Mesoporous silica nanoparticles for drug and gene [624027]

REVIEW
Mesoporous silica nanoparticles for drug and gene
delivery
Yixian Zhoua,†, Guilan Quana,†, Qiaoli Wub, Xiaoxu Zhangc, Boyi Niua,
Biyuan Wua, Ying Huanga, Xin Pana,n, Chuanbin Wua,d,n
aSchool of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
bZengcheng District People's Hospital of Guangzhou, Guangzhou 51006, China
cQingdao Huanghai University, Qingdao 266427, China
dGuangdong Research Center for Drug Delivery Systems, Guangzhou 510006, China
Received 25 September 2017; revised 26 November 2017; accepted 22 January 2018
KEY WORDS
Mesoporous silica
nanoparticles;
Poorly soluble drug;Cancer therapy;Abstract Mesoporous silica nanoparticles (MSNs) are attracting increasing interest for potential
biomedical applications. With tailored mesoporous structure, huge surface area and pore volume,
selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for
therapeutic agents and controlled release properties if modi fied with stimuli-responsive groups, polymers
or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug
bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly,Chinese Pharmaceutical Association
Institute of Materia Medica, Chinese Academy of Medical Sciences
www.elsevier.com/locate/apsb
www.sciencedirect.comActa Pharmaceutica Sinica B
https://doi.org/10.1016/j.apsb.2018.01.007
2211-3835 &2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by
Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).Abbreviations: AO, acridine orange; APTES, 3-aminopropyltriethoxysilane; APTMS, amino propyl trimethoxysilane; BCL-2, B-cell lymphoma-2; BCS,
Biopharmaceutical Classi fication System; Bio-TEM, biological transmission electron microscopy; C dots, Cornell dots; CMC, critical micelle concentration;
CPT, camptothecin; CTAB, cetyltrimethyl ammonium bromide; EPR, enhanced permeability and retention; FDA, Food and Drug Administration; GI,gastrointestinal; GNRs@mSiO
2, mesoporous silica-encapsulated gold nanorods; LHRH, luteinising-hormone releasing hormone; MDR, multi-drug
resistance; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide; MRP1, multidrug resistance protein 1; MSN-Dox-G2, Dox-load ed and
G2 PAMAM-modi fied MSNs; MSNs, mesoporous silica nanoparticles; MSNs@PDA-PEG-FA, poly(ethylene glycol)-folic acid-functionalized poly-
dopamine-modi fied MSNs; MSNs-HA, hyaluronic acid-conjugated MSNs; MSNs-RGD/TAT, RGD/TAT peptide-modi fied MSNs; MSNs-TAT, TAT
peptide-modi fied MSNs; NIR, near-infrared; PAMAM, polyamidoamine; PDEAEMA, poly (2-(diethylamino)ethylmethacrylate); PDMAEMA, poly(2-
(dimethylamino)ethylmethacrylate); pDNA, plasmid DNA; PEG400, polyethylene glycol 400; PEI, polyethyleneimine; P-gp, P-glycoprotein; PLL, po ly-L-
lysine; PTX, paclitaxel; Q-MSNs, quercetin encapsulated MSNs; RGD, arginine-glycine-aspartate; TAT, trans-activating transcriptor; TMB, 1,3, 5-
trimethybenzene
nCorresponding authors.
E-mail addresses: [anonimizat] (Xin Pan), [anonimizat] (Chuanbin Wu).
†These authors made equal contributions to this study.
Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.Acta Pharmaceutica Sinica B ]]]];](]):]]]–]]]
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

Multidrug resistance;
Gene deliverythe exciting progress in the development of MSNs-based effective delivery systems for poorly soluble
drugs, anticancer agents, and therapeutic genes are highlighted.
&2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical
Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).
1. Introduction
In recent years, there has been a rapid growth in the area of
biomedicine, particularly in exploring new drug/gene delivery
systems. More recently, nanotechnology emerged as a promisingapproach which has motivated researchers to develop nanostruc-
tured materials. Among various integrated nanostructured materi-
als, mesoporous silica nanoparticles (MSNs) have become a newgeneration of inorganic platforms for biomedical application.
MSNs with uniform pore size and a long-range ordered
mesoporous structure were first introduced by Mobil corporation
scientists in 1992
1. In general, supramolecular assemblies of
surfactants are necessary in the synthesis of MSNs. Usually, the
surfactant will self-aggregate into micelles at a concentration
higher than the critical micelle concentration (CMC). Then, thesilica precursors can condense at the surface of the micelles
forming an inorganic-organic hybrid material. Finally, the template
surfactant can be removed either by calcination or by solventextraction to generate pores ( Fig. 1 ). The resulting silica-based
mesoporous matrices may offer the following unique structural
and biomedical properties:
1)Ordered porous structure . MSNs have a long-range ordered
porous structure without interconnection between individual
porous channels, which allows fine control of the drug loading
and release kinetics ( Fig. 2 ).
2)Large pore volume and surface area . The pore volume and
surface area of MSNs are usually above 1 cm3/g and 700 m2/g,
respectively, showing high potential for molecule loading and
dissolution enhancement.
