Mesoporous Silica Nanoparticles as a Prospective and Promising Approach for Drug Delivery and Biomedical Applications

Abstract

Background:
With the development of nanotechnology, nanocarrier has widely been applied in such fields as drug delivery, diagnostic and medical imaging and engineering in recent years. Among all of the available nanocarriers, mesoporous silica nanoparticles (MSNs) have become a hot issue because of their unique properties, such as large surface area and voidage, tunable drug loading capacity and release kinetics, good biosafety and easily modified surface.

Objective:
We described the most recent progress in silica-assisted drug delivery and biomedical applications according to different types of Cargo in order to allow researchers to quickly learn about the advance in this field.

Methods:
Information has been collected from the recently published literature available mainly through Title or Abstract search in SpringerLink and PubMed database. Special emphasis is on the literature available during 2008-2017.

Results:
In this review, the major research advances of MSNs on the drug delivery and biomedical applications were summarized. The significant advantages of MSNs have also been listed. It was found that the several significant challenges need to be addressed and investigated to further advance the applications of these structurally defined nanomaterials.

Conclusion:
Through approaching this review, the researchers can be aware of many new synthetic methods, smart designs proposed in the recent year and remaining questions of MSNs at present.

Full text

Current Cancer Drug Targets
ISSN: 1568-0096
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BENTHAM
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Current Ca ncer Drug Targets, 2019, 19, 285-295
285
REVIEW ARTICLE
Mesoporous Silica Nanoparticles as a Prospective and Promising Ap-
proach for Drug Delivery and Biomedical Applications
Xiaohui Pua, Jia Lia, Peng Qiaoa, Mengmeng Lia, Haiyan Wanga, Lanlan Zonga,b,∗, Qi Yuana and
Shaofeng Duana,∗
aInstitute of Materia Medica, School of Pharmacy, Henan University, Jinming Road, Kaifeng, 475004, China; bNational
& Local Joint Engineering Research Center for Applied Technology of Hybrid Nanomaterials, Henan University, Jin-
ming Road, Kaifeng, 475004, China
A R T I C L E H I S T O R Y
Received: June 04, 2 018
Revised: June 11, 2018
Accepted: November 26, 201 8
DOI:
10.2174/1568009619666181206114904
Abstract: Background: With the development of nanotechnology, nanocarrier has widely been ap-
plied in such fields as drug delivery, diagnostic and medical imaging and engineering in recent
years. Among all of the available nanocarriers, mesoporous silica nanoparticles (MSNs) have be-
come a hot issue because of their unique properties, such as large surface area and voidage, tunable
drug loading capacity and release kinetics, good biosafety and easily modified surface.
Objective: We described the most recent progress in silica-assisted drug delivery and biomedical ap-
plications according to different types of Cargo in order to allow researchers to quickly learn about
the advance in this field.
Methods: Information has been collected from the recently published literature available mainly
through Title or Abstract search in SpringerLink and PubMed database. Special emphasis is on the
literature available during 2008-2017.
Results: In this review, the major research advances of MSNs on the drug delivery and biomedical
applications were summarized. The significant advantages of MSNs have also been listed. It was
found that the several significant challenges need to be addressed and investigated to further advance
the applications of these structurally defined nanomaterials.
Conclusion: Through approaching this review, the researchers can be aware of many new synthetic
methods, smart designs proposed in the recent year and remaining questions of MSNs at present.
Keywords: Mesoporous silica nanoparticles, manufacture technology, drug delivery, biomedical applications, anti-cancer and
target, preclinical trial.
1. INTRODUCTION
Along with the development and wide application of
modern nanotechnology, material development at the
nanoscale level has become a hot issue in recent years.
Nanomaterials, a new category of carriers with the particle
size of 10-1000 nm [1], have been widely used in the field of
chemistry, biology, and pharmaceutics because of their envi-
ronmental friendliness, low cost, good biocompatibility and
low toxicity [2]. Among the available nanomaterials, porous
silica nanoparticles (NPs) have been investigated by numer-
ous studies because of their unique properties, such as large
surface area and void content, tunable particle size and good
biocompatibility [3, 4]. Such materials can be divided into
three categories: microporous with a pore diameter less than
2 nm, macroporous with a pore diameter more than 50
nm, and mesoporous with a pore diameter in between.
*Address correspondence to this author at the Institute of Materia Medica,
School of Pharmacy, Henan University, Jinming Road, Kaifeng, 475004,
China; Tel/Fax: +86-371-25152066;
E-mail: lanlan198903@126.com (Zong L.L.) and
Tel/Fax: +86-371-23880680; E-mail: dsf_2007@163.com (Duan S.F.)
Mesoporous materials have a larger surface area and pore
volume than their macroporous counterparts, and their pore
size is larger than that of the microporous ones, which facili-
tates them in loading drug and providing great loading ca-
pacity [5-8]. Moreover, mesoporous silica materials exhibit a
uniform pore distribution, good stability, high pore volume
and excellent biocompatibility, which are favorable for effi-
cient encapsulation, controllable release [9, 10] and intracel-
lular delivery of therapeutic agents [11, 12] so they have
been considered as good candidates for drug delivery [13]
and biomedical application [14-16].
Since a series of mesoporous silica molecular sieves
(including MCM-41, MCM-48, MCM-50) were first re-
ported by Kresge in 1992 [17], a lot of research work has
been increasing in this field. To date, many synthetic meth-
ods of MSNs have been reported including the incipient wet-
ness method [18], reverse micelle [17, 19], co-precipitation
[20], template-directed method [21], and evaporation-
induced self-assembly [22], among which the template-
directed method has been most widely used. MSNs are syn-
