical Engineering, Taipei Medical University, Taiepi 110, Taiwan
#These authors contributed equally to this work

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Contents
1. Introduction
2. Structure and Properties of Mesoporous Silica Nanoparticles
2.1. M41S type MSNs family
2.2. SBA-15
2.3. ORMOSIL nanoparticles
2.4. Hollow type MSNs
2.4.1. Hard-template MSNs
2.4.2. Soft-template MSNs
2.4.3. Self-Assembled MSNs
3. Silica Nanoparticles in Cancer Therapy
3.1. Early Cancer Detection and Diagnosis
3.1.1. Silica Nanoparticles as Imaging Contrast Agents
3.1.2. Mesoporous Nano Silica Chips
3.1.3. Fluorescent Silica Nanoparticles for Optical Imaging
3.2. MSNs-based drug delivery systems for cancer therapy
3.2.1. Passive delivery system
3.2.2. Active delivery system
3.2.3. Controlled-release drug delivery systems
3.2.3.1. pH-triggered drug release system
3.2.3.2. Temperature-triggered drug release system
3.2.3.3. Redox potential-triggered drug release system
3.2.3.4. Enzyme-triggered drug release system
3.2.3.5. Light-triggered drug release system
3.2.3.6. Other stimuli-triggered drug release system
3.3. Co-delivery of gene and drugs assisted by MSNs-based drug delivery system for combatting
cancer multidrug resistance
4. Multifunctional delivery platform based on MSNs
5. Conclusion and Future perspectives
References

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Review Article: Highlights
 The properties and structures of different types of MSNs are discussed.
 Various configurations of MSNs-based systems for cancer diagnosis and therapy are
highlighted.
 Role of MSNs -based drug delivery systems for combatting the ca ncer multidrug
resistance is outlined.
 A comprehensive timeline of the evolution of MSNs for biological applications is
presented.

Abstract
Cancer is among the most serious diseases characterized by uncontrollable cell growth and
spread of abnormal cells. Cancerous cells form tumors that negatively impact the functions of the
body, inducing serious malfunctioning leading to fatalities in most cases. Up to now, the effective
diagnosis and treatments of cancer have remained a big challenge. Nanotechnology is an
emerging field encompassing science, engineering and medicine, which has attracted great
attention for cancer therapy in recent years. Among the numerous nanomaterials, Mesoporous
Silica Nanomaterials (MSNs) have attract ed great attention and are being considered as
promising biomedical materials for the development of cancer therapies because of their size
tunability, surface functionality, optically transparent properties , low toxicity and high drug
loading e
fficiency . In this review, we first outline the properties and structure of different
configurations of MSNs and their subsequent application in the field of cancer theranostics.
Thereafter, the potential of MSNs as multifunctional delivery platforms for therapeutic agents
and their significance in next generation cancer therapy is discussed.

Keywords: mesoporous silica nanoparticles, MCM-41, SBA-15, ORMOSIL, drug delivery,
stimuli
1. Introduction
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Cancer is characterized by abnormal and uncontrollable cell growth. With malignant phenotypic
behavior such as metastasis and invasion, cancer adversely affects different parts of the body and
is considered among the most chronic diseases all over the world [1, 2]. In recent years,
worldwide incidence and mortality rates of cancer have been rising sharply. Based on the 2004
World Health Organization (WHO) statistics, cancer stands as the primary factor of death in
developed countries. In developing countries, it is the leading cause of fatality second only to
cardiovascular disease. The number of worldwide deaths due to cancer is increasing at an
alarming rate, from 10 million (13% of all deaths) in 2000 to 12 million in 2020 [3, 4]. Based on
the different stages of cancer, patient age and health status, cancer treatments need to be
customized and combined with several other therapies. Contemporary cancer treatment
modalities such as surgery, chemotherapy, radiotherapy and photodynamic therapy (PDT) are
able to prolong patient’s lives to some extent. Although physical methods like surgery are
effective for patients with non-metastatic cancer, other systemic therapies are required in cases
where the cancer has entered metastasis and spread throughout the body. Radiotherapy is the
common
alternative for surgery which utilizes high-energy rays to cause damage to cancer cells,
followed by apoptosis. Nevertheless, radiotherapy can pose serious side-effects including the risk
of secondary malignancy in the irradiated area and severe damage of normal and healthy tissues.
Another method, chemotherapy, involves the use of one or more chemotherapeutic agents to
destroy cancer cells. Most chemotherapeutic agents lack cell specificity, resulting in damage of
normal cells with irreversible systemic side-effects. Besides the non-specificity, the development
of multi-drug resistance (MDR) by cancer cells is a critical limitation for the low therapeutic
index of chemotherapy [5]. More selective methods such as PDT, which is relatively new, use
photosensitizing agents to kill cancer cells upon light activation . Photosensitizing agents are
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effective only if they have been activated by a specific type of light precisely directed at the
cancer cells, thus making PDT more selective and less toxic than chemotherapy [6]. The limiting
factor of this method however, is the low efficiency of light penetration for deeply located
tumors within the body and the development of MDR towards the PDT agents in the treated
cancer cells [7]. As a consequence, tumor recurrence, metastasis, resistance to chemotherapy and
side effects caused by radiotherapy and chemotherapy remain the major bottlenecks in cancer
therapy. Well -designed diagnostic, therapeutic and prognostic stra tegies are urgently needed for
the effective treatment of cancer.
Nanomedicine is an emerging field, integrating nanotechnology and biomedicine, which offers
promising therapeutic potential for various diseases including cardiovascular disease, diabetes,
tissue engineering and cancer theranostics. The rapid development of new nanomaterials has
provided great opportunities to overcome chemotherapeutic side-effects while promising the
diagnosis of cancer at preliminary stage. The first Food and Drug Administration (FDA)-
approved nano-drug, Doxil, is a typical example, where Doxorubicin (DOX) is encapsulated in
liposomes for prolonged circulation time and bioavailability of DOX, and diminished side-
effects to heart muscles and other normal tissues [8]. In 2011, the first silica-based tumor
diagnostic nanoparticles- Cornell dots (C-dots) were approved by FDA for stage I human clinical
trial. C-dots are dye-entrapped silica nanoparticles with ultra-small size (<10 nm), which can be
utilized as diagnostic tools to assist surgeons in identifying tumors [9]. Subsequently,
tremendous efforts have been devoted towards functionalized nanoparticles for cancer
theranostics. Christopher Loo et al. have pioneered this field through the engineering of immune-
targeted nanoshells to detect and destroy breast carcinoma cells, by demonstrating bioimaging
coupled with cancer therapy [10]. Another group has utilized anti-epidermal growth factor
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receptor ( EGFR )-gold nanorods ( AuNRs ) to treat malignant oral epithelial cells, developing
AuNRs as reagents for cancer cell diagnostics and selective photothermal therapy [11]. Similarly,
MSNs bear enormous potential as functionalized nanomaterials. The earliest examples include
the synthesis of folic acid (FA) modified-MSNs for targeted delivery of the hydrophobic
antic
ancer drug camptothecin (CPT) [12, 13]. These studies have shown significant in vitro and
in vivo tumor suppression effects by mesoporous silica nanoplexes, and achieved imaging and
cancer therapy concurrently [12, 14]. With further progress in nanomaterial research,
nanomedicine is envisaged to hold a strong stake in cancer diagnosis and therapy.
Silicon dioxide (SiO 2), also known as silica, is among the most abundant naturally available
minerals on earth and a crucial component for human health, especially for skin, bones, hair and
nails. Classified by the FDA as “Generally Recognized As safe” (GRAS ), SiO 2 is widely used in
food additives, cosmetics and pharmacy. Due to the biosafety and easy synthesis of silica, silica-
based nanomaterials occupy a prominent status in biomedical research. In recent years, MSNs
have attracted increasing attention for optical imaging, magnetic resonance imaging ( MRI ), PDT
and drug delivery [15-20]. Since the proposal of MCM-41 type MSNs as nanocarriers for
delivering therapeutics in 2001 [21], a variety of MSNs such as MCM48 [22], SBA-15 [23, 24],
TUD-1 [25], HMM-33 [24] and FSM-16 [26] have been engineered and applied as drug delivery
systems extensively. As drug delivery vehicles, MSNs offer several advantages: (i) large internal
surface area and pore volume enabling MSNs an effective drug delivery vehicle for a range of
therapeutic agents, (ii) tunable particle size (50 -300 nm) permitting facile endocytosis across
living
animal and plant cells with minimal cytotoxic effects, (iii) a tunable porous structure with
controllable narrow pore size distribution, allowing the loading of different therapeutic agents
with highly precise drug release kinetics, (iv) a highly hydrophobic and rigid matrix structure
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facilitating MSNs to remain uniformly dispersed in water and resist changes due to pH, heat,
mechanical stress and hydrolysis-induced breakdown, (v) the internal and external surface can be
selectively functionalized, enabling MSNs to offer targeted delivery and controlled release, (vi) a
uniquely porous structure preventing premature release of its loaded components even when its
pores are not fully capped [ 19, 20, 27, 28 , 29]. MSNs exhibit incredible advantages over other
drug delivery nanocarriers and provide promising opportunities for simultaneous cancer
diagnosis and therapy.
In this review, we focus on the current advances of MSNs as drug delivery systems for cancer
theranostics. The structure and properties of different types of MSNs such as nanoparticulate
MSNs, hollow/rattle MSNs and organically modified silica (ORMOSIL) nanoparticles are first
discussed. Next, the recent research and progress of MSNs based -cancer therapies is highlighted.
The applications of MSNs in cancer detection, diagnosis and drug delivery are summarized in
this content. Furthermore, we pay special attention on discussing these MSNs -based drug
delivery platforms in cancer therapies, which highlight th eir clinical applications for cancer
theranostics, especially in the early diagnosis of pancreatic cancer and other malignant tumors.
2. Structure and Properties of Mesoporous Silica Nanoparticles
MSNs are defined as a type of nanomaterial between the microporous and macroporous
materials, with the pore diameter spanning from 2 nm to 50 nm [ 30]. MSNs can be classified as:
M41S type MSNs family, organically modified silica (ORMOSIL) nanoparticles and hollow type
MSNs (F
igure 1). In 1992, MSNs were first synthesized through sol –gel technique and the pore
diameter was adjustable from 2 to 10 nm [31]. This kind of MSNs , also known as Mobile
Crystalline Material -41 (MCM -41), has since been extensively use d in biomedical research. In
2001, the application of MCM -41 nanoparticles in drug delivery was first described by Vallet –
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Regi and co-workers, opening up a novel platform for the use of MSNs in biomedical
engineering [21]. Thereafter, a range of MSNs have been proposed, developed and utilized for
drug delivery. Presently, the most commonly studied MSN structures for drug delivery
applications are based on MCM-41 and/or Santa Barbara Amorphous-15 (SBA-15).
2.1.M41S type MSNs family
The discovery of a family of nano-structured MSNs called M41S , laid the foundation for the
application of MSNs in drug delivery systems [32, 33]. MCM-41 is the basic model of
mesoporous silica nanocarriers, with a hexagonal porous structure and is most widely studied
material in the M41S family and has wide applications in biomedicine (Figure 2A and 3A) . With
large surface area, high thermal stability and narrow pore size distribution, MCM-41 is a
substantial improvement over other mesoporous nano materials [34, 35]. Today, synthesis of
MCM-41 is highly controllable, and the Stöber method (commonly called the sol-gel technique)
is employed to synthesize monodispersed silica nanoparticles [36, 37]. The physical structures of
these nanoparticles are highly controllable, with different structures being synthesized using
different solution compositions, concentrations [38] and temperature [39]. Variations in the
synthesis parameters alter the material structure at different levels, such as material size (Figure
3D) [40], surface area (up to 700 m2/g) and pore size (1.6 nm to 10 nm) (Figure 3B) [28, 34].
These structural tunabilities supplement M41S family with many beneficial properties for
biomedical applications. Modification s in the shape of these MCM-41 nanoparticles
considerably affect the drug delivery characteristics [21]. For instance, spherical and tubular
shaped MCM-41 were commonly used as drug delivery systems due to their high surface area
and narrow pore diameters (Figure 3C) [41]. Another property of MCM-41 nanoparticle is their
ability to conjugate with metal ions and form complexes such as Al-MCM-41 [42], Mn-MCM-41
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[43], and Fe-MCM41 [44]. These metal ion-MCM-41 complexes enhance the p erformance of
MCM-41 silica nanoparticles for MRI-based imaging capabilities in addition to its ability to act
as efficient drug delivery systems [16, 17, 45].
When arranged into three dimensional structures to form the cubic MCM-48 and laminar MCM-
50, M41S MSNs exhibit even more unique properties which can be exploited for cancer
treatment. MCM-48 features a three-dimensional pore system with a cubic structure, modeled as
a g
yroid minimal surface [46] (Figure 2B) . MCM-48 possesses a higher surface area (upto 1600
m2/g), more than double of MCM-41. Additionally, it has an interwoven and branched pore
structure providing it enhanced thermal stability [47]. The unique penetrating bicontinuous
channel in MCM-48 allows rapid molecular transport and promotes eas y molecular accessibility,
which are vital in some drug delivery systems [48]. On the other hand, lamellar phase- MCM-50
consists of silicate or porous aluminosilicate layers separated by surfactant layers (Figure 2C) .
This phase is obtained by sheets or bilayers of surfactant molecules with hydrophilic head groups
pointing towards the silicate at the interface [49]. MCM-50 nanoparticles are used as catalysts
and sorbents in the fabrication processes of other mesoporous solids such as silica galleries,
which have diverse biomedical applications [50].