3)Tunable particle size . The particle size of MSNs can be
controlled from 50 to 300 nm, which is suitable for facileendocytosis by living cells.
4)Two functional surfaces . MSNs have two functional surfaces,
namely cylindrical pore surface and exterior particle surface.These silanol-contained surfaces can be selectively functiona-
lized to achieve better control over drug loading and release
2.
Moreover, the external surface can be conjugated with targetingligands for ef ficient cell-speci fic drug delivery.
5)Good biocompatibility . Silica is “Generally Recognized As
Safe”by the United States Food and Drug Administration
(FDA). Recently, silica nanoparticles in the form of Cornelldots (C dots) received FDA approval for stage I human clinical
trial for targeted molecular imaging
3,4. It was reported that
MSNs exhibited a three-stage degradation behavior in simulatedbody fluid
5, suggesting that MSNs might degrade after admin-
istration, which is favorable for cargo release. Several in vivo
biodistribution studies of MSNs have been reported recently6,7.
Liu et al.6evaluated the systematic toxicity of MSNs after
intravenous injection of single and repeated dose to mice. The
results of clinical features, pathological examinations, mortal-ities, and blood biochemical indexes indicated low in vivotoxicity of MSNs. It was also reported that MSNs were mainly
excreted through feces and urine following different adminis-tration routes
7.
These unique features make MSNs excellent candidate for
controlled drug/gene delivery systems. Since the first report using
MCM-41 type MSNs as drug delivery system by Vallet-Regi et
al.8in 2001, the research on biomedical application of MSNs has
steadily increased, with an exponential rise in last decade. Variousmesoporous materials with different porous structure and function-
ality have been developed for controlled and targeted drug/gene
delivery. Here, we give an overview of the recent researchprogress and future development of MSNs in biomedical applica-
tions, particularly focused on the practical applications of MSNs as
delivery systems for poorly soluble drugs, anticancer agents, andtherapeutic genes. Based on the review, we have also included our
perspectives on the further applications of MSNs.
2. Mesoporous silica-based system for poorly soluble drugs
With the increasing numbers of innovative new drugs in develop-
ment, almost 70% of new drug candidates exhibit low aqueous
solubility, ultimately resulting in poor absorption
9. In an attempt to
overcome this solubility obstacle and to improve the oral bioavail-
ability, a growing number of drug delivery technologies have been
developed. Presently, nanotechnology is attracting increasing atten-tion as it can be applied in two aspects
10: processing the drug itself
into nano-sized particles or preparing drug-contained nanoparticles
from various materials. With the excellent features including hugesurface area and ordered porous interior, mesoporous silica can beused as a perfect drug delivery carrier for improving the solubility of
poorly water-soluble drugs
11–14and subsequently enhancing their
oral bioavailability15–17.
When water-insoluble drug molecules are contained in meso-
porous silica, the spatial con finement within the mesopores can
reduce the crystallization of the amorphous drug18. Compared with
the crystalline drug, the amorphous drug can reduce the lattice
Fig. 1 Schematic diagram showing the preparation of mesoporous
silica nanoparticles (MSNs).Yixian Zhou et al. 2
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

energy, subsequently resulting in improved dissolution rate and
enhanced bioavailability15,19. Moreover, the huge hydrophilic
surface area of mesoporous silica facilitates the wetting and
dispersion of the stored drug, resulting in fast dissolution20.I n
one example, the poorly water soluble drug clotrimazole wasloaded into MSU-H type mesoporous silica through supercriticalCO
221. The experimental and theoretical results indicated that
clotrimazole was not crystalline and drug molecules were homo-
genously distributed in the mesopores. He et al.22also reported
that the solubility of paclitaxel was signi ficantly enhanced after
loaded into MSNs. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl
tetrazolium bromide (MTT) assay revealed that paclitaxel loadedmesoporous silica nanoparticles exhibited obvious cytotoxicity on
HepG2 cells as compared with paclitaxel. SBA-15 mesoporous
silica was successfully used to accelerate the dissolution rate offurosemide which is a representative class IV drug according to the
Biopharmaceutical Classi fication System (BCS)
23. About 71% of
the drug was released from SBA-15-based preparation at 2 hdissolution, whereas only 49% of drug release from the commer-cial product Lasix. In addition, when the dissolution medium was
changed from pH 3.0 to pH 6.8, the drug was rapidly and
completely released from the inclusion preparation against theincomplete release of 83% drug from the commercial product
during the whole test.
There are several factors which can in fluence drug release rates
from MSNs. Pore size plays an important role in the release rate
since the drug release is mainly controlled by diffusion
24. Jia et
al.25prepared paclitaxel-loaded MSNs with different pore sizes
from 3 to 10 nm. The in vitro drug release test showed that the
release rate decreased as the pore sizes changed from 10 to 3 nm,
which might be attributable to the reason that paclitaxel loaded in
relatively small pores has less opportunity of escaping from poresand diffusing into the release medium. The effect of pore size on
the drug release rate was further veri fied in the celecoxib loaded
mesoporous silica system. The release rate of celecoxib frommesopores increased with the increase of the pore size (3.7 –
16.0 nm)
26. In addition, the surface chemistry is another factor
which can in fluence the drug release rate. Ahmadi et al.27loaded
ibuprofen into amino-modi fied SBA-15. Compared with SBA-15,
the release rate from amino-modi fied SBA-15 was much slower.