thesized via this method using a supramolecular surfactant
that aggregates into a structure-directing template. Surfactant
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286 Current Cancer Drug Targets, 2019, Vol. 19, No. 4 Pu et al.
micelle interface reacts with inorganic silicon sources to
form a regular and orderly wrapped silica assembly body.
The template material is then removed by calcination or sol-
vent extraction. The silica skeleton was reserved and used to
form ordered porous nanostructures. For instance, Mou [23]
and co-workers developed a series of MSNs via the tem-
plate-directed method using a cationic surfactant for intracel-
lular drug delivery and bioimaging. Che et al. [24] used ani-
onic surfactants as co-structure directing templates to synthe-
size silica nanoparticles with highly ordered structures. In
2001, the Vallet-Regi group [25] first attempted to use
MCM-41 as the carrier of ibuprofen and opened up MSNs
application in the field of medicine. In the course of the re-
searches on MSNs, the scientists have gradually found that
they have the following advantages in the medical field are
as follows: (1) their large surface areas and/or pore interior
volumes in favor of drug permeation and loading into the
pore channels [26], (2) their easy surface modification for
controlled release and targeted delivery of cargoes, which
increases their versatility and flexibility and reduces their
toxicity [27], (3) their unique mesoporous structures and
adjustable apertures are even more suitable for control drug
loading and release kinetics [28], (4) their good biocompati-
bility due to appropriate biodegradation, biodistribution and
excretion, even at high doses of silica nanoparticles [29], and
(5) bioactive materials for bone regeneration as magnetic
candidates [30], (6) simultaneous drug delivery and bioimag-
ing by combination with magnetic and/or luminescent com-
pounds [31, 32]. In addition, MSNs have caused a great deal
of interest in biomedical and biosensing applications [33-35].
Herein, we highlight the recent advances in silica-assisted
drug delivery and biomedical application according to differ-
ent types of Cargo, including (1) anticancer drugs, (2) anti-
bacterial agents, (3) gene delivery, (4) photodynamic thera-
peutic agents, (5) bioimaging agents and (6) other silica con-
taining drug delivery systems. Furthermore, we delineate the
bioactivity of MSNs in vitro and in vivo, current status of
preclinical trials, and reactive oxygen species-MSNs.
2. MANUFACTURE TECHNOLOGY OF MESOPO-
ROUS SILICA
Manufacture technology of mesoporous silica nano-
materials mainly includes sol-gel method [36], hydrothermal
synthesis method [37], temperature synthesis, microwave
synthesis [38, 39], precipitation [40] and non-aqueous sys-
tems synthesis method [41]. There are some factors affecting
the synthesis of the mesoporous materials, e.g. species of
surfactant, silicon source, reactant concentration, pH of the
reaction system, reaction time and temperature. In the fol-
lowing paragraphs, we will especially introduce two com-
mon preparation methods of mesoporous silica nano-
materials.
2.1. Sol-gel Method
Sol-gel method is a synthetic method which has been
very widely utilized. Its reaction principle equations mainly
consist of two processes:
1) Hydrolysis reaction: A(OR)n + xH2O→ A(OH)x(OR)n-x +
xROH
2) Polymerization: -A-OH + HO-M- → -A-O-M- + H2O
Sol-gel method combined with template technology
could be used to prepare nanometer materials [42]. Template
agent of inducing supramolecular structure can self-assemble
to form regular and orderly nanometer materials by affecting
the interface between inorganic and organic compounds [43].
Its principle is shown in Fig. (1). Mainly composed of hy-
drolysis and condensation reactions, the sol-gel method is
pretty mild with such merits as controllable reaction condi-
tion and favorable biocompatibility. However, there also
exist some disadvantages like long reaction times, easy gas
escape from the drying process, and material easy to crack,
etc. Therefore, more and more modification work has been
done on Sol-Gel method to overcome the above defects.
Fig. (1). Sol-gel schematic.
2.2. Hydrothermal Synthesis Method
The hydrothermal synthesis, a very simple process em-
ploying surfactant as a template agent, has also been popular
for the preparation of nano-mesoporous materials in recent
years [44]. Briefly, the surfactants are prepared in a solution
of acid or alkali, followed by dropwise addition of inorganic
Si materials [45] under continuous stirring. After being
stirred for a period of time, the mixture solution is loaded
onto the autoclave, followed by a short-time hydrothermal
treatment to obtain the reaction precursor. Finally, the nano-
mesoporous materials are obtained via calcination or other
chemical treatment to remove organic materials, such as sur-
factants. The obtained mesoporous materials have different
structures, assembly, shape and pore size. According to the
mode of action of inorganic ions and surfactants, there are
six different ways to synthesize mesoporous materials (Table
1). For example, MCM-41 could be commonly obtained by
an anion-cation mode with the interaction of silicate ions (I-)
of sodium silicate and surfactant molecules (S+) in alkaline
conditions (hydrothermal temperature 120 C), in which cetyl
trimethyl ammoniumbromide was used as the template and
sodium silicate as the silica source [46].
As for the hydrothermal synthesis method, the precursor
can be completely dissolved and constitute the atomic or
molecular growth units to form a nuclear crystal. Hydro-
thermal synthesis method has a very significant feature [37,
44-46] as the condition that it provides for the preparation of
the precursor and crystallization is far beyond any other
method. As the structure, pore size and morphology of the
product can easily be controlled by the reaction conditions
(such as the ratio of temperature, time, ratios and species of
the reactants and etc.), the hydrothermal synthesis has be-
come a widely used method for the synthesis of nano-
mesoporous materials in recent years [45, 46]. However,
the solution
Preparation of Sol
Stersses
Wet Gel
Remove
of solvent
Heat
treating
Aerogel
Evaporation
Coating
Drying
Dried Gel
membrane Nanoparticles
Nanofilm Nano block
Agglomeration
Dried Gel