2.2.SBA-15
Santa
Barbara Amorphous (SBA-15) is another type of MSNs which is extensively explored as a
drug delivery system. These MSNs are synthesized using polymer templates such as amphiphilic
triblock copolymers, which have mesostructural ordering properties [51]. The structure of SBA-
15 mainly depends on the pH-levels durin g the synthesis process [52]. Likewise MCM-41, the
temperature during synthesis varies its physical characteristics such as its pore size [53]. SBA-15
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nanoparticles share many similar characteristics with MCM-41 such as a well-ordered hexagonal
mesoporous structure and one-dimensional parallel channels [54, 55]. However, compared to
MCM-41, it has several structural differences. The thicker pore walls (3.1 – 6.4 nm) of SBA-15
provide a higher hydrothermal and mechanical stability. The wide pore sizes (5 nm to 30 nm) ,
large particle diameter (>200 nm) and high internal surface area (400-900 m2/g) make SBA-15 a
promising material for numerous applications, such as adsorption and separation [56, 57],
advanced optics [58, 59] and catalysis [60]. In addition, SBA-15 has a rougher surface
morphology with larger pore diameters of 5- 30 nm, compared to MCM-41 which has relatively
smoother pore wall surfaces and smaller pore diameters of 2- 10 nm [55]. Modified or
functionalized- SBA-15 nanoparticles are used as efficient catalysts [61], as tools for adsorption
and separation [62] and for bulk drug delivery applications [63]. Recent research has
concentrated on the synthesis of smaller SBA-15 type MSNs with particle size below 200 nm,
which can further improve its drug delivery capabilities [64].
2.3.ORMOSIL nanoparticles
As discussed above, ordered mesoporous silica nanoparticles (M41S family, SBA-15, etc.)
encompass a large scope for applications in various fields. A major reason for this is the
interesting set of properties they offer, such as tunable diameter, pore size, large surface area,
ordered mesoporous structure and good biocompatibility. However, their large particle size
(>200 nm), structural and colloidal instabil ities still need to be addressed for wider applications.
ORMOSIL nanoparticles (Figure 4) have emerged as an exciting hybrid materials having
attracted great interest in biochemical field in the past decade. With the combination of tetraethyl
orthosilicate (TEOS)/ vinyltriethoxysilane (VTES) as inorganic silica precursors, ( 3-aminopropyl)
triethoxysilane (APTES)/ mercaptopropyltrimethoxysilane (MPTMS)/ diethylenetriamine
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(DETA) as organic silica precursors and weak alkali solutions as catalysts, ORMOSIL
nanoparticles can be easily obtained as an oil- in-water microemulsion at room temperature.
Without the reliance on surfactants and corrosive solvents, the synthetic formation process of
ORMOSIL is simple, feasible and time-saving. ORMOSIL nanoparticles bear various
advantages for biomedical applications : (i) they can be incorporated with a host of surface
functionalities (hydroxyl/amino/thiol/carboxyl groups depending on the organic precursors),
supplementing them with additional functions such as fluorescence and bio-targeting capabilities
[65]; (ii) the presence of hydrophobic and hydrophilic groups on the precursors help their self-
assembly both as normal and reverse micelles to satisfy the polarity of cargos [66]; (iii) their
particle size (from 10 to 100 nm) can be easily tailored by varying the concentrations of
surfactant and precursors for different applications [67, 68]; (iv) biodegradation of ORMOSIL
nanoparticles can be skillfully realized by the decomposition of their Si-C bond; (v) their inert
and transparent properties make them suitable for doping with diverse fluorophores for optical
imaging; (vi) their robustness and storage stability enhance the shelf-life and convenience for
long-term research.
2.4.Hollow type MSNs
The large porosity of MCM-41 and SBA-15 type MSNs have demonstrated excellent reagent
loading capabilities. Optimization has resulted in MSNs with higher loading efficiency for a
broader spectrum of biomedical applications. One of the obvious improvement is the emergence
of hollow type MSNs, which possess a hollow core-mesoporous shell structure. These hollow
type MSNs have been extensively explored in many research fields, including catalysis [69],
acoustic [70], absorption [71] and bioimaging [72]. Due to their super-high drug loading capacity
(> 1 g drug per 1 g silica) and ease of surface functionalization, hollow type MSNs are now
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being considered as an ideal drug delivery system for chemotherapy, to overcome the
chemotherapeutic failure by inefficient intracellular accumulation [69, 73, 74]. Hollow type
MSNs are further classified according to the fabrication methods used in their synthesis: hard-
template MSNs, soft-template MSNs and self-template MSNs.
2.4.1. Hard-template MSNs
Hard-template MSNs are the most commonly utilized MSNs due to their simple and effective
fabrication methods. These MSNs have structures with tunable thickness, mesoporosity, and
functionality. To fabricate these structures, non-silica nanomaterials such as polymer beads,
metal or metal oxide nanoparticles and semiconductor nanoparticles are usually used as
templates for assembly of the silica-shell structure. Major steps involved in the hard-template
method are: core template synthesis, surface activation of the polymer latexes, silification to
form shell layer and selective removal of templates (Figure 5) [75]. The structural properties of
the synthesized MSNs are primarily governed by the templates used. Excellent size tunability has
been
achieved using polymer core templates [76]. A unique characteristic of hollow type MSNs
is that the direction of the pores can be precisely controlled, and mesopores perpendicular to the
core surface can be fabricated using dual-latex surfactant templates [77]. The direction of the
porosity greatly influences the MSNs release characteristics, providing a promising advantage
over solid core MSNs [78]. Shell thickness, which determines the diffusion length of loaded
reagents, can be controlled using precursors such as a basic ethanol/water mixture that affect the
core properties [79]. Furthermore, the use of stimuli-responsive agents ( or capping agents) can
block the pore entrances of drug-encapsulated MSNs, regulating drug release while concurrently
avoiding aggregation or fusion. To date, a series of capping agents such as metal nanoparticles
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[80], polymers [81] and proteins [82] have been produced for the controlled release of MSNs-
based drug delivery systems, which promote further applications of MSNs in biomedicine.
A significant advantage of the hollow type MSNs is their ability to leverage upon other
functional nanoparticles. Using other nanoparticles as templates for MSN shell fabrication, the
strengths of both the nanostructures can be combined for diverse applications. Additionally,
using polymer cores based on other functional nanoparticles solves many of the limitations faced
in traditional synthesis routes, such as the aggregation or fusion of hollow type MSNs, non-
uniform hollow type MSNs with rough shell texture, and a mixture of solid MSNs in the final
product [83]. Metal, metal-oxide and semiconductor nanoparticles form the core templates for
the fabrication of these hollow type MSNs. Mesoporous silica -coated gold nanorods (Au@SiO 2)
is a classic example for cancer theranostics, possessing a high drug payload and photothermal
effect [84]. With mesoporous silica as shells, the silica -shelled single quantum dot (QD) micelles
is used as fluorescent cell tracers without cytotoxicity [85]. Using functional nanopart icles as
templates generate uniform pore channels in hollow, yolk -shell structured mesoporous spheres
that exhibit high catalytic activity [86]. Although hard -template MSNs have been extensively
utilized in the synthesis of hollow type MSNs, the major weak ness of hard -template MSNs is the
tedious multistep and time -consuming procedures in fabrication. These factors call for further
refinement in synthesis procedures for the widespread u se of hard -template MSNs .
2.4.2. Soft-template MSNs
Soft- template MSNs are fabricated using soft materials such as “micelles”, microemulsion
droplets or vesicular structures formed by surfactants as soft templates. A variety of amphiphilic
surfactants have been studied and utilized to build the structure of hollow type MSNs. Compared
with hard-template MSNs, soft-template MSNs involve simpler fabrication processes and are
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facile under mild reaction conditions [87]. Another attractive feature of soft-template MSNs is
their ability to encapsulate other reagents during its synthesis process [88]. This potentially
allows soft-template MSNs to have a wide range of multifunctional capabilities, making them
more versatile than hard-template MSNs. Mou et al . have used a simple ternary water- in-oil
microemulsion system to produce rattle-type gold nanocatalysts embedded within hollow type
MSNs (Au@HSNs), creating poison-resistant nanoparticles with high levels of catalytic activity
[88]. More recently, magnetic hollow type MSNs have been fabricated by a co-surfactant-
independent water- in-oil microemulsion system. This resulted in MSNs with magnetic properties
and minimal residual surfactant impurities after synthesis, which enabled them to be used for
wide applications including MRI [89]. One of the limitations of soft-template MSNs is their poor
size controllability due to the large amount of surfactants used in their synthesis processes [90].
In order to overcome this limitation, the chemical processes during synthesis must be closely
controlled. Currently, by adjusting the hydrolysis and condensation kinetics of precursors and
surfactants, it is possible to fabricate small hollow type MSNs of approximately 20 nm in size
[91]. More recent work using emulsion/micelle dual-templates have not only increased the sizes
of soft-template MSNs to 80 – 220 nm, but also improved the control on other parameters like
shell thickness and pore size [88].
2.4.3. Self-Assembled MSNs
Unlike hard-template MSNs and soft-template MSNs, self-assembled MSNs are formed without
the use of an additional template structure. These MSNs make use of their own structure as a
“self -template” to create the hollow structure. The self -template method is a simple, self-driven
and low-cost process, with no additional requirement of templates or protective surfactants [28,
92]. In general, there are two major steps involved in fabrication: the synthesis of template
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nanomaterials and the formation of hollow structures from these templates. The field of self-
assembled MSNs is wide and there are various synthesis methods available to produce hollow
MSNs of different structural properties. The size of these MSNs is particularly determined by the
dissolution and regrowth of their corresponding preformed solid spheres (Figure 6A). Tang et al.
had first proposed the preparation of hollow type MSNs by alkaline treatment of the cationic
polyelectrolyte pre-coated mesoporous silica spheres (Figure 6B) [93]. In this approach, poly-
dimethyldiallylammonium chloride (PDDA) was coated over the mesoporous silica spheres,
followed by treatment of these PDDA coated-mesoporous silica spheres in ammonia solution.
Hollow MSNs were obtained by the interaction of the anionic silicate oligomers and the
polyelectrolyte shell. Through the selection of suitable etching reagents and starting core
structures, monodispersed hollow MSNs of 70 nm to several micrometers can be synthesized
[94]. Based on these works, other functional nanomaterials have also been incorporated into the
hollow core [95]. Precise control of the surface area and pore size of self-assembled MSNs has
been achieved through selective etching technique based on structural differences. This has
produced hollow type MSNs-based structures with variable morphologies and particle/pore sizes
(Figure 6C-D) [96]. In this synthetic process, selective etching of the silica core (as
homogeneous template) was performed while the mesoporous shell was unmodified. In addition,
the interior volume and pore structure of these self-assembled MSNs could be tuned based on the
reaction conditions during the core transformation, such as etching time, concentration of silica
and acidity of the environment [97]. Polymer protective layers used during core transformation
allow the hollow structures to be formed with even higher morphological fidelity (Figure 5A)
[98]. Core transformation using this route is known as surface-protected etching.
3. Silica Nanoparticles in Cancer Therapy
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Over the past few decades, there has been extensive research towards safe and effective
treatment for cancer. The emergence of nanomaterials offers high expectation for better detection
and treatment of cancer. S ilica-based nanoparticles play a significant role in cancer therapy due
to their distinct advantages such as tunable and uniform pore size, high surface area and interior
pore volume, nontoxicity and biocompatibility. The mesoporous structure of silica nanoparticles
does not only make them active drug delivery systems for canc er treatments, but also allow their
doping with diverse materials (such as fluorophores, nanoparticles etc.) for various applications
in cancer therapy (Table 1 ).