This was due to the interaction between carboxyl groups ofIbuprofen and amino groups of the amino-modi fied SBA-15.
Hollow structure was also reported to retard drug release from
mesoporous silica nanoparticles
28. Furthermore, during the degra-
dation, highly ordered hexagonal mesoporous structure will bedegraded into a disordered network where the walls have beenpartly destroyed
5, which might affect the release of drug cargo
loaded in MSNs.
To obtain a suitable release rate and high bioavailability of
poorly soluble drugs from mesoporous silica, mesoporous silicawere combined with other materials into different kinds offormulations. Chen et al.
29constructed a liquisolid formulation
in which liquid polyethylene glycol 400 (PEG400) and model drug
carbamazepine were absorbed into mesoporous silica to achieveimproved adsorption capacity and high drug loading. The obtained
liquisolid system was mixed with starch slurry, then granulated,
andfilled into gelatin capsules. The in vivo study demonstrated
that the bioavailability of the liquisolid capsules was improved to
182.7% compared with the commercial carbamazepine tablets. Hu
and his co-workers
30encapsulated felodipine-loaded MSNs using
chitosan and acacia through layer by layer self-assembly method.
The release rate of felodipine decreased with the increase of the
number of chitosan/acacia bilayers coated on MSNs. The produc-tion of immediate-release carbamazepine pellets was reported byWang et al.
31based on mesoporous silica SBA-15 using extrusion/
spheronization method. The dissolution results showed that the
incorporation of drug-loaded SBA-15 into pellets did not changethein vitro release behavior. Moreover, the oral bioavailability of
pellets was 1.57-fold higher than that of fast-release commercial
tablets in dogs ( Po0.05). In another study, MSNs were formu-
lated into hydrogel beads with polysaccharides matrix, resulting in
a sustained drug release pro file maintaining for 24 h
32.
3. Mesoporous silica-based system for cancer therapy
Recently, the combination of nanotechnology with drug delivery
in the field of cancer therapy has been a research hotspot. The
defective vascular architecture and impaired lymphatic drainage/
recovery system of tumors allow small nanocarriers and macro-molecules to extravasate the endothelial barrier and accumulate in
the tumor tissues
33. Owing to this so-called enhanced permeability
and retention (EPR) effect, the passive targeting of nanocarrierscan be partially achieved
34. Though organic nanocarriers such as
nanocapsules35, liposomes36, polymeric micelles37, and nanopar-
ticles38can easily encapsulate anticancer drugs, their physico-
chemical instability and unexpected drug leakage have severelyimpeded their application. In contrast, inorganic silicate (SiO
2)
carriers have several merits, such as excellent biochemical and
physicochemical stability, biocompatibility, and degradability39.
Among the recent breakthroughs that brought new exciting
possibilities to this area, MSNs have commonly been suggested
as effective carriers for anticancer drugs because of their excellentdrug delivery and endocytotic behaviors
40,41. In this part, we
review the applications of MSNs in cancer therapy.
3.1. Intracellular uptake mechanism of MSNs
3.1.1. Pathways for the cellular internalization of MSNs
Since the cell membrane is the biggest barrier for intracellularanticancer drug delivery, it is important to thoroughly investigate
the cellular internalization and intracellular traf ficking of MSNs as
drug carriers.
Generally, the uptake pathways can be divided in two groups:
phagocytosis and pinocytosis (macropinocytosis and endocytosis)
42.
Phagocytosis usually occurs in specialized cells (professionalphagocytes) such as monocytes, neutrophils, macrophages, and
dendritic cells, for particles with minimum size of 1 μm
43. Small
Fig. 2 Transmission electron microscopic images of MSNs.Mesoporous silica nanoparticles for drug and gene delivery 3
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

nanoparticles ( o200–300 nm) are usually taken up by cells via
endocytic pathways, which involve various routes such as clathrin-
mediated, caveolae-mediated, or the clathrin and caveolae indepen-
dent mechanism, depending on the cell type, particle size, particleshape, particle surface charge, and even culture conditions
44.
Since most endocytic pathways are energy dependent, use of an
inhibitor or a method of energy depletion can directly identify an
endocytic pathway. It was reported that incubating KB cells withMSNs at 4 °Cs i g n i ficantly impeded the cellular uptake and the
internalization also markedly decreased in the presence of sodium
azide
45.T h e s e findings demonstrated that the uptake of MSNs by
KB cells was an energy-dependent endocytic process. To further
investigate the role of speci fic endocytic pathways involved in the
cellular internalization of MSNs, KB cells were pre-incubated with aseries of metabolic inhibitors, including chlorpromazine (inhibits the
formation of clathrin vesicles), nystain (binds sterols and disrupts
the formation of caveolae), cytochalasin D (inhibits clathrin- andcaveolae- independent endocytosis). Finally, the authors proposedthat the uptake of MSNs into KB cells was predominated by
clathrin-mediated endocytosis and required energy. Similar results
were found in A549
46,47,P A N C – 148, and 3T3-L1 cells49.O t h e r
researchers50,51also reported that MSNs were taken up by Hela
cells through caveolae-mediated endocytosis.