Mesoporous Silica Nanoparticles as a Prospective and Promising Approach Current Cancer Drug Targets, 2019, Vol. 19, No. 4 287
Table 1. The syn thesis of mesoporous materials.
Synthetic Route Medium Conditions Grafting Way Examples of Mesoporous Materia ls
S+I-[107] Alkaline Direct combination MCM-41, MCM-48
S+X+I+[107] Strong acid Link by the middle of the transitional ion MCM-41, SBA-11
S-I+[107] Alkaline Link by electrostatic interactions FeO, PbO
S+M+I-[107] Strong acid Link by the metal cations ZnO, Al2O3
S0I0[44] Neutral Link by hydrogen bonding HMS, MSU
S-I [108] Acidity Link by covalent bonds MCM-41
(S: Surfactant, I: Inorganic silicate ion, X: Transition ion, M: Metal ions).
there still remain such disadvantages as longer reaction time,
cumbersome operating procedures. Hence, it is a great
challenge for the nano-mesoporous materials researchers to
explore a new synthetic method that saves time and energy.
3. THE PREPARATION OF MESOPOROUS SILICA
NANOPARTICLES LOADING CARGO
With the development of nanomaterial science in recent
years, people have had a strong interest in the peculiar prop-
erties of ultrafine particles. Due to the effect of quantum,
nano-sized particles with big surface area and small size of-
ten exhibit more interesting physical and chemical properties
than their bulk counterparts [47, 48], e.g. light sensitivity,
electricity sensitivity, and heat sensitivity. Because of the
large surface areas and great pore volumes of MSNs, it can
provide the research of superfine particles with better mate-
rial conditions, and thus obtaining its properties of bigger
surface areas, greater pore volumes and higher drug loading.
MSNs mainly have two drug loading methods, namely,
physical adsorption [49] and solvent evaporation [50, 51].
With the physical adsorption method, including situ loading
in the synthesis process and post sorption (via physisorption
or chemisorption), MSNs are soaked in the drug containing
solution until equilibrium is reached [52]. During the proc-
ess, most drugs can enter into the pore channels of the carrier
due to the interactions between mesoporous surface and
drugs such as hydrogen bonding, ionic bonding, electrostatic
and hydrophobic interaction. The extent of drug adsorption
can be further increased through surface modification of
MSNs. For example, Popova et al. [53] modified the surface
of MSNs by the 3-amino-propyl triethoxy silane (silane cou-
pling agent). Compared with undecorated MSNs, the loading
of sulfadiazine has increased from 39% to 50% while its
release in vitro was significantly slow. This is because the
force between the amino of sulfadiazine and the carboxyl on
the surface of MSNs is significantly higher than undecorated
silicon-hydroxyl. Xie et al. [54] prepared a series of
mesoporous silica nanoparticles (DOX-MSN/COOH) to load
doxorubicin and functionalized by negative-charge, and then
successfully used for imaging and targeting therapy of hepa-
tocellular carcinoma. The in vitro studies showed that DOX-
MSN/COOH manifested greater cytotoxicity and fewer side
effects than free DOX (Fig. 2), and that the nanoparticles
could easily be endocytosed by liver cancer cells (HepG2)
and well-accumulated in this organ by passive targeting. The
in vivo studies proved the ability of DOX-MSN/COOH to
inhibit tumor growth and prolong the survival time of mice
bearing hepatocellular carcinoma in situ. Moreover, the his-
tological examination showed no histopathological abnor-
malities of normal liver cells and heart cells after the treat-
ment with DOX-MSN/COOH, while the administration of
free DOX caused harm to these organs. The other drug load-
ing method, solvent evaporation [55], includes physical ad-
sorption, following rapid solvent evaporation. The solubiliz-
ing speed of drug by the solvent evaporation is faster than by
the physical absorption method, which could be attributed to
that the drug absorbed or loaded on the surface of MSNs
immediately is broken down. Yet, drugs in the pores take a
longer time to dissolve and subsequently diffuse into the
release medium.
Fig. (2). (A) In vitro cytotoxicity of blank MSN/COOH against
HepG2 cells for 24 h. (B) In vitro cytotoxicity of free DOX or
equivalent DOX concentration of DOX-MSN/COOH against
HepG2 cells for 24 h. Results are expressed as means±the standard
error from three independent experiments, each performed in dupli-
cate. (Modified after Xie, et al. [51]).
120
90
60
30
0
0.01
0.02
0.2
1
2
10
20
50
250
0.1
0.2
0.5
1
2
4
10
100
80
60
40
20
0
Concentration(mg mL )
-1
Concentration(mg mL )
-1
Free DOX
DOX / MSN-COOH
Cell viability (%) Cell viability (%)
A
B