3.1.Early Cancer Detection and Diagnosis
In order to provide timely and more effective cancer treatment, early detection and diagnosis of
cancer is essential for minimizing mortality. Currently, tissue biopsy, where tissues are removed
from the patient to look for cancerous cells, is the most widely used method of diagnosis. With
imaging guidance from ultrasound (US), X-ray, computed tomography or MRI, suspected
canc
erous tissues can be detected through biopsy. However, low sensitivity and poor selectivity
of the traditionally used contrast agents in these types of imaging modalities limit early diagnosis.
During the last decade, various nanomaterials like gold nanoparticles [99], quantum dots ( QDs)
[100] and silica nanoparticles [101] have been employed for early detection of cancer and
diagnosis. Although gold nanoparticles have achieved encouraging development in cancer
therapy, optical imaging using gold nanoparticles possess limited clinical future because of the
weaker optical signal of gold nanoparticles compared with certain fluorescent dyes or QDs [102].
Perhaps QDs are being considered as multifunctional nanoparticles in biomedical applications
including in situ optical imaging and drug delivery, more efforts have nonetheless to be devoted
to toxicity effects before their extensive application in clinical diagnosis and therapy [103]. On
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the other hand, silica nanoparticles are biocompatible, non-toxic, biodegradable, and have a high
loading capability for different agents, which thus renders silica-based treatments potentially
more effective and safer for diagnostic approaches.
3.1.1. Silica Nanoparticles as Imaging Contrast Agents
Imaging technologies such as US and MRI have been largely used for cancer diagnosis as they
are low-cost, possess low radioactivity and real-time monitoring properties [101]. However, the
commonly used contrast agents for US or MRI are small molecules including gadolinium
chelates and calcium and other metal ions [104], which cannot provide high contrast images for
early cancer diagnosis, due to the low specificity and inherent noise present during imaging
[101]. Due to their robustness, high drug loading capacity, multiple-functionalization and facile
biodegra
dation in the body in a timely fashion , silica nanoparticles are used as US- and MRI-
contrast agents with specific targeting and low toxicity, and show promising results for cancer
diagnosis (Figure 7A-C). In 2010, perfluorocarbon gas-filled hollow porous silica microshells
were developed to be inject ed directly into tissues. These nanoparticles could remain in the
tissues for several days without toxic effects and were easily imaged by US imaging in human
breast tissue in all three dimensions. The long residence time of these agents within the body
promoted novel applications, such as Doppler imaging using US and contrast specific imaging
for longer duration [105]. In subsequent studies, hollow type silica as well as silica-boron
nanoparticles were systemically applied in tumor bearing mice for US imaging [106]. For
example, Daewon and co-workers engineered MSNs with Herceptin (a special recognizer for
epidermal growth factor receptor 2), which can selectively target certain types of breast cancers.
These functionalized MSNs could confer sufficient mean pixel intensity to generate higher
quality US images [107]. MRI can access deep tissues and provide valuable high spatial
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resolution information without radioactivity; however, it requires highly sensitive contrast agents
for practical application [108]. Further studies have investigated the possibility of using silica
nanoparticles as a novel type of MRI agent [109]. With longer nuclear relaxation time and ease
of surface modification with biologically compatible ligands, silica nanoparticles can be used as
hyperpolarized, targetable MRI agents. The in vivo sensitivity of silica nanoparticles and other
MRI nanoparticle probes have also been compared. The hyperpolarized silica nanoparticles were
injected into the prostate tumor bearing mice and could be easily imaged with high sensitivity at
low magnetic field, subsequently demonstrating other potential applications such as real-time
MRI [110]. Furthermore, Kazuya et al. have developed a novel MRI contrast agent composed of
a core micelle containing liquid perfluorocarbon inside a robust silica shell [111]. This type of
silica nanoparticle-based agent has high sensitivity, sufficient in vivo stability, modifiability of
the surface, and biocompatibility, which can propel promising future applications in early cancer
detection and diagnosis.
3.1.2. Mesoporous Nano Silica Chips
Proteomic analysis by mass spectrometry and chromatography has greatly revolutionized the
early diagnosis of cancer, which can distinguish the differences between normal cells and cancer
cells at molecular level [112-114]. However, there are several limitations to be addressed [115,
116], such as the signal interference from high concentration proteins to low concentration
proteins, distinct spectra features of one sample from different types of mass spectrometry or
chromatography and poor selectivity to identify changes in protein concentration between the
normal and abnormal states. Moreover, the traditional samples have complicated preparation
steps and the well-fractionated quality of samples is difficult to obtain. These difficulties cause
detection to become time-consuming and inaccurate [117, 118]. Mesoporous silica-based chips
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(Figure 8A-B ) with specific pore size and inert properties, act as a filter in protein mass
spectrometry for the identifying cancer biomarkers in early detection and diagnosis [119-122].
Nanopor
ous silica chips allow the separation of low molecular weight proteins in serum from the
higher weight proteins [122]. This in effect concentrates the low molecular weight proteins and
enhances the signals. With the aid of mass spectrometry and biostatistical analysis, unique
protein signatures pertaining to various stages of cancer development can be identified. In
addition, surface engineering by the attachment of metal ions [120] or other functional groups
[123] enhance the selectivity and sensitivity of mesoporous silica chips, which can selectively
concentrate the low molecular weight proteins and identify proteomic biomarkers in various
cancers. The use of functionalized mesoporous silica chips therefore provides a promising
platform for the analysis of post-translational modifications in the human proteome and the
potential diagnosis of early symptoms of cancer and other diseases, which may significantly
enhance the possibility and accuracy of early cancer detection and therapy.
3.1.3. Fluorescent Silica Nanoparticles for Optical Imaging
Fluorescent optical imaging has attracted great attention and has become essential in imaging-
based therapy for preclinical investigations, especially for early cancer detection and diagnosis.
Fluorescent dyes, fluorescent and bioluminescent proteins are traditional fluorescent probes that
have been applied in optical imaging, but the rapid degradation, inadequate photostability and
unpredictable toxicity limit their further application [124, 125]. The combination of silica
nanoparticles and fluorescent materials overcomes these limitations and offers more effective,
safer and affordable approaches for early cancer detection and diagnosis. There are two main
types of fluorescent silica nanoparticles: (i) dye-doped silica nanoparticles and (ii) combination
of QDs with silica nanoparticles.
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Dye-doped silica nanoparticles, which are prepared by incorporating fluorescent organic dye into
silica nanospheres, have been extensively utilized for optical imaging. Among numerous
fluorescent nanoparticles, dye-doped silica nanoparticles stand out and exhibit several
advantages: (i) they contain high amounts of dye units within a silica matrix and exhibit a much
stronger intense fluorescence signal compared with normal organic fluorophores [125] (e.g.
small organic dyes, fluorescent proteins, metal-ligand complexes); (ii) the silica matrix serves as
a robust shell and prevent the fluorophores from quenching and degradation; (iii) they can be
surface-functionalized for a range of applications such as targeted imaging or evasion of capture
by the reticuloendothelial system [126-128]. The organic dye-doped silica nanoparticles are
commonly synthesized by two methods – the Stöber method [127] and the microemulsion
method [126]. The simple microemulsion method is usually preferred as the conjugated cell-
target moieties (e.g. antibodies [129], peptides [130], aptamers [131]) have higher cancer
selectivity. With these specific cell-target moieties conjugated onto the surface, organic dye-
doped silica nanoparticles can target specific cancer cells more efficiently and selectively. This
allows the in situ diagnosis and treatment monitoring during clinical therapy. In our studies, we
synthesized dye-entrapped and FA-conjugated ORMOSIL nanoparticles for in vivo cancer
targeting and imaging (Figure 9A-B ) [132]. With low-toxicity, biocompatibility and robust
properties, our optical nanoprobes exhibit promising potential in clinical applications for cancer
theranostics, especially in the early diagnosis of pancreatic cancer and other malignant tumors.
Fluorescent semiconductor nanocrystals, or QDs, have been widely utilized in biomedical
research over the past decade. In contrast to the conventional organic dye, QDs possess many
superior optical characteristics, such as size-tunable wavelength absorption and emission, broad
excitation wavelength, narrow emission bandwidth and long fluorescent lifetime [125, 133].
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However, the potential toxicity of QDs [128, 129] during in vivo applications [134, 135] and
instability of nanocrystals in buffers [136], are some limitations which need to be addressed
before one can utilize them for translational medicine research. To overcome these limitations,
QDs can be embedded into silica -based nanoshells or alternatively, incorporated into silica
nanostructures, forming silica -QDs hybrid nanoparticles. In one st udy by Tomas et al. , QD –
doped silica nanoparticles were surface functionalized with neutravidin to target T -lymphocytes
[137]. In this research, the fluorescent nanoassembly was subjected to receptor -mediated
endocytosis by Jurkat T -lymphocyte cells and wa s partially released to lysosomes, which was an
excellent representation for construction of specific intracellular nanoprobes and transporters.
Another group has embedded silica nanoparticles with a large number of hydrophobic QDs and
obtained QD -embedded silica nanoprobes with high quantum yield [138]. These nanoprobes
exhibited high fluorescent activity and are useful for tumor imaging in vivo (Figure 10). Unlike
the silicon QDs, their particle surface have been modified with hydrogen, halogen or oxide
terminated surface, thereby resulting in different photoluminescence properties [139]. The
intracellular internalization of QDs alkyl -functionalized silica nanoplex has been investigated
recently and a higher cellular uptake rate of the nanoplex is observed in the malignant cells as
compared with normal cells [140]. These nanoparticles point to a feasible direction towards
selective tumor imaging. According to these studies, QDs -embedded silica nanoparticles
envision an attractive roadmap for cancer cell ima ging and detection in vitro . However, more
research for silica nanoparticle s needs to be implemented in vivo for the further application in
cancer detection and diagnosis.
3.2.MSNs-based drug delivery systems for cancer therapy
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During the last decade, silica nanoparticles, particularly MSNs have been widely used as drug
delivery nanocarriers [48, 78, 141, 142]. With tunable particle size, large surface area and
interior volume, uniform mesoporous structure and multi-functional surface, MSNs are a
preferred drug delivery system over other drug carriers. First, the tunable pore diameter endows
the MSNs with the ability to deliver drugs of diverse sizes for different kinds of cancer [19].
Secondly, the encapsulation of drugs inside MSNs effectively prevents the premature release and
degradation, as well as reduces the toxicity impact to the healthy tissues during the transport
process in vivo [28]. Thirdly, the water solubility of hydrophobic drugs can be improved by
encapsulating them with water-dispersible silica nanoshells [12]. Meanwhile, the sustained
release effect caused by MSNs’ mesoporous structure enhance s the medication persistency [143].
Moreover, the multi-functional surface of MSNs can be tailored to serve as case-specific drug
delivery systems for different cancer treatments [141]. These advantages outline MSNs as an
excellent and flexible drug delivery platform for cancer therapy [144-146]. In general, MSNs-
based drug delivery systems are classified into three types : passive delivery system, active
delive
ry system and controlled-release drug delivery system.