3.1.2. Intracellular traf ficking of MSNs
After penetrating the cell membrane barrier, MSNs need to reach
the cytoplasm to release therapeutic drugs. Biological transmissionelectron microscopy (Bio-TEM) is usually adopted to observe the
intracellular distribution of MSNs after endocytosis
52–54. It was
found that MSNs were transported to large vesicular endosomesafter internalization, and then fused with lysosomes. The mem-
branes of endosomes/lysosomes eventually disrupted, suggesting
that the nanoparticles could escape from the endosomes/lyso-somes. In addition, a large number of nanoparticles were observedin the cytoplasm maintaining their spherical morphology. No
particles were found in the nucleus.
The traf ficking of MSNs inside cells also can be studied by
confocal fluorescence microscopy using stained cells and fluores-
cently labeled MSNs. Lu et al.
55used acridine orange (AO) to
specifically stain acidic organelles (endosomes and lysosomes) red
but stained other cellular regions green. The green fluorescence of
labeled MSNs overlapped mostly with the red fluorescence of AO
exhibiting yellow fluorescence, which indicated that MSNs were
mainly internalized into the acidic organelles. Lin et al.56stainedthe endosomes by a red endosome marker (FM 4 –64) and
observed the Hela cells after incubating with green fluorescent
FITC-cytochrome c-labeled MSNs using confocal fluorescence
microscope ( Fig. 3 ). Interestingly, after 24 h of incubation, no
yellow spots were observed, indicating there was no overlapbetween the red endosomes and the green MSNs. This suggested
that MSNs could escape from the endosomal entrapment.
Recently, Tang and co-workers
57showed that different shaped
MSNs-PEG were internalized into cells and partially located in the
acidic organelles, and the green fluorescence observed inside the
cytoplasm also suggested the nanoparticles could successfullyescape from the endosomes/lysosomes.
3.2. MSNs as anticancer drug delivery vehicles
With porous interiors and large surface areas, MSNs can be used as
reservoirs to store different molecules with high loading capacity
and tunable release mechanisms. As a promising drug delivery
system, the pore size of MSNs can be tailored to selectively loadeither hydrophobic or hydrophilic anticancer agents, and their sizeand shape can be controlled to maximize cellular internalization.
The cytotoxic effect of camptothecin (CPT)-loaded MSNs on
several cancer-cell lines was evaluated
55, and the clear growth
inhibition was found in three pancreatic cancer-cell lines (Capan-1,
PANC-1, AsPc-1), one stomach cancer-cell line (MKN45) and one
colon cancer-cell line (SW480). Tao et al.58reported when loaded
into MSNs, transplatin, an inactive isomer of cisplatin, exhibited
enhanced cytotoxicity similar to that of cisplatin on Jurkat cells after
24 h exposure. This work indicated that even less potent anticancerdrugs could become biomedically effective after proper combinationwith MSNs.
3.2.1. Active targeting therapy using MSNs
Over the last decade, the development of MSNs as anticancer drugdelivery systems has been mainly based on the premise that the
tailored nanoparticles can store high volume of chemotherapeutics
in their pores and accumulate in tumor tissues achieving passivetargeting viaEPR. To enhance the uptake of MSNs in targeted
cells, MSNs have been conjugated with various targeting ligands,
which have speci fica ffinity to the receptors over-expressed on the
surface of cancer cells, including folic acid
59–63, mannose64,65,
monoclonal antibody66,67, galactose derivatives68,69, lactobionic
acid70,71, hyaluronic acid72, arginine-glycine-aspartate (RGD)73,
transferrin74and others ( Table 1 ).
Fig. 3 Confocal microscopy images of Hela cells incubated with FITC-cytochrome cat incubation time of (a) 2 h; (b) 14 h; and (c) 24 h.
Endosomes were stained red with fluorescent FM 4-64, and FITC was shown as green fluorescence. Reproduced with permission from Slowing et
al.56. Copyright (2007) American Chemical Society.Yixian Zhou et al. 4
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

Successful speci fic drug delivery to cancer cells has been
reported by Sarkar and coworkers59. Quercetin encapsulated
MSNs (Q-MSNs) modi fied with folic acid exhibited increased
cellular uptake and higher cytotoxicity in breast cancer cells. In
another study, signi ficant improvement of tumor suppression
in vivo was also achieved by folic acid modi fied MSNs60.M ae t
al.72synthesized hyaluronic acid-conjugated MSNs (MSNs-HA)
by a facile amidation reaction. The cellular uptake study showed
that MSNs-HA were more effectively endocytosed by CD44-positive cancer cells (Hela cells) through receptor-mediatedendocytosis mechanism. In contrast, no selective endocytosis of
MSNs-HA was found in CD44-negative cells, such as L929 and
MCF-7 cells. Model drug CPT loaded in the nanoparticlesexhibited enhanced cytotoxicity to Hela cells.
3.2.2. Environment-responsive therapy using MSNs
Although vast effort has been devoted to active targeting therapy
using MSNs, the delivery ef ficacy still needs to be strengthened.