288 Current Cancer Drug Targets, 2019, Vol. 19, No. 4 Pu et al.
4. DRUG DELIVERY AND BIOMEDICAL APPLICA-
TIONS
4.1. Anticancer Drugs
Cancer is the primary cause of death worldwide. Among
cancer diagnosis and therapeutic drug, conventional chemo-
therapy agents often show low water solubility, poor clinical
curative effect and serious side-effects. New genetic engi-
neering drugs have poor solubility, short half-life, and low
bioavailability mainly because of the nonspecific cell/tissue
biodistribution and destruction by drug metabolizing en-
zymes in the body during blood circulation. Efficient MSNs
contribute to solving the problems of drug delivery systems.
The development of mesoporous silica materials in the past
decades has promoted the progress of various nanocarriers
for laboratory study and clinical application as drug delivery
systems to overcome these problems [56]. Mesoporous silica
has good biocompatibility, water solubility and stable
chemical properties. Its surface is easily functionalized and
its large pore volume is conducive to load drug molecules.
Mesoporous silica can be modified by targeting molecules
[57, 58], magnetic particles [59], fluorescent molecules [60]
to form a multi-functional drug delivery system. According
to different functional modification, the functionalized
mesoporous silica conveying system can be divided into
targeted delivery system (such as connection biomolecular
folic acid [58, 61], polypeptide molecule [62], magnetic
modification [63], hyaluronic acid [64]) and fluorescent
imagining system [65] (such as fluorescent dyes [66], quan-
tum dots, rare earth luminescent material, etc.). These versa-
tile nano-drug delivery systems require that targeting, imag-
ing, diagnosis and treatment be effectively mixed into a car-
rier. MSNs have a wide range of applications in drug deliv-
ery system, such as oral administration, injective and tar-
geted administration, intelligent drug delivery, MSNs-based
composite delivery system. In recent years, tumor diagnosis
and treatment have become hot issues. For example, MSNs
delivery system loading testing reagent with a highly sensi-
tive probe can detect cancer or tumor markers and receive
more intuitive tumor imaging, which is helpful for early di-
agnosis of tumor and to explore the formation mechanism of
tumor at the molecular level. MSNs probes can detect tiny
amounts of tumor cells and tumor markers. Qian et al. [67]
detected immunoglobulin G antigen (IgG) and carcinoem-
bryonic antigen (CEA) accurately by water-soluble quantum
dots coated with MSNs. MSNs with optical dyes, radionu-
clides or magnetic contrast agents as a probe can obtain
highly specific and sensitive imaging, therefore it can im-
prove cancer detection rate. More and more imaging diagno-
ses and medical therapies with MSNs emerged, which has
built a platform to meet the different requirements of multi-
function tumor diagnosis and greatly promote the treatment
and research of tumor.
MSNs drug delivery system delivers drugs to cancer
sites, mainly through the active target, passive target or
physical target. In vivo studies showed that active targets of
MSNs mainly use folic acid as a targeting ligand. Yang et al.
[68] constructed novel type of pH-sensitive multifunctional
envelope-type mesoporous silica nanocontainers (SBDAPF)
for targeting drug delivery to cancer cells by folic acid (FA).
FA was applied as a targeting index and bonded on the PEG
outer layer to achieve active-targeting ability. According to
in vitro experiments, it was proven that SBDAPF could ten-
dentiously cling to the surface of tumor cells through a me-
diation with folate receptor and be endocytosed into cells so
that SBDAPF could accumulate the loaded DOX in cancer
cells when exposed to slightly acidic intracellular microenvi-
ronment and finally killed cancer cells.
4.2. MSNs-based Stimuli-responsive Contro lled Drug
Delivery Systems
4.2.1. pH Sensitive Controlled Drug Delivery Systems
The pH value of the normal blood is about 7.4, but in tu-
mor cells has it lower pH. The reason is that tumor tissue
reproduces rapidly and the cells produce large amounts of
lactic with anaerobic respiration. Thus, researchers use the
natural difference in the human body to control drug release,
achieve targeted drug delivery and improve bioavailability of
the drug. The pH-responsive controlled release systems are
mainly divided into two types. One is to use responsive poly-
mers as pore gatekeepers. These polymers usually bear some
ionizable acidic (Carboxyl, sulfonic group, etc) or basic
groups (Primary amine, tertiary amino, secondary amino)
which are sensitive to tiny pH changes in the microenviron-
ment and prompt to change the physical properties of the
polymer, such as size, shape, hydrophobicity and so on.
These responsive polymers generally include polypropylene
acid polymers [69, 70] (PAA, PMAA, PEAA, etc.) and ami-
ne-containing polymer [71, 72] (PDMAEMA, PDEAEMA,
PVP, etc.). The other method is that drugs are connected to
polymers or polymer chains with an introduction by some
environment-sensitive linkages, such as hydrazone bonds,
amide linkages, cis-aconitic acid research bonds, acetal or
ketal bonds, etc. Drugs are released by bond breakage and
structural degradation under the particular pH value. Jun
Wang et al. [73] covered polyelectrolyte multilayers (PEM)
of chitosan (CHI)/dialdehyde starch (DAS) onto the surface
of MSNs by a layer-by-layer assembly method. DOX release
behavior of the DOX-MSN@PEM nanoparticles was inves-
tigated at pH 7.4 and 5.0 over a period of 72 h, respectively.
The drug release rate was obviously pH dependent and in-
creased with the diminution of pH value. After 72 h, about
34.25% of the DOX was released at pH 5.0, while less than
9% of the DOX was released at pH 7.4. This difference of
release rate should mainly be attributed to the pH depend-
ence of cleavage of the C=N, which is sensitive to pH
change.
4.2.2. Light-stimuli Responsive Controlled Drug Delivery
Systems
Light as a "trigger" can accurately control drug release,
and has a good prospect in clinical applications. Light-
sensitive polymers (azobenzene derivatives, o-nitrobenzyl
alcohol, coumarin dimers, etc.) were linked onto the surface
of MSN. For instance, Wang et al. [74] synthesized
Fe3O4@nSiO2 with core-shell structure and covalently
grafted light-responsive azobenzene derivatives on the sur-
face, which integrated magnetic targeting and stimuli-
responsive release property. Presence and absence of light
actuation (450nm) triggers the release of ibuprofen (IBU)
loaded in the mesopores. After 10h, the rates of drug cumu-
lative release respectively were 100% and 0%. In addition,