3.2.1. Passive drug delivery system
Briefly, passive drug delivery strategies are based on the enhanced permeability and retention
(EPR) effect – a consequence of pathophysiological characteristics of diseased tissues for better
drug accumulation in pathological sites [147]. With leaky vasculature in the blood vessels’
epithelial layers and inefficient lymphatic drainage system, tumor tissues offer superior
conditions for passive drug delivery (Figure 11A). However, the size of most commonly used
anticancer drugs is not large enough for passive delivery. To overcome this limitation , a number
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of nanovehicles including liposomes [148], micelles [149], dendrimers [150] and nanoparticles
[151], have been designed to facilitate the delivery of these anticancer drugs into the tumor site
with improved pharmacokinetics. Among these numerous nanovehicles, MSNs with unique
structural features are largely applied for passive drug delivery. In 2001, the application of
MCM41 type- MSNs as drug delivery systems was first reported, o pening a new era in MSNs –
based drug delivery [21]. To date, researchers have made numerous efforts to explore the
application of MSNs -based drug delivery systems for cancer theranostics. One significant
achievement is the loading of hydrophobic anticancer drugs into MSNs to transport them into
human cancer cells. With MSNs -based nanoshells, the poor water solubility of hydrophobic
anticancer drugs has been overcome, achieving highly efficient cellular uptake [12]. These
findings suggest the prominent role o f MSNs as an effective vehicle in overcoming the
insolubility issue of many anticancer drugs. Consequently, MSNs with size of ~100 nm were
utilized as a drug delivery vehicle to deliver anticancer drug into a nude mice bearing human
breast cancer (MCF -7) xenograft [13]. These nanoplexes were taken up and accumulated in
tumors by EPR effect, following which the growth of tumors was significantly suppressed . To
determine the appropirate size of MSNs for EPR effect, Andre et al. calculated the EPR effect for
different sizes of MSNs -based passive drug delivery systems [152]. They demonstrated a drastic
improvement in the EPR effect by the size reduction of MSNs down to ∼50 nm and by
modification of the particle surface with a PEI -PEG copolymer. Notably, EPR effe ct does not
exist in all kinds of tumors, which may limit the application of passive delivery systems [153].
Furthermore, even in a single tumor, the permeability of vessels may not be the same. Therefore,
MSNs- based passive delivery approaches should be m odified prior to application in particular
cases of cancer therapy.
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3.2.2. Active drug delivery system
An effective way order to overcome the limitation of passive delivery approaches is to conjugate
affinity ligands on the surface of nanocarriers (Figure 11B). These affinity ligands include
antibodies [154 , 168 -171], peptides [155 , 172 -180], proteins [156 , 164, 184 ], aptamers [157 , 185,
186], small molecules [13, 1 4, 160, 162 -167] and saccharides [18, 144, 187, 188] (Table 1). Due
to the expression of receptors on the target cells, nanocarriers can accurately recognize and bind
to these cells by ligand -receptor interaction, as well as transfer drugs to the target cells actively
and efficiently. Depending on the type of receptor expressed on the target cells, dive rse kinds of
multi -functional MSNs -based drug delivery vehicles have been developed. FA, a vital nutrient
required by all living cells, has high affinity for the folate receptor (FR). Because the expression
of the FR is selectively upregulated in certain m alignant tumor cells, such as ovarian, lung,
kidney, breast, endometrial, brain and colon cancer cells, FA is considered as a common target
molecule for these cancer cells. Lin et al. first studied the cellular uptake properties of surface
functionalized -MSNs and reported the active role of FA groups functionalized on MSNs in
facilitating receptor -mediated endocytosis for increased uptake by tumor cells [158]. Further
studies have confirmed that the internalization of FA functionalized -MSNs in HeLa cells (human
epithelial cells) was 5 -6 times higher as compared with normal cells [159], which suggest FA
functionalized -MSNs as a useful drug delivery system for FR -positive cancer cells due to
increased toxicity of FA -conjugated MSNs prodrug in FR -positive cance r cells [160]. In addition,
the biomolecular targeting agents like peptides and proteins are conjugated to the MSNs surface
for other treatment effects. For instance, TAT peptide -conjugated MSNs were used as a nuclear –
targeted drug delivery system, which exhibited significant enhancement in the anticancer activity
by nuclear internalization [155]. Transferrin is another candidate for conjugation on the surface
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of MSNs to enhance the recognition of brain glioma cells [156]. Transferrin increases the
transport efficiency of nanoplex across the blood-brain barrier, thus enhancing the
chemotherapeutic efficiency for treating brain glioma. Till date, the MSNs-based active drug
delivery systems are being extensively utilized in in vitro and in vivo cancer-related research .
Howe
ver, for the clinical application, much more effort needs to be devoted to address the
limitations, including harmful degradation byproducts, and the high cost of preparing the
nanoformulation [161].
3.2.3. Controlled-release drug delivery systems
Using numerous kinds of ligands with different cell affinities conjugated onto the MSNs surface,
MSNs-based drug delivery systems are capable of accurately recognizing and targeting diverse
types of tumors. Furthermore, the most distinguishing feature of MSNs-based drug delivery
systems is the “zero premature controlled -release” property. Briefly, drug delivery systems are
able to deliver drugs with precisely controlled release to the target cells and do not prematurely
release their loaded drugs en route . This property is one of the necessary prerequisite in the
evaluation of a system’s degree of therapeutic enhancement and decrease in the cytotoxicity of
its loaded chemotherapeutic drugs [189]. This is a major challenge for other available drug
delivery systems. Recently however, several multifunctional MSNs -based drug delivery schemes
have achieve d “zero premature controlled -release” [190 -192], b y bloc king the pore entrances of
drug-encapsulated MSNs with stimuli responsive agents, also named as “caps”. Once triggered
by external or internal stimuli unique to the desired location, these caps disassemble from the
pore entrances and the loaded drugs are released to the targeted sites (Figure 11C). Lin and co –
workers first introduced the “zero premature controlled -release” concept in the control release
system of MSNs [190]. They utilized MCM41 type -MSNs as drug nanocarriers capped with
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inorganic CdS nanoparticles to efficiently deliver drugs into neuroglial cells with “zero
premature controlled -release”. Up to now, a variety of materials have been applied as capping
moieties, such as CdS [190], Au [1 93], Fe 3O4 nanoparticles [194], rotaxanes [163], dendrimers
[195], polymers [196] and proteins [192] . However, there are some potential risks of toxicity or
biocompatibility from the capping chemical or metal agents [184, 197]. Subsequent
developments in t hese caps propose the use of biomolecules, especially proteins, to reduce
toxicity. Lin and coworkers designed a glucose -responsive drug delivery system by
functionalizing the external surface of MSNs with gluconic acid -modified insulin 8 (G -Ins 8)
protein [191]. The release of G -Ins 8 and cyclic adenosine monophosphate (cAMP) inside
MSNs- based nanocarriers was triggered by the controlled introduction of glucose. Another
example is the biomolecule -based enzyme -responsive cap system constructed from biomolec ules
and MSNs composites [192]. In this research, tetrameric protein avidin was utilized as a cap and
could be disintegrated by enzymatic hydrolysis. As highlighted in the previous section, the
application of caps in drug delivery can efficiently prevent p remature release and enhances the
therapeutic effect of a drug. Based on the different types of caps, many reports have emerged
highlighting the development of the stimuli -responsive triggers, including pH, temperature,
redox potential, light, enzyme, etc. These triggers have been successfully applied in vitro and in
vivo, and promote the application of MSNs -based drug delivery systems in cancer theranostics.
3.2.3.1.pH -triggered drug release system
Due to acute hypoxia, disorganized vasculature and elevated interstitial pressure in the internal
environment of tumors, the lactate produced through glycolysis in tumor cells cannot be
exhausted rapidly enough, resulting in low pH in tumor tissues (pH<7) [198]. Therefore, pH
triggering is the most common and feasible approach for application in a controlled drug release
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system. pH-responsive linkers have been conjugated to MSNs-based nanocarriers for controlled
drug release in tumor cells. Latorre and co -workers explained the earliest example of a pH –
triggered release system [199] . In their studies, they utilized MCM -41 type MSNs as drug
carriers and conjugated the surface with amino groups. Employing this pH -controlled and anion –
controlled drug delivery system, successful release of squaraine dye aided by MSNs nanocarriers
was obtained . Subsequently, other groups proposed pH -triggered MSNs drug delivery systems
decorated with different functional groups. For example, Che et al. have developed a novel pH –
triggered MSNs -based drug delivery system which uses coordinate bonding of the functional
groups present on the pore surface with metal ions and drugs [200]. The “host -metal -guest”
architecture exhibited attractive stability and rapid pH -responsivity, and provided a new direction
for pH -triggered release system in cancer therapy. Lee and co -workers fabricated calcium
phosphate (CaP) capped -MSNs as drug delivery system, which could release drugs under pH
control [201]. As a novel pore blocker and nontoxic inorganic b iomineral, CaP plays an
instrumental role in the natural bone regeneration process (Figure 12A). Compared with
traditional MSNs, the capped -MSNs can effectively prevent the premature release of DOX and
administer DOX under pH influence (Figure 12B). The in vivo anti-tumor studies strongly
support capped MSNs -based nanocarriers as promising specific intracellular drug carriers for
cancer therapy (Figure 12C).
3.2.3.2.Temperature-triggered drug release system
Unlike the normal tissues which are generally stable in the body, the tumor tissues are highly
active with continuous cell replication. Therefore, the temperature in tumor -bearing tissues is
higher as compared with most normal tissues [202]. This temperature difference is used as an
internal trigger for instigating controllable drug release. In addition, near infrared (NIR) light or
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magnetic materials which induce the hyperthermal effect can also be utilized as external triggers
for controlled drug release.
The most commonly employed thermal-sensitive polymer, poly ( N-isopropylacrylamide)
(PNIPAAM), is been functionalized onto MSNs for modulating controlled drug release [203-
205]. These polymers present swollen hydrated states below a low critical solution temperature
(LCST) and are able to cover the cavities of MSNs to prevent the drug release. As the
temperature exceeds LCST, the polymers undergo a reversible phase transition to a shrunken
hydrophobic state in aqueous medium, thereby causing pore opening and drug release [206].
Early studies conducted by Lopez group, have demonstrated switchable behavior (from
hydrophilic to hydrophobic state) of PNIPAAM on the surface of silica materials upon an
increase in temperature and suggest that the hybrid material composed of silica and PNIPAAM
could act as a controlled-release system under temperature transition [207-209]. Consequently,
more studies have been devoted to the application of PNIPAAM-functionalized silica
nanoparticles in drug delivery. Voelcker et al. grafted PNIPAAM to the su rface of porous silicon
materials by surface -initiated atom transfer radical polymerization technique [210]. The
composite material exhibited high drug loading ability and excellent drug controlled -release
property. Zhao et al. described a novel NIR -stimul us controlled drug release system, which
comprised of cores composed of gold nanocages, shells composed of mesoporous silica and
PNIPAAM as the thermal -sensitive gatekeepers [205]. Under NIR light, Au -nanocage cores
convert NIR light to heat following whic h the PNIPAAM gatekeepers change from the
hydrophilic to hydrophobic state, resulting in pore opening and drug release (Figure 13A). With
the synergistic photothermal therapy effect and efficient drug release by NIR light, these MSNs –
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based nanocarriers exhibit cancer cell killing ability (Figure 13B) and can be further applied for
biomedical research.
Although PNIPAAM as thermal-sensitive gatekeepers have been utilized for MSNs-based
controlled drug release systems, the LCST of pure PNIPAAM is 32°C and may be not very
useful for clinical applications (normal body temperature ranges between 36.1 and 37.2°C). A
series of PNIPAAM analogues have been developed for applications at higher temperature . For
example, Poly (ethyleneoxide-block-N-vinylcaprolactam) can be u sed as a gatekeeper on MSNs
surface that maintain the pore opening temperature at ~36°C [211]. Zwitterionic sulfobetaine
copolymer which is conjugated onto the MSNs enhances the LCST to 50°C [212]. Recent studies
on other temperature-responsive caps, such as DNA oligomers or peptides, have made notable
progress in drug release. Thomas group conjugated biotin-labeled DNA strands with the external
surface of MSNs and modulated the pore opening temperature by the length of DNA strands
(Figure 13C) [213]. Kros and co-workers utilized coiled-coil peptide motifs as a temperature-
responsive cap to control the drug release inside MSNs (Figure 13D) [214]. These gatekeepers
are nontoxic and biodegradable, which place them as worthy candidates for clinical cancer