During the blood circulation and penetration into tumor matrix,anticancer drugs may leak from mesopores of MSNs, leading toinsufficient drug concentration at the tumor site. To overcome this
obstacle, “smart ”MSNs-modi fied with environment-responsive
gatekeepers were designed. Since the microenvironment of tumortissue differs from that of normal tissue ( e.g., acidic pH [4.5 –6.5],
high concentration of glutathione [2 –10 mmol/L] and high tem-
perature [40 –42°C]
75), environment-speci fic drug release at a
tumor site is envisioned upon removal of gatekeepers.
According to the microenvironment of cancer cells, the
“smart ”environment-responsive gatekeepers of MSNs can be
divided into pH-responsive gatekeepers76–78, redox-responsive
gatekeepers79–82, temperature-responsive gatekeepers83–85and
enzyme-responsive gatekeepers80,86,87. Cheng et al.76designed
poly(ethylene glycol)-folic acid-functionalized polydopamine-mod-ified MSNs (MSNs@PDA-PEG-FA) for controlled delivery of
doxorubicin (Dox). As illustrated in Fig. 4 , when MSNs@PDA-
PEG-FA were dispersed in acidic conditions, the PDA film would
be destroyed and the loaded doxorubicin would be released rapidly.
Thein vivo experiments indicated that this system exhibited superiorantitumor effects. Li and his coworkers
79developed a glutathione-
responsive MSNs system. The gatekeeper (RGD containing peptide)was conjugated on the surface of MSNs by disul fide bonds which
could be cleaved by the high concentration of glutathione at tumor
site, leading to a burst release of doxorubicin.
To improve the control release of anti-tumor drugs, MSNs were
designed to be sensitive to multi-stimulus. Zhao and colleagues
80
developed a redox and enzyme- responsive doxorubicin deliverysystem based on MSNs. The in vitro experiments demonstrated that
the release of doxorubicin was dependent upon glutathione and
hyaluronidase. Moreover, the anticancer effects of doxorubicin were
enhanced in HCT-116 cells as compared with free doxorubicin.
MSNs based on photodynamic and photothermal therapy have also
shown great potential in cancer therapy, which exerts a therapeutic
effect following irradiation with a near-infrared (NIR) laser. Comparedwith microenvironment-responsive systems, NIR-responsive systems
can achieve remote spatiotemporal control and in-demand drug
release. Qian et al.
88synthesized mesoporous-silica-coated zincTable 1 Summary of targeting drug delivery system based on MSNs.
Receptor Cell type Ligand Refs.
α-Folate receptor MDA-MB-231 Folic acid 58
PANC-1, MiaPaCa-2 Folic acid 59
MCF-7, Hela Folic acid 60
Hela Folic acid 61
Hela Folic acid 62
Mannose receptor MDA-MB-231 Mannose 63
MCF-7, HCT-116, MDA-MB-231 Mannose 64
CD105/endoglin HUVEC TRC105 antibody 65
Mucin-1 glycoprotein MMT, Mtag Mucin-1 antibody 66
Galactose receptor A549, Hela Galactose 67
Y-79 Galactose 68
HepG2 Lactobionic acid 69
HepG2 Lactobionic acid 70
CD44 protein Hela Hyaluronic acid 71
Integrins MDA-MB-231 RGD 72
Transferrin receptor Huh7 Transferrin 73
Fig. 4 Schematic illustration of DOX-loaded MSNs@PDA −PEG
−FA. Reprinted with permission from Cheng et al.77. Copyright
(2017) American Chemical Society.Mesoporous silica nanoparticles for drug and gene delivery 5
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

phthalocyanine nanoparticles. Zinc phthalocyanine, a photosensitizer,
can convert NIR light to visible light, then release reactive
singlet oxygen to kill cancer cells. It was demonstrated that the
photosensitizers loaded into mesoporous silica were protected fromdegradation in the biological environment and could continuouslyproduce singlet oxygen with NIR irradiation. Yang and colleagues
89
developed mesoporous silica-encapsulated gold nanorods(GNRs@mSiO
2) as a doxorubicin delivery system as well as a
photothermal conversion system. The results showed that the
combined treatment had a higher therapeutic ef ficacy for cancer
therapy compared with either chemotherapy or photothermal treatmentalone.
3.2.3. Overcoming multidrug resistance
Multidrug resistance (MDR) is a major obstacle in cancer
chemotherapy and severely impedes the ef ficacy of anticancer
drugs. Drug resistance at tumor tissues is complicated, and usuallyinvolves multiple dynamic mechanisms. MDR can commonly be
divided into two categories, pump and non-pump resistance. Pump
resistance mainly refers to the expression of drug ef flux pumps,
such as P-glycoprotein (P-gp) and multidrug resistance protein(MRP1), which expel many anticancer agents to decrease theintracellular drug concentration. The main non-pump resistance
refers to the activation of cellular antiapoptotic defense pathway,
such as drug-induced expression of B-cell lymphoma-2 (BCL-2)protein, leading to a decrease in drug sensitivity. Moreover, these
two resistance mechanisms can mutually interact.