Mesoporous Silica Nanoparticles as a Prospective and Promising Approach Current Cancer Drug Targets, 2019, Vol. 19, No. 4 289
Shun Yang [75] assembled photodegradable amphiphilic
copolymer onto the surface of the hollow mesoporous silica
(HMS). The cumulative release rate of the drug significantly
improved via the irradiation of green light (540nm). The
experimental results showed that light stimulation could con-
trol the release of the drug.
4.2.3. Redox-responsive Type
Mesh disulfide compounds can trap drug molecules in
the mesoporous. Glutathione (GSH) levels in tumor cells are
100 to 1000 times of those in extracellular. Therefore, disul-
fide bond will be unstable and release the drug in GSH re-
ductive environment after the carrier enters into the tumor
cells [76]. In vitro, we can add disulfide reducing agent such
as DTT, GSH or ME. Luo et al. [77] used a redox-cleavable
disulfide bond as an intermediate linker via grafting
adamantanamine onto the orifices of HMSNs. Lactobionic
acid-grafted-b-cyclodextrin (β-CD-LA), was immobilized
onto the surface of HMSNs through specific complexation
with the adamantyl group, where β -CD served as an end-
capper to keep the loaded drug in HMSNs. The released
amounts of DOX increased to over 82% after being treated
with 10 mM GSH for 26 h, while only 9.2% without stimula-
tion. The survival rate of HepG2 cells treated by drug-
loading nanoparticles was obviously lower than that treated
by free DOX. Zhang et al. [78] packaged solidified cyto-
chrome c (CytC) onto the MSNs as a doorkeeper via disul-
fide bonds for redox-triggered intracellular drug delivery.
AS1411 aptamer was further loaded onto MSNs for
cell/tumor targeting. About 78.9% of FITC was released
from MSNs-CytC-Apt system after being stimulated with
DTT incubation for 3h, however only 5.11% of FITC was
released when the cells were not treated with DTT (Fig. 3).
Fig. (3). Cumulative release profiles of FITC from MSNs-CytC-
Apt@FITC with (●)/without(■) DTT, respectively (Revised from
Zhang, et al. [75]).
4.3. Gene Delivery
Gene carriers can be divided into two categories: viral
and non-viral vectors. Viral vectors [79-81] have higher effi-
ciency and are widely used in target cells, which is attributed
to their strong transport capacity and exogenous gene ex-
pression. The exogenous gene is wrapped onto the virus shell
of viral vector, and then carried into the host cell by cell in-
fectivity of the virus. However, viral vectors also have some
disadvantages: cytotoxicity and high immunogenicity, likely
to cause inflammation, high cost, limited size and loading
amount of DNA. To compensate for the above-described
defects of viral vectors, non-viral vectors [82, 83] which
have low toxicity and immune response is progressively de-
veloped. Non-viral vector delivery can be acquired by
magnetofection, electroporation and sonoporation. In recent
years, MSNs in the form of DNA-carrier complexes and po-
rous polymer nanoparticles have been studied as potential
carriers. For example, Chen et al. [84] encapsulated vascular
endothelial growth factor (VEGF)-small interfering RNA
(siRNA) into a magnetic mesoporous silica nanoparticle (M-
MSN)-based, polyethylenimine (PEI)-capped, polyethylene
glycol (PEG)-grafted, fusogenic peptide (KALA)-functiona-
lized siRNA delivery system, termed M-MSN-VEGF
siRNA@PEI-PEG-KALA, which showed significant effect
on the VEGF gene silencing in vitro and in vivo. The pre-
pared siRNA delivery system showed selective cellular in-
ternalization and easy endosomal escape, resulting in re-
markable RNAi effect without related cytotoxicity in
SKOV3 cells. In the in vivo studies, prominent impediment
of tumor increase was observed in orthotopic oophoroma-
bearing mice, which was put down to obvious inhibition of
angiogenesis by intravenous administration of this nanocar-
rier. Further, the magnetic core of M-MSN-VEGF siRNA
@PEI-PEG-KALA proved to be able to explore the site and
size of ovarian cancer in mice on magnetic resonance imag-
ing.
4.4. MSNs in Alternative Therapeutic Strategies: Pho-
todynamic Therapy
Photodynamic therapy [85] (PDT) combined with photo-
sensitizer and light source is an effective therapeutic method
which selectively destroys the target tissue via photodynamic
reaction. The PDT includes three parts: visible light,
photosensitizer, and tissue oxygen [57]. The photosensitizer
is a lipid molecule which naturally permeates the hydropho-
bic bilayer and accumulates at desired sites to induce apopto-
sis of tumor cells. When the photosensitizer which has ab-
sorbed photons, transfers its photon energy to the surround-
ing molecular oxygen, the excited delta singlet oxygen (1O2)
and other reactive oxygen species are produced. Singlet oxy-
gen leads to oxidative damage towards tumor cells or tissues,
which further induces cell apoptosis. PDT has many advan-
tages, such as low toxicity and less injury [86], but its cura-
tive effect is limited because of the hydrophobic photosensi-
tizer, easy gathering, low singlet oxygen production rate,
poor targeting and other factors. However, MSNs can be
used as an effective carrier to load the hydrophobic photo-
sensitizer because of their good structural properties. Their
pore structure also enhances the permeability of oxygen
molecules and singlet oxygen, which has attracted wide-
spread attention. As such, PDT combined with drug delivery
or imaging patterns has a great potential clinical prospect.
4.5. Non-cancer Application
The drug delivery property of MSNs has attracted much
attention in different medical fields. MSNs can package os-
teogenic agents which accelerate the formation of new bone
in vivo. In this case, MSNs act as bone regenerators. The
with DTT
without DTT
Apt@FITC
Apt@FITC
MSNs-CytC-
MSNs-CytC-
100
120
80
60
40
20
0
0 5 10 15 20 25 30
Time (hours)
Release percentage (%)