therapy.
3.2.3.3.Redox potential-triggered drug release system
In general, the level of antioxidant species in intracellular space is considerably higher than in
extracellular space, which is the reason for high redox potential difference [215]. The basic
principle of redox potential -triggered drug release system is to utilize the high redox potential
difference to destroy the disulfide bond between caps and carriers. Compared to the normal cells,
the redox potential difference is more pronounced in tumor cells. Therefore, the disulfide linkage
is more susceptible to breakage in cancer cells, amounting to higher dru g concentration at tumor
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locations [216]. Wang et al. assembled a multilayer on the surface of drug encapsulated -MSNs
by disulphide bond [157]. No obvious release of loaded drug molecules was detected in cells
even after 24 hours of incubation. In contrast , dithiothreitol ( DTT ) treatment led to
deconstruction of the disulphide bond and the consequent release of drug molecules. With the
cancer cell -specific DNA aptamer sgc8, the MSNs -based nanocarriers possess high cell
recognition and cause pronounced cance r cell death. Besides the polymers, Lin and co -workers
conjugated the inorganic Fe 3O4 nanoparticles as caps to the surface of MSNs and achieved drug
release by cell-produced antioxidants [217]. These magnet ic-MSNs -based nanocarriers possess
“zero release” prior reaching the target site and release the cargos after internalization by the
cells.
3.2.3.4.Enzyme-triggered drug release system
The development of enzyme-triggered controlled-drug release systems is viewed as effective
strategy to cancer therapy, owing to the excellent biocompatibilities, rapid and specific biological
activities of enzymes. The first MSN based- enzyme-triggered release syste m was shown by Zink
and co-workers [218]. They u sed α-cyclodextrin ring as a snap-top, which consisted of
polyethylene glycol chemically bonded to MSNs through an enzymatically cleavable bond.
Following enzyme-mediated hydrolysis, the snap-top system could successfully release the
encapsulated cargo molecules. In recent studies, the enzyme-triggered release system based on
MSNs has been widely applied for drug delivery in cancer theranostics research. There exist
FDA-approved peptide capping agents, such as protamine, which have been complexed with
MSNs to produce a non-toxic and biocompatible drug delivery system [82]. When the
protamine-capped MSNs carriers encounter the proteolytic enzyme trypsin, the caps disintegrate
and the encapsulated drug is released (Figure 14A,B). The nanocarrier itself exhibits non-toxicity
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and can enhance the toxicity of hydrophobic anti-cancer drugs for cancer cell treatment (Figure
14C,D ). The next phase of development of these enzyme -triggered release systems would be to
increase their specificity to the cellular level [219]. Biopolymer capping agents such as
chondroitin sulfate , are multifunctional capping agents, which provid e MSN drug retention, cell
targeting and bio -responsive drug release. Chondroitin sulfate capping agents specifically target
cancer cells -CD44 biomarkers over-expressed on the cell membrane, releasing the encapsulated
drugs after being triggered by enzymes such as lysosomal hyaluronidase which are abundant
within cancer cells.
3.2.3.5.Light-triggered drug release system
Leveraging on the various advancements in PDT, light irradiation as a means of triggered release
is effective for site-specific drug release. The speed and range of drug release is controlled via
the exposure of the MSNs to light with specific wavelengths and duration. The first light-
triggered release system based on MSNs was reported by Tanaka group [220]. In their approach,
coumarin ligands, which are UV-light sensitive, were used as capping agents at the surface of
MSNs, effectively regulating porosity of the MSNs in response to UV light (λ=250 nm). Since
then, various photochemical responsive linkers for example, azobenzene, thymine, o-nitrobenzyl
ester, aluminium phthalocyaninedisulfonate and graphene oxide (GO) were discovered to be
effective light-triggered release capping reagents for MSNs. These different capping reagents
respond to different wavelengths of light, allowing MSNs to be used for a wider variety of
applications. For instance, aluminium phthalocyaninedisulfonate, a red-light sensitive
photosensitizer (~800 nm) , was used for light-triggered release in deeper tissues, as the
penetration of higher light wavelengths is more effective through tissues [164]. When used with
other target ligands, such as FA and epidermal growth factor (EGF ), these MSN drug
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nanocarriers c an specifically recognize and target cancer cells. These multifunctional MSNs are
the next wave of development. Other approaches used photochemical responsive linker GO an d
cancer cell recognizer-AS1411 (Figure 15A) to create a light-triggered system which exhibited
manageable drug release and accurate cancer cell recognition [221]. NIR light was utilized as the
exogenous stimuli to trigger drug release (Figure 15B,C). Base d on the lower toxicity and
photothermal effect of NIR light, the light -triggered drug delivery system showed synergistic
dual-mode chemotherapy and photothermal therapy to cancer cells (Figure 15D). Two -Photon
Excitation (TPE) in the NIR region is a noteworthy alternative which was used as a trigger for
MSNs- based drug delivery system [222]. This system possesses zero premature release of
anticancer drugs and is efficient for TPE trigg ered-drug release in cancer cells upon irradiation
from a focused laser beam.
3.2.3.6.Other stimuli-triggered drug release system
Besides enzyme- and light-triggered drug release systems, other types of stimuli for the
controlled release of drug reagents from MSNs are developed which aim to increase the
specificity of such treatments. Lin et al. demonstrated a stimuli -triggered release system, namely,
a glucose -responsive drug release system, described in section 3.2.3 [191] . In this system, G-Ins
8 encapsulate cAMP molecules into the MSN mesopores. The nanocarriers are endocytosed by
cells and release the dr ugs upon the introduction of glucose. A biomolecule -sensitive controlled
release system was described by Wang group [223]. Depending on the high affinity -based
aptamer -target interaction, cargos c an be accurately released at the specific site without
prema ture release.
Following with the investigations on single stimuli-triggered drug release systems, there is rapid
ongoing effort to create the next generation of therapeutic MSNs with multiple stimuli-triggered
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drug release systems. These systems achieve complex drug release profiles either independently
or synergistically, regulating drug release under different specific conditions for better targeting
of the therapeutic agents. Yang and co -workers utilized the copolymer of 2 -(2-methoxyethoxy)
ethyl methacr ylate and oligo (ethylene glycol) methacrylate cross -linked by disulfide bonds to
coat hollow type MSNs [224]. The presence of glutathione or temperature change c an trigger the
drug release, causing the death of glutathione overexpressing -cancer cells [225 ]. Cui et al.
developed a pH – and temperature -based dual -controllable drug release system [226]. In such a
system, MSNs act as the drug carriers, wherein the dual stimuli responsive -gating shell is
composed of the copolymer -lipid layer. With greater drug l oading capacity and dual stimuli –
responsive releasing ability, this system exhibits high anticancer ability and c an be further u sed
for clinical applications.
In recent years, stimuli-responsive drug delivery systems are gaining advancing position in
biomedical research. However, most studies are focused on in vitro studies and there are fewer
reports on in vivo applications. Although cell-based assays can provide some information,
cultured cells still cannot mimic the complicated physiological environment and complex
interactions in the cell -tissue habitat . To achieve the goals of clinical cancer therapy, more efforts
should be devoted to in vivo studies based o n these stimuli -responsive drug delivery systems.
3.3.Co-delivery of gene and drugs assisted by MSNs-based drug delivery system for
combatting cancer multidrug resistance
Cancer MDR is the process wherein cancer cells become simultaneously resistant to a vari ety of
drugs with dissimilar structure, molecular target and mechanism of action [227]. The
development of MDR to chemotherapy has become a major limitation to cancer therapy. Cancer
MDR can be classified into two types: pump resistance and non -pump resist ance. Pump
resistance is related to ATP -binding cassette transporters, which function as drug efflux pumps,
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for example, MDR -associated protein 1 (MRP1) and P-glycoprotein (Pgp) [228]. These efflux
pumps can exploit the energy generated by ATP hydrolysis to pump the drugs and decrease the
intracellular drug concentration. With these efflux pumps, intracellular drug uptake is reduced
which thereby induces drug resistance. Non -pump resistance is mainly caused by the activation
of cellular anti -apoptotic defen ce, such as the expression of anti -apoptosis protein Bcl -2 [229].
The application of drug delivery systems based on MSNs is a major advancement towards the
suppression of MDR in cancer therapy. These nanocarriers have changed the routes of drugs
entering into tumor cells to avoid binding by the efflux pumps, resulting in the accumulation of
drugs in tumor cells [230, 231]. Furthermore, due to high loading capacity and efficient
encapsulation of cargos, multiple drugs can be simultaneously delivered into ca ncer cells without
premature release and degradation by intracellular enzymes [232]. Several groups have utilized
MSNs- based delivery system to co -deliver genes and anti -cancer drugs, which effectively target
both pump and non -pump resistance and significa ntly increase drug efficacy to cancer cells [233,
234]. Improvement of cytotoxicity in cancer cells promotes this strategy as a suitable approach
for the therapeutic treatment of MDR -dominant cancers. For example, Zhao and co -workers
improved the MSNs -based co -delivery systems with high cell recognition and pH -triggered
controllable –release [235]. They utilized F A as the target ligand and PEI as the gatekeeper to
functionalize the surface of MSNs (Figure 16A-D). PEI layers collapse due to the acidic
intracellular environment of cancer cells, following which drugs and siRNA can be released
naturally. Besides the co -delivery of siRNA and anti -cancer drugs, multiple combination
delivery systems based on MSNs have been developed, such as therapeutic peptides with anti-
cancer drugs [236], biomacromolecules with anti -cancer drugs [237] and hydrophilic molecules
with hydr ophobic drugs [238], etc. In contrast to single delivery systems, the co -delivery systems
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provide more effective therapeutic strategies to reverse MDR in cancer cells [239]. MSNs -based
drug delivery systems offer high loading capability, numerous controlle d-release approaches and
outstanding biocompatibility, which are considered to become the best transporters for
therapeutic drugs to cure cancers and other diseases in clinical trial.
4. Multifunctional delivery platform based on MSNs
To date, nanotechnology has provided a varied range of technologies for developing new
pathways for cancer detection, diagnosis and treatment. Owing to the unique properties, which
include high loading capability and multi-functionalized surface properties, MSNs serve as
nanocarriers which can simultaneously be conjugated with versatile molecules to bring forward
multifunctional capabilities. The combination of targeted drug delivery and concurrent real-time
in vivo monitoring is the most representative example of multifunctional delivery platform based
on MSNs, which successfully implements the synchronization of tumor diagnosis and treatment.
Yeh et al. utilized hollow type MSNs to co-deliver fluorescence and anti-cancer drugs [240].
This co-delivery system can simultaneously act as imaging probes for tumor optical imaging in
vivo and perform drug release by the appropriate selection of pH-dependent molecules to kill
cancer cells.
To expand the application of MSNs in cancer therapy, combinations of MSNs with additional
functional nanoparticles have been developed. This combination can integrate diverse diagnostic
and therapeutic methods into one single system for better cancer theranostics. One of the
noteworthy benefits of MSNs over other nanoagents is the capability to co-deliver hydrophobic
and hydrophilic anti-cancer drugs [241]. The co-delivery system predominantly enhances tumor
cell apoptosis and inhibition of growth, and simultaneously traces and investigates the process of
endocytosis in cells. Meanwhile, the magnetic core supplements the MSNs with magnetic
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properties for MRI or magnetic field manipulation for extended biomedical applications.
Combination of (AuNRs) and MSNs is another commonly used platform for cancer theranostics
[84, 242, 243]. In the combined platform, AuNRs efficiently convert the NIR light to heat and
induce photothermal effect. This multifunctional platform combines chemotherapy, photothermal
therapy and multimodal imaging into a single system simultaneously, as well as provides a more
comprehensive approach for cancer theranostics (Figure 17A-D ). In addition, the combination of
QDs and MSNs has been investigated by Brinker group [244]. In their system, targeting peptides
on the surface of MSNs exhibit greater affinity for human hepatocellular carcinoma, multi-
therapeutic drugs and QDs that are encapsulated inside MSNs realize the synchronization of
cancer diagnosis and treatment, and the fluid-supported lipid bilayer prevents premature release.
This system sums up the multiple applications based on MSNs nanocarriers and promotes the
development of their integration for cancer diagnosis and treatment. Table 3 is an elaborate
timeline of the journey of MSNs since their synthesis and evolution pe rtaining to cancer
theranostics and gene delivery applications.