Several design strategies based on the unique properties of MSNs
have been utilized to overcome drug resistance. First, nano-scaled
MSNs can facilitate cellular uptake, increase intracellular accumula-
tion, and improve drug ef ficacy. The energy-dependent endocytosis
of MSNs can bypass the drug ef flux pumps
40,90,91. Recently, Shi
and co-workers91confirmed the enhanced cellular uptake and
nuclear accumulation of DOX-loaded MSNs in MCF-7/ADR cells,which may have resulted from bypassing the drug ef flux mechanism
Fig. 5 In vitro anti-tumor activity: (A) in vitro anti-tumor activity of free PTX and free PTX țfree TET against MCF-7/ADR cells; (B) in vitro
anti-tumor activity of PTX-cetyltrimethyl ammonium bromide (CTAB)@MSN and PTX/TET-CTAB@MSN against MCF-7/ADR cells; (C)
in vitro anti-tumor activity of free PTX and free PTX țfree TET against MCF-7 cells; and (D) in vitro antitumor activity of PTX-CTAB@MSN
and PTX/TET-CTAB@MSN against MCF-7 cells. M,mol/L Reproduced with permission from Jia et al.93. Copyright (2015) Elsevier B.V.Yixian Zhou et al. 6
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

and/or down-regulation of P-gp by MSNs. The IC 50of Dox-loaded
MSNs against MCF-7/ADR cells was 8-fold lower than that of freeDOX, which demonstrated that MSNs increased the suppression of
cell proliferation by DOX in ADR cells.
Another advantage of MSNs is the ability to co-deliver different
agents, such as antitumor drugs and MDR reversal agents.
Jia et al.
92fabricated MSNs for co-delivery of paclitaxel (PTX)
and tetrandrine (TET) to overcome MDR of MCF-7/ADR cells. Asshown in Fig. 5 , TET could inhibit the ef flux of P-gp to enhance
the antitumor effect activity of PTX. Many researchers also used
MSNs to deliver chemotherapeutic agents and nucleic acids.
Nucleic acids provide the opportunity to silence the genesresponsible for drug resistance, such as drug ef flux transporter
gene P-gp
93,94and antiapoptotic protein gene BCL295, thereby
restoring the intracellular drug concentration required for effectiveapoptosis and cytotoxicity. In another study
94, MSNs were
functionalized to effectively deliver anticancer drug DOX as well
as P-gp siRNA to MDR cells (KB-V1 cells). It was found the dualdelivery system signi ficantly increased the intracellular and intra-
nuclear drug concentrations as compared with free DOX or DOX
delivered alone by MSNs.
In addition, MSNs have been designed as stimulus-responsive
drug delivery systems to control drug release and increase the
accumulation of antitumor agents in nuclei of cancer cells. Wang
and coworkers
96prepared sericin-coated MSNs with pH and
protease-responsive properties, which could deliver doxorubicin
into perinuclear lysosomes of cancer cells, leading to burst release
of doxorubicin into cell nuclei. These doxorubicin-loaded MSNsinhibited the growth of MCF-7/ADR tumor by 70%, showing that
this system could effectively overcome MDR in vivo .
It is currently thought that an ideal nuclear-targeted nanoparticle
drug delivery system can effectively overcome MDR. Recently,MSNs were modi fied with trans-activating transcriptor (TAT)
peptide to construct a nuclear-targeted anticancer drug delivery
system
97–99. This novel TAT peptide-modi fied MSNs (MSNs-
TAT) system facilitated intranuclear localization in multidrug
resistant MCF-7/ADR cancer cells and released the drug directly
into the nucleoplasm. As illustrated in Fig. 6 , the authors also
constructed a MSN-based vasculature-membrane-to-nucleus
sequential drug delivery strategy exploiting RGD and TAT dual-
peptides as targeting ligands99. RGD/TAT peptide-modi fied MSNs(MSNs-RGD/TAT) first bound to the tumor vasculature and then
to the cell membrane. Finally, the TAT served as a nucleartargeting ligand for enhanced nuclear uptake. This sequential
targeting system remarkably enhanced the therapeutic ef ficacy
in vivo .
4. Mesoporous silica-based system for gene delivery
Besides conventional drug delivery, mesoporous silica can also be
applied as carrier for gene transfection. It is well known that
carriers play an important role in gene delivery, since the naked
nucleic acids show little penetration of cell membranes
100. There
are two main gene delivery systems, namely viral and non-viral
systems. The more effective viral systems face signi ficant safety
concerns, such as immunogenicity, gene recombination101, and
nonspeci ficity102. The non-viral systems, including cationic com-
pounds103, recombinant proteins104, polymeric105,106and inorganic
nanoparticles107, have been widely studied in recent years.
However, cationic materials are often associated with high
toxicity, and the recombinant proteins show a low cost-perfor-
mance ratio108. Though liposomes have attracted much attention
and can provide ef ficient gene transfection, their main drawback is
instability. Inorganic nanoparticles possess several advantages
over the others, such as simple preparation and surface-functiona-
lization, good biocompatibility, and excellent physicochemicalstability. Among various materials, MSNs are particular attractive
due to their unique properties. Therefore, MSNs are considered to
be a promising vehicle for gene delivery to increase the cell uptakeand transfection ef ficiency.