290 Current Cancer Drug Targets, 2019, Vol. 19, No. 4 Pu et al.
ability of MSNs to ship osteogenic agents demonstrates the
potential for designing MSNs with particular applications in
medicine. Mendes et al. [87] evaluated the loading capacity
and release of different concentrations of osteogenic growth
peptide (OGP) for application in bone rebirth via the prepa-
ration of inorganic mesoporous materials from silica, cal-
cium phosphate and a nonionic surfactant. Meanwhile,
MSNs have other potential applications in other medical
fields. For example, MSNs are identified as a promising vac-
cine delivery material [88] and potentiated antigen-specific
T-cell response [89].
4.6. Other Silica Containing Drug Delivery Systems
4.6.1. MSN-based Proteins Agent Delivery
As a promising therapeutic drug, protein has been widely
used in the field of cancer treatment, regenerative medicine
and vaccine. The inner attribute of protein has limited its
application in the drug delivery system as follows: (1) fluid
containing rapid degradation of protease or peptide enzyme;
(2) a weak structure, which causes degeneration; and (3)
membrane impermeability. Thus, MSNs may be a preemi-
nently potential drug carrier. MSNs with tunable pore size
entered cells by endocytosis, which effectively pipes the
drug into cells. Moreover, MSNs can be used in the field of
vaccine, which increases the immune response. Mody et al.
[90] delivered a model protein antigen ovalbumin (OVA) in
mice with MCM-41 mesoporous silica nanoparticles as the
means of novel vaccine delivery. The experimental results
indicate that AM-41 nanoparticles were vaccine adjuvant and
caused an immune reaction at smaller dosages of antigen
compared to a traditional delivery system. More importantly,
there were no topical and systemic side effects in animals
administrated with AM-41 nanoparticles.
4.6.2. MSN-assisted Bioimaging Application
Because of their size and versatile chemistry, nanomate-
rials have gained attention as powerful tools for bioimaging
application. As nanomaterials, MSNs could offer an optically
transparent solution for fluorescent agents as their particle
size would not inhibit the emission of fluorescent agents.
The wet surface of MSNs could render the fluorescent agents
well disperse in aqueous solution. Therefore, MSNs have
been widely used as a carrier of fluorescent agent in the field
of tumor metastasis detection [65], diagnostic imaging [60],
and so on.
Liu et a l. [91] developed a kind of NIR dye (Cy754, with
the emission wavelength of 795nm)-based mesoporous silica
nanoparticles (Cy754-MSNPs) which bear a core/shell struc-
ture. An additional thin silica shell was selected to install the
outer layer for the improvement of the photostability of MSN
The Cy754-MSNPs were used for PA and fluorescence dual
modalities imaging to visualize T-SLNs in a 4T1 tumor me-
tastasis model were visualized by virtue of the fluorescence
dual modalities imaging. These SLNs are so stable that the
signals from them drained by tumor are detectable up to 2
weeks.
The functional nanoparticles had potential use for the
controlled release of multi-component. Xie et al. [54] pre-
pared MSNs functionalized using carboxyl groups and a
near-infrared fluorescent dye (MSN/COOH-Cy5). The deliv-
ery system was made suitable for the controlled release of
drug and simultaneous bioimaging by the conjugation of a
near-infrared (NIR) fluorescent dye to the surface of
MSN/COOH, as tissues (or cells) emit low auto-fluorescence
in the region of NIR fluorescence which has a large penetra-
tion depth.
Multifunctional MSNs-based composite nanoparticles
(M-MSNs) have been developed with different structures,
compositions and functionalities. MSNs integrated with con-
trast agents (CAs) can be endowed with the capability of
diagnostic imaging and simultaneous chemotherapy, which
is typically regarded as the theranostic function [60].
5. IN VITRO BIOACTIVITY
Previous studies have shown that MSNs could be effi-
ciently endocytosed and trafficked in mammalian cells. It is
well known that cellular uptake and subsequent intracellular
process determine the final delivery efficiency of guest mole-
cules by nanocarriers [92-94]. Current evidence indicates that
the nanoparticles could enter cells by means of endocytosis. It
is obvious that different endocytotic pathways, such as
clathrin-mediated endocytosis, caveolae-mediated endocyto-
sis, and macropinocytosis, might affect the intracellular kinet-
ics and final fate of nanoparticles loading guest molecules
[95]. For a deeper understanding about the intracellular fate of
nanocarriers and efficiently delivery of encapsulated guest
molecules into specific cells, much attention should be paid to
the research on cellular uptake kinetics, the concerning uptake
mechanism, and the intracellular trafficking as well. As yet, it
has been demonstrated that the uptake behavior could be
controlled by cell types and the features of nanoparticles, such
as size, particle composition, and surface chemistry. Jia et al.
[96] prepared MSNs of three pore size (PTX-MSN0, PTX-
MSN1h and PTX-MSN2h) via the etch method, and then loaded
paclitaxel (PTX) into these MSNs. In vitro release of pure
drug and drug loaded in MSNs was conducted in PBS solution
(pH 7.4). The result showed that the release rate of PTX-
MSN2h was fastest among the three MSNs. The possible ex-
planation is that the PTX molecules loaded in the relatively
large pores (MSN2h was 9.68 nm) had a bigger probability of
releasing from pores channels and then diffusing into the re-
lease medium compared to the other two MSNs (Fig. 4).
Fig. (4). In vitro anti-tumor activity of free PTX and PTX-loaded
MSNs against MCF-7 cells after 72 h incubation (n=3 experiments)
(Reprinted from Jia, et al. [93]).
PTX-MSNO
PTX-MSN1h
PTX-MSN2h
PTX-solution
7.8 15.6 31.25 62.5 125 250
(ng/mL)
Paclitaxel concentration
Inhibitory rate (%)
0
20
40
60
80
100