Page 36 of 69

5. Conclusion and Future perspectives
The advancement of MSNs-based nanocarriers is considered of great importance in drug delivery
and provides a wide range of strategies for cancer theranostics. In this review, we discuss the
structure and properties of various configurations of MSNs and their applications in cancer
theranostics. Based on Stöber method, diverse synthesis conditions have been developed t o
successfully fabricate a series of MSNs, such as MCM-41, SBA-15, hollow type MSNs,
ORMOS
ILs, etc. By regulating the reaction conditions (for e.g. the molar ratio of silica
precursors and surfactants, temperature, pH value and addition of co-surfactants), the particle
size, pore structure and morphology of MSNs can be facilely controlled. The particle diameter
spans tens to hundreds of nanometers, which can passively target diverse cancerous tissues by
EPR effect [13]. Furthermore, the most distinguishing feature of MSNs-based drug delivery
systems is their “zero premature controlled release” property [ 308]. This occurs because MSNs
can encapsulate drugs inside and immobilize other materials as porous capping reagents on the
surface to block the pore entrances. These capping reagents are sensitive to a certain trigger and
open the entrance by dissolving or phase transition. Triggers can be internal or external, for
example, pH, light, redox potential, temperature and enzymes. Functionalizing the surface of
MSNs with capping reagents and targeting ligands can fabricate a powerful drug delivery system
with controlled-release and cell recognition properties, which exhibit incomparable advantages
over other drug delivery systems for cancer theranostics.
Despite encouraging progress and research in the biomedical applications of MSNs-based drug
delivery systems, several major challenges still need to be addressed for achieving clinical
success . The first issue is the in vivo toxicity caused by MSNs. Albeit silica is considered as
GRAS and the C dots hav e secured FDA approval for stage I human clinical trial [ 308], many in
Page 37 of 69

vivo studies describe dose-dependent toxicity of MSNs [ 309], such as inflammatory response
[310], liver injury [ 311], neurotoxic [ 312] and pregnancy complication [ 313]. In addition, the
particle size, surface charge and surface functional groups also play significant roles in MSNs
cytotoxicity [ 314]. Therefore, more careful and sufficient in vitro and in vivo studies require to
be conducted to outline the proper dose and type of MSNs before clinical trials . Another critical
issue is bridging the gap between the successful in vitro experiments to challenging in vivo
applications. By conjugating with targeting ligands and multifunctional “caps”, various in vitro
studies have demonstrated the capability of MSNs-based drug delivery systems to recognize the
target cancer cells and release drugs controllably. However, the complicated physiological
environment and highly dynamic and heterogeneous properties of tumors impede the active
targeting and effective release in vivo . To overcome these barriers, MSNs-based drug delivery
systems should be modified to have longer circulation time, ability to extravasate into tumors
and multiple functional groups for cancer cell targeting. Furthermore, a single formulation of
drug delivery system is impossible to effectively cure all patients with cancer. The development
of multifunctional MSNs-based nanocarriers, such as the combination of AuNRs nanoparticles
and MSNs, magnetic nanoparticles and MSNs, that can achieve the synergistic effect of
photothermal therapy, chemotherapy and multiple imaging together, exhibit much better
therapeutic effect than single therapy.
In conclusion, the research on MSNs-based drug delivery holds promising evaluation for cancer
theranostics. With the high loading capacity, good biocompatibility, tunable particle and pore
size and multifunctional surface properties, MSNs are considered as an ideal drug delivery
system. This system holds great promise for reversing MDR by co-delivery of multiple drugs
and targeting the tumor site actively, and possesses the “zero premature release” until a certain
Page 38 of 69

stimuli is triggered. Moreover, MSNs-based drug delivery systems can be conjugated with
versatile molecules to bring forward multifunctional capabilities simultaneously, which offer a
multifunctional delivery platform including drug delivery, optical imaging and controlled-release
for treatment. With tremendous efforts to overcome the existing bottlenecks, it is worthwhile to
envision a conclusive position of multifunctional MSNs-based drug delivery systems to catalyse
the progress of clinical cancer theranostics.
Acknowledgements
This study was supported by the Ministry of Education , Singapore (Grants Tier 1 M4010360.040
RG29/10 and Tier 2 MOE2010- T2-2-010 (M4020020.040 ARC2/11)), NTU-NHG Innovation
Collaboration Grant (No. M4061202.040), A*STAR Science and Engineering Research Council
(No. M4070176.040) , NTU-A*STAR Silicon Technologies, Centre of Excellence under the
program grant No. 11235100003 and School of Electrical and Electronic Engineering at
Nanyang Technological University.
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Figure 1. Schematic illustrations of three types of MSNs with the mean particle size range: a) M41S-type MSNs, b)
organically modified silica (ORMOSIL) nanoparticles and c) hollow type-MSNs (HMSN).

Figure 2. Structural arrangements of M41S family members: A) MCM -41 nanoparticles : hexagonal phase, B)
MCM -48 nanoparticles: cubic phase and C) MCM -50 nanoparticles : lamellar phase.

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Figure 3 . The schematic illustration of MCM-41 preparation by surfactants and silica precursors and their
characterization. (A) Synthesis of MCM-41; a) micelle formation, b) condensation, c) alignment, d) calcination. The
surfactant self-assembles into micelle formation and then condensates into micellar rods in a hexagonal array, while
the silicate precursors solidify the structure. (B) TEM images of MCM-41 materials with different pore sizes; a) 20
A°, b) 40 A°, c) 65 A° and d) 100 A° (Reproduced from ref. [34] with permission of American Chemical Society ).
(C) SEM (a, c) and TEM (b, d) images of two main shapes of MCM-41 materials: spherical and tube-shape silica
particles (Reproduced from ref. [41] with permission of Elsevier Science B.V .) (D) SEM images of various spherical
shapes of MCM-41 under different reaction conditions. (Reproduced from ref. [40] with permission of Elsevier
Science B.V . )

Figure 4. TEM images of ORMOSIL nanoparticles of sizes A) 30 nm, B) 50 nm and C) 80 nm. (Reproduced from
ref. [68] with permission of Royal Society of Chemistry )

Page 55 of 69

Figure 5. Synthesis of hard-template method for hollow type MSNs by using surfactant or polymer. (Reproduced
from ref. [75] with permission of Royal Society of Chemistry)

Figure 6. The self-template method for synthesizing hollow type MSNs. (A) Spontaneous transformation of silica
colloids from solid spheres to hollow structures; a) Fabrication process of hollow type MSNs, b) TEM images of
SiO 2 spheres, c-d) TEM images of hollow type MSNs in different etching conditions. (Reproduced from ref. [98]
with permission of WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) (B) Fabrication process of hollow type
MSNs with silica shell in the presence of ammonia solution. TEM images show the PDDA pre-coated mesoporous
silica spheres during different instants of 1M ammonia solution treatment. (Reproduced from ref. [93] with
permission of American Chemical Society) (C) The selective-etching procedure (left) for the fabrication of hollow
type MSNs (left) with different etching conditions are exhibited in Route A (Na 2CO 3 solution) and Route B
Page 56 of 69