4.1. Gene delivery by positive charge-functionalized MSNs
Untreated MSNs often possess a negative charge due to the
ionization of surface silanol groups which reduces binding to
negatively charged nucleic acids, such as DNA. Therefore, silicananoparticles are usually modi fied to express net positive charges
by methods including amination-modi fication, metal cations co-
delivered vector and cationic polymer functionalization. Use ofthese modi fied MSNs promotes gene loading by enhanced
electrostatic interactions with nucleic acids.
Fig. 6 Schematic diagram of vasculature-to-cell membrane-to-nucleus sequential targeting drug delivery based on RGD and TAT peptides co-
conjugated MSNs for effective cancer therapy. Reproduced with permission from Pan et al.100. Copyright (2014) WILEY-VCH Verlag GmbH &
Co. KGaA, Weinheim.Mesoporous silica nanoparticles for drug and gene delivery 7
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

Amination modi fication is a simple and common attempt to
enhance the gene loading capacity of MSNs, 3-aminopropyl-triethoxysilane (APTES)
109–112or amino propyl trimethoxysilane
(APTMS)113,114have been commonly used to modify MSNs.
Yang et al.111also analyzed and reported the positive correlation
between the adsorption amount of plasmid DNA (pDNA) andamination degree.
Metal cations which can enhance the interactions between DNA
and the silica surface have also been used to facilitate MSNs-mediated gene delivery. Solberg and Landry
115investigated the
effect of metal counter ions on gene adsorption, and found Mg2ț
had a higher af finity with DNA vs.N ațor Ca2ț. However, DNA
seemed to bind less strongly with MSNs through metal cations as
compared to the case with the presence of amino group.
Furthermore, cationic polymers, such as polyamidoamine
(PAMAM)95,116, polyethyleneimine (PEI)93,117–121, poly- L-lysine
(PLL)122,123, and poly- L-arginine124, can bind to and deliver genes
with high transfection ef ficiency. Radu et al.125successfully
employed PAMAM (second generation, G2) dendrimer-cappedMSNs to deliver plasmid DNA. Chen et al.
95reported the first
approach to utilizing G2 PAMAM-decorated MSNs to simulta-
neously deliver Dox and BCL-2 siRNA into multidrug-resistantcancer cells. As shown in Fig. 7 , strong fluorescence was observed
in almost every cell after incubation with Dox-loaded and G2
PAMAM-modi fied MSNs (MSN-Dox-G2) and BCL-2 siRNA
together. This indicated BCL-2 siRNA signi ficantly silenced the
BCL-2 mRNA and effectively suppressed the non-pump resis-
tance, enhancing the anticancer ef ficacy of Dox.
PEI coating is another ef ficient method to promote gene
transfection of MSNs because of the “proton sponge effect ”. This
approach is thought to facilitate the formulation's escape fromendosomes or lyposomes
126–129. Xia et al.116reported cationic
PEI-coated MSNs exhibited high binding af finity to both DNA and
siRNA, as well as a surprising high transfection ef ficiency up to
70% of cells. The advantages of using PEI for MSN modi fication
were also reported by other groups93,118–120. Furthermore, PEI can
conjugate with other molecules before the attachment to MSNs to
control the gene release121.
PLL polymers are commonly used for gene transfer since they
can carry large DNA and penetrate cell membranes easily130,131
with low immunogenicity. Moreover, PLL can be degraded by
enzymes to achieve a controlled release behavior132,133. Zhu et al.122
combined PLL with MSNs to form an enzyme-triggered system
which could control the release of drug and gene simultaneously.
Poly- L-arginine composed of natural amino acid may be more
biocompatible and less toxic than synthetic polycationic polymers,
such as PAMAM and PEI. Kar et al.124proposed a facile synthesis
of poly- L-arginine grafted MSNs, and found the transfection
efficiency reached up to 60% with plasmid DNA.Other materials, like polycation poly (allylamine hydrochloride)134,
cationic poly ( ε-caprolactone)135, poly(2-(dimethylamino)ethylmetha-
crylate) (PDMAEMA) or poly (2-(diethylamino)ethylmethacrylate)
(PDEAEMA)136, histidine137, and cationic lipids138,139,h a v ea l s o
been used to modify MSNs for better transfer ef ficiency.
In conclusion, the positive charges of these modi fied materials
may lead to strong electrostatic interactions with the negatively
charged cell membrane, resulting in enhanced particle wrapping
and cellular uptake as well as toxicity to cells. Therefore, it iscritical to control the amount of cationic polymer used in order to
balance the transfection ef ficiency and toxicity of the modi fied
MSN system for gene delivery.
4.2. Gene delivery by pore-enlarged MSNs
To date, MSNs with small pores ( o3n m )
94,116,140,141,s u c ha s
MCM-41 (pore size about 2 –3 nm), have been studied as potential
vectors to deliver genes. However, limited by the small pore size of
MSNs, genes or plasmids were found to primarily be adsorbed onthe outer surface of MSNs rather than loaded in the pores, leading to
burst leakage of genes. In addition, genes located on the outer
surface of MSNs cannot be protected from nucleases or lysosomes.Therefore, nanoparticles with large pores have been synthesized tofacilitate the internal gene storage and protection
100,142.