Mesoporous Silica Nanoparticles as a Prospective and Promising Approach Current Cancer Drug Targets, 2019, Vol. 19, No. 4 291
6. IN VIVO PERFORMANCE AND BIOACTIVITY
Ideal and efficient transmission systems not only deliver
targeted drug molecules, but also release drugs in the target
area. In order to reduce the drug adverse reactions, many
anti-cancer drugs demanded a zero-order release before
reaching lesions sites. The traditional drug carrier of
mesoporous material can adjust its own structure parameters
to control the drug release. In the study on distribution in
mice, it was found that this kind of material was widely dis-
tributed in the liver, lung and kidney (80%) after intrave-
nous administration. In addition, the particle size has an ef-
fect on clearance rate [97]. Smaller size could quickly move
through urine and bile, but bigger size was easily gathered
and phagocytosed by macrophages in the liver and kidney
instead. Zhang et al. [78] conjugated immobilizing cyto-
chrome c (CytC) onto the MSNs as “door guarder” via
intermediate linkers of disulfide bonds and used it for redox-
responsive intracellular drug delivery. AS1411 aptamer was
subsequently tailored onto MSNs for cell/tumor targeting. To
examine the anticancer effect of MSNs-CytC-Apt@DOX,
heterotopic xenografts of human liver hepatocellular carci-
noma were established by subcutaneous injection of HepG2
cells at the right lateral abdominals of 18 nude mice (3 per
group). Three days after injection, tumor-bearing nude mice in
different groups were treated by periodic caudal vein injection
of equivalent saline, MSNs, MSNs-CytC-Apt, free doxorubi-
cin (DOX), MSNs@DOX and MSNs-CytC-Apt@DOX, re-
spectively. It was revealed that tumor growth was negatively
inhibited by the conjugated CytC and AS1411 aptamer. Most
importantly, MSNs-CytC-Apt@DOX had a final tumor vol-
ume of around 156 mm3, which represented the highest tumor
inhibition among all groups.
7. CURRENT STATUS OF PRECLINICAL TRIALS
MSNs have been commercially available for clinical di-
agnosis and treatment because of their biocompatibility, bio-
degradability, and nontoxicity. Lately, Cornell dots [98] (C
dots) have been approved by the Food and Drug Administra-
tion (FDA) to investigate new drug approval of their class
and properties for a first-in-human clinical trial. This has an
important directive meaning on the development and clinical
application of silica nanoparticles. Herein, the current re-
search progress and future challenges of MSNs are described
and discussed.
7.1. Evaluation of Particle Design
This study was carried out by Chen et al. [99], where
three generations of MSN (DOX, MSN-DOX, and P-MSN-
DOX groups) were tested for the antitumor efficacy evalua-
tion in vivo. They used subcutaneous S-180 tumor-bearing
mice, one of the classical tumor models so far, as the animal
model. It was disclosed that the blank P-MSN had no anti-
tumor effect. Among the DOX, MSN-DOX, and P-MSN-
DOX groups, the tumor weight of the P-MSN-DOX group
was the smallest. This result was consistent with the antitu-
mor effect of various DOX nanoparticle formulations. The
antitumor efficacy of P-MSN-DOX was much higher than
that of DOX and MSN-DOX in the subcutaneous S-180 tu-
mor model. However, the antitumor efficacy in vivo for
DOX, MSN-DOX, and P-MSN-DOX was in agreement with
the cytotoxicity in vitro. All these results, the author be-
lieved, could be attributed to the increased local concentra-
tion of DOX in the tumor which resulted from the long circu-
lation time and the EPR effect of MSNs.
7.2. Preclinical Trials
MSNs are a new kind of materials with special structures,
physical and chemical properties, which have been widely
used nanomaterials and biomedicine. MSNs have demon-
strated excellent biocompatibility in vitro/in vivo. To prove
the slow-release, biocompatibility of nanoparticles, it would
be compared with marketed drugs and agents. Next, we will
talk about the studies of Luo et al. [100], where β-
cyclodextrin (β-CD) served as an end-capper to keep the
loaded drug within HMSNs. It was tested for systemic toxic-
ity and therapeutic efficacy along with DOX. To evaluate the
curative effect of DOX-loaded nanoreservoirs in vivo, sixty
mice with tumor models were employed, which were sepa-
rated into five groups. They were intravenously treated with
normal saline, HMSNs, DOX, HMSNs-S-S-Adα/β-
CD@DOX, and HMSNs-S-S-Adα/β-CD-LA@DOX, respec-
tively, three times per week. The average weights of the
mice treated with normal saline, HMSNs, HMSNs-S-S-
Adα/β-CD@DOX and HMSNs-S-S-Adα/β-CDLA@DOX
increased to 25.0g, 24.9g, 24.0g, and 23.6g, respectively.
The results indicated that HMSNs could relieve the toxicities
of DOX in nude mice when they were loaded with the drug.
Moreover, the tumor tissues were measured at predetermined
time points to investigate the changes in tumor sizes after
being treated with DOX and DOX-loaded nanoparticles.
Tumor tissue observations and volume measurements
showed that in vivo tumor sizes increased during the tested
period for treated groups with both saline and HMSNs. It
was also observed that HMSNs-S-S-Adα/β-CDLA@DOX
significantly inhibited the growth of tumors after administra-
tion for 21 days.
7.3. Safety
Many studies have proved that the mesoporous silica
could improve the biocompatibility of nanoparticles and re-
duce cytotoxicity to normal cells [101]. So it has a wide po-
tential for application in the medical field. Wang et al. [102]
investigated the influence of core-shell mesoporous silica
(MPS) on the viability and activation of human THP-1
macrophages compared with colloidal silica particles. To
further investigate the potential cytotoxicity, authors evalu-
ated apoptosis of THP-1 macrophages induced by silica par-
ticles at two concentrations (100μg/mL and 200μg/mL) with
the measurement of activated caspase-3. The results showed
that both silica particles at the concentration of 200μg/mL
induced cleavage of pro-caspase to the active form of
caspase-3. At the concentration of 100μg/mL, activation
amount of caspase-3 in colloidal silica particles groups was
larger than that in core-shell MPS particles groups (Fig. 5).
8. NANOCRYSTALS OF UP-CONVERSION PHOS-
PHOR-MSNS
PDT has many advantages, such as low toxicity and less
injury. But its curative effect is limited because of hydro-
phobility of photosensitizer which readily induces