(ammonia solution). The local microscopic structure (right) shows the existence of long carbon chains of C18TMS
that constitute the hydrophobic cores. (D) TEM images of hollow type MSNs in different etching conditions; a-b)
sSiO 2@mSiO 2, c-d) in 0.6M Na 2CO 3 solution at 80°C for 0.5 h, e-f) in 0.12M and 0.24M ammonia solution at
150°C for 24 h, respectively. The inset of panel shows SEM image of broken hollow type spheres, g-h) The role of
different initial precursor concentrations (45 nm and 450 nm) on the fabricated hollow type MSNs. (Reproduced
from ref [96] with permission of American Chemical Society)

Figure 7. Silica nanoparticles as contrast agents for US and MRI. (A) SEM images of porous hollow silica nano-
and micro-shells with different particle size: a) 100 nm, b) 500 nm and c) 2 000 nm. (Reproduced from ref. [106]
with permission of Elsevier Ltd. ) (B) US imaging of gas-filled silica microshells in tumor -bearing mice; a)
Interperitoneal IGROV -1 ovarian tumor in the dissected nu/nu mouse, b) Cadence contrast pulse sequencing (CPS)
image and c) B -mode image of the particles through the tumor cross section 1 h post inje ction with silica
nanoparticles, d) Overlay of CPS image and B -mode imag e (red arrow – tumor, green arrow – spinal column, blue
arrow – bottom of the mouse). (C) In vivo accumulation of silica nanoparticles at tumor site; a) Structural schematic
of functio nalized silica nanoparticles, b) In vivo MRI of functionalized silica nanoparticles in tumor -bearing mice.
Liver and tumor positions are represented as L and T, respectively. (Reproduced from ref. [111] with permission of
WILEY -VCH Verlag GmbH & Co. KGaA, Weinheim )

Page 57 of 69

Figure 8. Production and assembly of mesoporous silica based chips for proteomic applications. (A) The chemical
evolution in the coating solution during the production stages of a mesoporous silica film; a) Fresh solution, b)
Formation of micelles, c) Spin -coating process leading to self -assembly, d) Magnified image of a pore post aging at
high temperature. (B) SEM and TEM cross -sectional images of GX6 chip on a) bulk silicon wafer surface (upper)
and b) mesoporous silica film -coated silicon wafer surface (lower). Scale bar is 500 nm. (Reproduced from ref. [119]
with perm ission of WILEY -VCH Verlag GmbH & Co. KGaA, Weinheim )

Figure 9. The organically modified silica nanoparticles ( ORMOSIL ) for optical imaging in vivo . (A)
Characterization of synthesized ORMOSIL nanoparticles; a) TEM image of the synthesized ORMOSIL
nanoparticles, b) Absorption and c) Photoluminescence spectra of the ORMOSIL nanoparticles (ORM) , dye -doped
Page 58 of 69

nanoparticles (ORMD) and DCM dye (DCM). Inset of c): The corresponding solutions under natural and UV light. d)
Hydrodynamic size distribution of the dye-doped ORMOSIL nanoparticles, e) FTIR spectra of FA, ORMD and FA-
conjugated dye-doped nanoparticles (FA-ORMD). (B) In vivo luminescence imaging post tail vein injection ; (a-d)
Fluorescence images of Miapaca -2 tumor tissues (pointed by white arrows) in mice taken at specified times , where
PBS served as control (right). (Reproduced from ref. [132] with permission of Royal Society of Chemistry )

Figure 10. The application of silica-QDs nanoparticles. (A) Cellular uptake in vivo test of QDs-embedded silica
nanoparticles; a) Schematic illustration of QDs-embedded silica nanoparticles in HeLa cells, b) Fluorescence images
of QDs-embedded silica nanoparticles in HeLa cells (silica QDs: Red, DAPI: blue), c) In vivo fluorescence images
of QDs-embedded silica nanoparticles in cell-transplanted mouse. ( Reproduced from ref. [138] with permission of
WILEY -VCH Verlag GmbH & Co. KGaA, Weinheim )

Page 59 of 69

Figure 11. Schematic representation of passive and active delivery system. (A) Passive drug delivery system: drug-
loaded MSNs nanocarriers cannot extravasate through normal endothelium and only small molecules of free drug
can traverse normal endothelium; with the la rge gaps between endothelial cells in tumor tissues, nanoparticles can
extravasate and accumulate in tumor tissues creating high local drug concentrations. (B) Active drug delivery
system: drug-loaded MSNs nanocarriers are modified with a specific ligand which is able to recognize certain
binding sites on the tumor cell surface. As a result, these nanocarriers can attach to the cell surface and release the
drug therein or can be internalized bringing the drug inside target cells. (C) Controlled -release process of MSNs –
based drug delivery systems: The capping agents block pore entrances to block the premature release of drug
molecules. After the specific stimuli triggers the disassembly of caps from MSNs, the encapsulated drugs can be
released to the target location.

Figure 12. pH-tunable CaP -coating MSNs as drug delivery systems for cancer theranostics. (A) D rug release from
CaP-coated MSNs under pH control; a) Synthetic route to urease -MSNs (UR-MSNs ): 1) APTES, 2) removal of
Page 60 of 69

CTAB, 3) modification with UR. b) TEM image of UR-MSNs. c) Drug release by surface CaP mineralized- DOX –
loaded UR-MSNs by pH-triggering. HAp=hydroxyapatite. (B) Fluorescent images of MCF-7 cells treated with
LysoTracker (Green color), free DOX (Red color), and D OX-MSNs-CaP; a) Free DOX after 1 h exposure, DOX-
MSNs-CaP after 1 h b) and 5 h c) exposure, DOX-MSNs-UR for 1 h d) and 5 h e) exposure. Scale bar: 20 mm. (C)
a) The tumor volumes after treatment with saline (●), free DOX (ș), DOX -MSNs- UR (▲) and DOX -MSNs- CaP (♦);
Inset: Images of excised tumors after 16 days of treatment; b) the tumor weights 16 days post-treatment by different
materials. The DOX-equivalent dose is 10 mg/kg. The results represent the mean SDs (n=4); *P<0.05. (Reproduced
from ref. [201] with permission of WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Figure 13. Different types of gatekeepers in temperature-responsive uncapping mechanism. (A) Controlled -drug
release of Au -nanocage@mSiO 2@PNIPAM nanocarriers under NIR laser irradiation. (B) Drug release and cell
viability test; a) Photothermal curves of H 2O and the Au -nanocage@mSiO 2@PNIPAM (50 μg/mL) exposed to NIR
laser irradiation, b) DOX release from the Au -nanocage@mSiO 2@PNIPAM nanocarrier in PBS buffer (pH 7.4 and
5), with or without NIR laser irradiation, c) Viability of HeLa cells with or without NI R laser irradiation, under
different concentration of carrier, DOX, and carrier + DOX, d) Micrographs of HeLa cells (trypan blue -stained) with
or without NIR laser irradiation, with carrier and carrier + DOX. (Reproduced from ref. [205] with permission of
American Chemical Society ) (C) Temperature -triggered c ontrolled -drug release of biotin -labeled DNA -MSNs
nanocarriers. (Reproduced from ref. [213] with permission of WILEY -VCH Verlag GmbH & Co. KGaA, Weinheim )
(D) Controlled -drug release of coiled -coil peptide -MSNs nanocarriers. (Reproduced from ref. [214] with permission
of Royal Society of Chemistry )

Page 61 of 69

Figure 14. Enzyme-triggered release system based on MSNs for cancer therapy. (A) Formation of drug-loaded
amine -functionalized protamine capped -MSNs (MSN –PRM) and subsequent enzyme -triggered release of payload.
(B) Anticancer drug release from MSN –PRM nanoparticles at the proximity of trypsin overexpressing -cancer cells.
(C) Fluorescent images of COLO 205 cells incubated with a) curcumin loaded -MSN –PRM nanoparticles and b) free
curcumin in H 2O. Drug release from the MSN –PRM nanoparticles leads to decreased fluorescence. (D) In vitro cell
viability at a) different MSN –PRM concentrations, b) free curcumin and curcumin loaded -MSN –PRM nanopartic les.
(Reproduced from ref. [82] with permission of WILEY -VCH Verlag GmbH & Co. KGaA, Weinheim)

Page 62 of 69

Figure 15. Light-triggered release system based on MSNs for cancer therapy. (A) Dox-loaded GO-wrapped MSNs
(MSN -Dox@GO) bind with Cy5.5 -As1411 aptamer and the corresponding intracellular drug release under NIR light.
(B) Regulation of drug release under NIR light at different times; a) Temperature variation of MSN -Dox@GO
solution upon 808 nm laser irradiation for six 10 min on/ off cycles, b) Cumulative release of Dox by MSN –
Dox@GO and MSN -Dox in the presence and absence of laser irradiation. (C) Fluorescent images of MCF -7 cells
incubated with MSN -Dox@GO -Apt without and with laser. (Dox – red color, Cy5.5 -As1411 – green color and DAPI
(nucleus staining) – blue color were recorded). (D) The synergistic dual -mode chemotherapy and PTT of MSN –
Dox@GO -Apt; a) Cell viability of MCF -7 cells under MSN -Dox@GO -Apt, MSN@GO -Apt and control at different
laser power densities, b) PTT and chemother apy percentages of MSNDox@GO -Apt at different laser power
densities, c) Fluorescent images of MCF -7 cells treated with MSN@GO -Apt or MSN -Dox@GO -Apt for 4 h
followed by laser irradiation for 10 min, and incubated for 24 hours followed by staining with Live/ Dead assay.
(Cells irradiated only with laser served as control; Calcein (green, live cells) and PI (red, dead cells)). (Reproduced
from ref. [221] with permission of Royal Society of Chemistry )

Figure 16. Co-delivery system with drugs and siRNA based on MSNs. (A) pH-responsive HMSNPs-assisted co-
delivery of targeted drug and siRNA. (B) Dox release profiles under varying different pH conditions (4.5 ( ș), 6.0
(▲), 7.4 ( ●)). (C) Confocal microscopy images of FA-MSNs- DOX -siRNA-treated HeLa (FA+) and MCF-7 (FA- )
cells. FITC (green), Dox (red) and DAPI (violet). (D) MTT cytotoxicity assay of a) HeLa and b) MCF-7 cells after
treatment by FA- MSNs+scrambled siRNA (ș), FA -MSNs- DOX (●) and FA -MSNs-DOX+Bcl- 2 siRNA (▲).
(Reproduced from ref. [235] with permission o f WILEY -VCH Verlag GmbH & Co. KGaA, Weinheim )