292 Current Cancer Drug Targets, 2019, Vol. 19, No. 4 Pu et al.
Fig. (5). Effects of core-shell MPS and colloidal silica particles on the cytotoxicity in human THP-1macrophages. (A) CCK8 assay results in
cells treated with the two different types of silica particles at 25~400 μg/mL concentrations for 24 h. (B) The concentration dependent mem-
brane damage as determined by LDH leakage from THP-1 macrophages exposed to silica particles at 24 h. (C) The blot was examined with
anti-cleaved caspase-3 antibody. Data were the mean±SEM of at least three independent experiments. Statistical significance was indicated
by: *P < 0.05 particles treated cells compared with untreated cells, #P < 0.05 core-shell MPS particles treated cells compared with colloidal
silica treated cells. LDH, lactic dehydrogenase; MPS, mesoporous silica (Revised from Wang, et al. [96]).
aggregation, low yield of singlet oxygen, poor targeting and
other factors [57]. Recently, many researches have indicated
that nanocrystals of up-conversion phosphor are an effective
way to solve the challenging problem [103]. Up-conversion
fluorescence materials [104]UCNPsusually consist of
main substrate, activator and sensitizer. NaYF4 [105] and
NaGdF4 are widely studied and most common nowadays in
matrix materials. Photodynamic therapy for cancer treatment
uses nanocrystals of up-conversion phosphor as thermal me-
dia and has the following functions: 1) it overcomes the poor
targeting problem of traditional photodynamic therapy by
active or passive targeting properties. 2) the modified sur-
faces can get the hydrophilic nanocrystals of up-conversion
phosphor. So the nanocrystals of up-conversion phosphor
can be used as supporter loaded hydrophobic photosensitizer
molecule and solve the problem of photosensitizer being
easy to reunite and difficult to transport. 3) Near-infrared
light (NIR, 700~1000 nm range) is the ideal light source for
PDT. Nanocrystals of up-conversion phosphor can be con-
verted into visible light by the excitation of NIR (980 nm).
Then, visible light stimulated the loaded photosensitizer.
NIR, bearing a strong penetration capacity, can overcome the
obstacle of photodynamic therapy which can hardly pene-
trate deep into the tissue. 4) Nanoparticles of up-conversion
phosphor could bring the photosensitizer into deep tissue and
up-convert the highly penetrating near-infrared light into
visible light to excite loaded photosensitizer, which would
effectively overcome the difficulties that non-nanoparticle of
photosensitizer permeated the tissue in PDT. So, nanocrys-
tals of up-conversion phosphor would have a broad range of
application prospects in PDT and biological test.
Wang et al. [106] loaded Chlorine 6 (Ce6) on polymer-
coated UCNPs by the non-covalent modification method to
form a UCNP-Ce6 supramolecular complex. UCNP-Ce6 was
administrated intravenously to mice via the tail vein at dif-
ferent time points after PDT treatment in animal experi-
ments. The results found that 70% of the breast tumor was
completely melted with no tumor re-growth over 2 months.
Compared with the control group, the survival time of the
UCNPs-Ce6 group was obviously prolonged, which proved
that the near-infrared light could reach deeper tissue in vitro
and vivo experiments.
CONCLUSION
In conclusion, the synthesis of MSNs and their applica-
tion in the drug delivery and biomedical field has been de-
scribed. MSNs have their potential advantages in drug deliv-
ery system because of their multi-function structure, poros-
ity, low cytotoxicity and some other good characteristics.
Firstly, MSNs can load drug molecules of different sizes
since their pore sizes and morphologies are adjustable. Sec-
ondly, MSNs could increase the solubility of poorly water-
soluble compounds and enhance their bioavailability because
the silanol groups on their surfaces make them soluble in
water. Lastly, the surface of MSNs was easily modified with
functional groups that were pH sensitive, redox-sensitive,
temperature-sensitive, and so on. Overall, multifunctional
MSNs delivery system shows a good application prospect in
the field of tumor diagnosis and treatment. Nevertheless,
there still remain several questions that need to be overcome
to further advance the applications of these structurally de-
fined nanomaterials. For example, only the delivery technol-
ogy is not enough to make MSNs reach tissues and pass bio-
logical barriers, such as the blood-brain barrier or the intesti-
nal barrier; the long-term biocompatibility of the MSNs-
based nanosystems in vitro and in vivo; safety, biodistribu-
tion and biodegradation need to be systematically addressed
by certified testing systems. Although we have evaluated the
cell toxicity of MSNs, clinical diagnosis and treatment of
MSNs still have a long way to go.
Core-shell MPS particles
Colloidal silica particles
Core-shell MPS particles
Colloidal silica particles
Cleaved Caspase-3
Control
-actin
b
100 200 100 200
Colloidal silica
Dose(mg/mL)Dose(mg/mL)
Core-shell MPS
C
BA
500
550
600
450
400
350
300
0 100 200 300 400 500
(mg/mL)
Concentration
(mg/mL)
Concentration
0 100 200 300 400 500
60
80
100
120
#
#
#
*
*
**
*
Viable cells (% of control)
LDH Activity(U/L)
*
*
*
*

Mesoporous Silica Nanoparticles as a Prospective and Promising Approach Current Cancer Drug Targets, 2019, Vol. 19, No. 4 293
With new generations of powerful and smart nano-
devices unceasingly being introduced to this field of re-
search, we envision that the questions mentioned above will
be overcome and vibrant development will also be brought to
MSNs sooner or later.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
We are grateful for financial support from the National
Nature Science Foundation of China (No. U1304826), from
Science and Technology Development Project of Henan
Province (No. 152102310077) and Key Project of Science
and Technology Research of Henan Provincial Department
of Education (No. 14A350003, 14B350012, 13A350092).
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