Page 63 of 69

Figure 17. Multifunctional MSNs for photothermo-/chemo-therapy and multimodal imaging. (A) a) and f) The
structure of Gold capped-magnetic core/mesoporous silica shell nanoparticles (AuNRs-MMSNEs) , b) TEM images
of Fe 2O3@SiO 2@mSiO 2, c-e) TEM images of AuNRs-MMSNEs. The arrow in the inset image depicts the PEG
layer on the gold nanorod surface. (B) Infrared thermal imag es of an AuNRs-MMSNEs-injected tumor subjected to
a) 1 Wcm-2 b) 2 Wcm-2 and c) PBS -injected tumor under 2 Wcm-2 laser irradiations. (C) In vivo MRI of a mouse
before and after intratumor injection of AuNRs-MMSNEs. (D) Cell viability test of MCF-7 cells treated by AuNRs-
MMSNEs-NIR (purple), AuNRs-MMSNEs-DOX (red), AuNRs-MMSNEs- DOX -NIR (green) and the additive
therapeutic efficacies (blue). (Reproduced from ref. [242] with permission of Elsevier Ltd. )

Table 1. The various modalities of MSNs in cancer therapy.
Mesoporous Silica Nanoparticles in Cancer Therapy
Early Cancer Detection and
Diagnosis Drug Delivery systems Anti -MDR MSN -Based
systems
Imaging Contrast Agents Passive delivery system Simultaneous delivery of
multiple drugs
Mesoporous Nano Silica Chips Active delivery system Co-delivery of gens and anti –
cancer drugs
Fluorescent Silica Nanoparticles
for Optical Imaging Controlled -release drug delivery
systems Multiple combination delivery
systems

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Table 2. Examples of ligands conjugated to the surface of MSNs
Ligand type Ligand name Anti-cancer drug Cell/Tumor type Ref
Small
molecule Folic acid (FA) Camptothecin
U2Os [162]
SK-BR-3, MCF -7, MCF POF [13]
Panc -1, MiaPaCa -2 [14]
Camptothecin Panc -1 [165]
Paclitaxel
Doxorubicin HeLa [160, 163]
KB [164]
PEI-assisted gene
delivery HeLa [165]
Methotrexate MTX HeLa [166]
FA+Dexamethasone (DEX) Doxorubicin HeLa [167]
Antibody Anti-TRC105 Doxorubicin HUVEC, MCF -7 [168]
Anti-HER2/neu MCF -7 [154]
NIH 3T3, MCF7, BT -474 [169]
Anti-ME1 MM, A549 [170]
Anti-ErbB2 (AB2428) TNF -α MCF -7 [171]
Peptide K4YRGD Doxorubicin HepG2 [172]
Transferrin
Cyclic -RGD Camptothecin Panc -1, HFF, BF549, MDA -MB-
435 [173]
RGD Doxorubicin U87 MG & COS 7 [174]
TAT Doxorubicin HeLa [155]
MCF -7/ADR [175]
Camptothecin HeLa, A549 [176]
cRGDyK Sunitinib U87MG [177]
c(RGDfE) Gemcitabine BxPC -3 [178]
RGDFFFFC Doxorubicin U-87 MG, COS7 [179]
K7RGD c -RGDFK HeLa [180]
N3GPLGRGRGDK -Ad Doxorubicin SCC -7 , HT -29 [181]
K8(RGD)2 Doxorubicin U87 MG [182]
pHLIP Doxorubicin MCF -7/ADR, mA549, U20S,
H1299, HepG2 [183]
Protein EGF HuH7tub [164]
Transferrin Doxorubicin HeLa, MRC -5 [184]
Doxorubicin &
Paclitaxel U-87 MG -luc2 [156]
Aptamer AS1411 Doxorubicin MCF -7 [185]
Sgc8 Doxorubicin HeLa [157]
TBA A 15 Docetaxel HeLa [186]
Saccharides Galactose Camptothecin HCT -116, MDA -MB-231, Capan –
1 [144]

Mannose TPE-PDT MCF -7, MDA -MB-231, HCT -116 [18, 187]
Hyaluronic acid Camptothecin MCF -7, L929 [188]

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Table 3. A timeline of evolution of MSNs and their cancer theranostics .

Year Structural Evolution of MSNs Applications Reference

I. Synthesis of MSNs, their structural modifications and functionalizations

1990 Mesoporous silica materials first synthesized using Stöber process [245]
1992 Mesoporous silica material with hexagonal porous structure [31, 246]
1997 First submicro n MCM -41 particles using a modified Stöber process [247]
1999 Initiation of functionalization of MSNs with various organic functional groups Loading of drugs into pores of MSNs by co-condensation and
post-synthetic grafting method [248]
2001 Synthesis of MCM -41 particles using a dilute surfactant solution (100 nm) [249]
2004 Synthesis of MSNs using a double surfactant system or dialysis process
(below 50 nm) [250]
2004 Synthesis of MSNs surface functionalised with second generation (G2)
PAMAM dendrimers [251]
2006
onwards Chemical modifications on MSNs with Small molecules (Folic acid and
Mannose), Biomacromolecules (Proteins and Antibodies) and
Bio-oligosomes (Peptides and aptamers) Trigger receptor -mediated endocytosis by selective binding
on cell surface receptors See Table 1
2009 Metal -core MSNs (embedded with gold, silver or iron oxide) Provide additional functionalities like, antimicrobial activity,
plasmonic effect or MRI capabilities [84, 252, 253]
2009
onwards
Functionalisation of MSNs with various organic functional groups, e.g.
PEI-coated MSNs
PEG -coated MSNs
PEI-FA functionalised MSNs
MSNs with PEI -PEG copolymer coating Targeting of cancer cells, drug delivery loading of drugs into
pores of MSNs by covalent attachment – by electrostatic
interaction, to adsorb siRNA and DNA constructs in vitro [13, 152,
159, 235,
254-258]
2013 Hollow -type and rattle -type MSNs [75, 87, 93]
2012 Synthesis of hollow silica/titania nanoparticles (HNPs) incorporating the
monoclonal antibody Herceptin Interior drug loading for reduced cancer cell viability. [259]
2012 Synthesis of core/shell magnetic MSN (MMSN) encapsulating nanodiamonds,
gold nanoparticles or graphitic carbon as the core of nanoparticles Theranostic applications, combined photothermal therapy
and chemotherapy for IR -light induced controlled drug
release [84, 88, 89,
242, 243,
260-263]
2013 Synthesis of MSNs with different configurations of mesopores with tunable
pore diameters – raspberry, stellate, worm -like [264]
2013 Au-capped MSNs For enzyme and substrate co -delivery [11, 193,
265]
2013 CdS QD -capped photosensitive nano -gated MSNs For CMT drug delivery [190, 266 ]
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II. Mechanized controlled – and trigger responsive – drug release systems

2003 Release of cargo from mesopores by breaking of covalent bonds between Mechanized nanovalves for drug delivery
molecules (e.g. coumarin) [267]
2003 Release of cargo from mesopores by shrinking and swelling of polymer Mechanized nanovalves for drug delivery
chains [268]
2007
onwards Nanovalves: Delivery of cargo from the mesopores by the Shuttling of a
cyclic molecule (e.g. [2]rotaxane) pH-sensitive nanovalve for trapping drug molecules inside the
MSN mesopores, and drug delivery (DOX) from MSNs. Also
help in overcoming cancer MDR [253,
269-275]
2007
onwards Nanoimpellers: Delivery of cargo from the mesopores by the wagging
motion of azobenzene. In vitro delivery of anti -cancer drug for tumor shrinking; NIR
light-induced drug delivery to cancer cells [276-278]
2010
onwards Cargo release assisted by bulky groups (e.g. Au, Fe3O4 nanoparticles,
CdS nanocrystals, rotaxanes, dendrimers, polymers, proteins,
coordination compounds) over the pore openings Surface functionalised MSN -based multifunctional theranostic
supramolecular assemblies. [163, 190 –
196, 279 -282]
2010 -11 Temperature sensitive MSN -Drug configurations Trigger -responsive nanovalves for drug delivery [199-201,
203-205, 207 –
210, 220, 252,
270, 271, 284,
285] pH-sensitive MSN -Drug configurations
UV light-sensitive MSN -Drug configurations
2007
onwards Various designs for light -responsive triggers – Rotaxanes
Cyclodextrins, Azobenzene -based nanoimpellers Drug delivery from MSN materials for PDT treatment [286-289]

III. Multifunctionalised MSNs for multifunctional applications

2011

2012

2012 Combination of QDs and MSNs

Gold capped -magnetic core/mesoporous silica shell nanoparticles
(AuNRs -MMSNEs)

DOX -loaded nanoellipsoids consisting of ellipsiodal Fe 3O4 cores, and
PEGylated gold nanorods conjugated -mesoporous silica shells
Affinity for multi -therapeutic drugs
Combined photothermo -/chemo -therapy and multimodal
imaging
A multifunctional platform enabling – Chemotherapy,
Phototherapy, T2 -wieghted MRI, Infrared thermal imaging and
dark-field optical imaging [244]

[242]

[290]
2013 CPT drug loaded -MSN mesopores capped with CdS nanoparticles Nanodevice for combination anti -cancer therapy [266]
2010, 2012 Gold nanocrystal -coated MSNs containing gold nanorods Plasmon -induced thermotherapy, TPE of tracers, and deep
tissue drug release [291, 292]
2010 Development of first trifunctionalised MSNs, incorporating a fluorescent
reporter, a peptide, and a photose nsitizer Tracking, targeting α 2β3 integrin expression, and for
photodyanamic therapy [293]
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2010 Coating of PEGylated -phospholipids onto hydrophobic, silane -modified
MSNs, combined with FITC and folate ligands Improve water suspension stability of MSNs and decrease
nonspecific protein binding, for imaging tracer, and for
targeting ligand [294]
2011 -13 Magnetic, pH -sensitive, Fe3O4 nanoparticle -capped MSNs Smart drug delivery platforms that prevent premature release
of conveyed cargo [280, 295,
296]
2012 MSNs embedded with iron oxide nanocrystals, and surface functionalized
with thermo -responsive copolymer PEI/NIPAM For treatment of MDR cancers where drug release is controlled
by external, alternating magnetic field. [297]
2012 A triple core/shell nanomaterial containing Fe3O4@SiO2@α -NaYF/Yb,Er,
with a nanorattle structure, and a middle hollow interior loaded with DOX. In vivo magnetic drug delivery system, and cancer targeting
based on applied magnetic field [298]
2012 Mesoporous silica coated with NaYF 4:Yb,Er upconversion fluorescent
nanoparticles (UCNs) Demonstration of NIR -light induced PDT treatment by in vitro
and in vivo studies [299]

IV. siRNA and pDNA delivery by MSN -based drug carriers

2010 -11 PEI-coated MSNs Adsorption of siRNA and DNA constructs in vitro [254, 256]
2009, 2011 Amino acid -functionalised layer porous MSNs Adsorption of plasmid DNA with lower cytotoxicity [300, 301 ]
2011, 2013 Fe3O4-inner core magnetic MSN DNA adsorption/desorption and for siRNA delivery after
surface modification of PEI and KALA peptides. [302-304]
2012 DOX -loaded, TAT functionalised MSN nanoparticles Targeted drug delivery to the nuclei of cancer cells [305]
2014 MSN -loaded with topotecan, and mitochondria -targeting moiety conjugated
to an antibiotic peptide. Targeted drug delivery to the nuclei and mitochondria of
cancer cells [236]
2009 siRNA/DOX MSN -based nanocarrier Simultaneous delivery of DOX and BCL -2 targeted siRNA
into cancer cells [233]
2013 PEI-coated functionalized MSNs Delivery of DOX and Pgp siRNA to cancer cells (both in vitro
and in vivo ) [234, 256,
306]
2014 Histidine -functionalised MSN pDNA transfection [307]
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