The production of MSNs with expanded pores is mainly
realized by temperature control115,123,142,143or pore-enlarging
agents100. Kim et al.100simply synthesized MSNs with ultra-large
pores (~23 nm) using the swelling agent 1,3,5-trimethybenzene
(TMB). The resulting MSNs ef ficiently protected plasmids from
nuclease degradation and exhibited higher transfection ef ficiency
compared to MSNs with small pores (2.1 nm). Meka et al.144
fabricated MSNs with large pores (9 nm) using ethanol as co-
solvent and fluorocarbon-hydrocarbon as template. After conjuga-
tion with hydrophobic octadecyl group, this type of MSN showed
high loading capacity and ef ficient delivery siRNA into cancer
cells, leading to inhibition of cancer cell proliferation.
4.3. Gene delivery by multifunctional MSNs
As brie fly mentioned above, nanocarriers provide a great potential
for delivering drug-nucleic acid combinations to overcome MDR
in cancer treatment145. As such, there is an increasing focus on the
development of multifunctional delivery systems based on MSNsand other multiple components, including drugs, genes, speci fic
targeting and imaging agents.
Besides modi fication with cationic materials to enhance the
loading of biomolecules and cell uptake, MSNs have been
functionalized with various targeting agents to achieve better
Fig. 7 Fluorescence microscope images of TUNEL-labeled A2780/AD human ovarian cancer cells incubated with medium, MSN-Dox-G2, and
MSN-Dox-G2 containing BCL-2 siRNA respectively for 24 h. Reproduced with permission from Chen et al.96. Copyright (2009) WILEY-VCH
Verlag GmbH & Co. KGaA, Weinheim.Yixian Zhou et al. 8
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

applications. Park et al.118coupled MSNs with mannosylated
polyethylenimine to target macrophage cells with mannose recep-
tors as well as to enhance the plasmid DNA expression. Peptides,
like luteinising-hormone releasing hormone (LHRH)146and
SP94138, have been reported to form multifunctional delivery
systems. Ashley et al.147developed a new type of nanocarrier (the
“protocell ”) based on mesoporous silica particles and liposomes,
modified with a targeting peptide (SP94), a fusogenic peptide
(H5WYG), and PEG. These nanocarriers can hold multiple cargos
like doxorubicin, 5- fluorouracil, cisplatin, and siRNA, forming
“cocktails ”. This system showed signi ficant advantages in stability,
targeting speci ficity, high delivery ef ficiency of multicomponents,
as well as dosage reduction.
Magnetic nanoparticles have also been widely used to effec-
tively delivery vehicles to target organs or tissues, and even permit
magnetic response imaging. PLL functionalized magnetic silica
nanospheres with large mesopores (13 –24 nm) were synthesized
by Gu and co-workers148. This platform showed strong adsorption
capacity for DNA and ef ficient cellular delivery capability for
miRNA, respectively. Yiu et al.149prepared PEI-Fe 3O4-MCM-48
particles, which showed 4-fold higher transfection ef ficiency
compared with the commercial reagent PolymagTM. Zhang et
al.119synthesized a multifunctional fluorescent-magnetic polyethy-
leneimine functionalized platform with mesoporous silica, whichsatisfied the fluorescent tracking and magnetically guided siRNA
delivery simultaneously.
5. Conclusions and perspectives
During the last decade, MSNs have exhibited many attractive
features which can be synergistically exploited in the development
of drug/gene delivery systems. It has been demonstrated that
MSNs can improve the dissolution rate and bioavailability of thewater insoluble drugs based on the following features: 1) non-
crystalline state of drug entrapped in the mesopores; 2) high
dispersibility with large surface area; 3) wettability enhancementby the hydrophilic surface of MSNs. Moreover, several factors can
influence the drug release rate from MSNs, including pore size,
surface chemistry and hollow structure.
Especially for cancer therapy, MSNs have shown obvious
advantages for delivery of chemotherapeutic agents over other
nanocarriers, such as excellent drug loading capacity and endocy-
totic behavior. The external surfaces of MSNs can be furthermodified with various tumor-recognition molecules and stimuli
responsive molecules to enhance the therapeutic effect of anti-
tumor agents. Moreover, the energy-independent endocytosis andco-delivery ability of MSNs can overcome the MDR in cancer
cells.
As for gene delivery, MSNs possessing large pores have been
designed to encapsulate abundant genes and protect genes fromnucleases. Through cationic modi fication, MSNs are able to
complex with genes and successfully be transfected into various
cells. In addition, multifunctional systems based on MSNs alsoshow great potential in controlled drug/gene delivery.
Despite the recent extensive research into the development of
MSN-based carriers for drug/gene delivery, there are critical issuesthat need to be addressed to facilitate their further development. In
particular, the biocompatibility, degradability and pharmacoki-
netics of these materials should be systematically investigated. Thein vivo therapeutic bene fits of MSNs-based systems in vivo should
be rigorously and extensively demonstrated. The essential infor-
mation regarding the circulation properties in blood, clearance
time in body, possible immunogenicity and accumulation intissues should be obtained before the clinical translation of MSNs.Given the satisfactory resolution of these issues, MSNs-based
formulations may make exciting breakthroughs in the treatment of
many important diseases and disorders.
Acknowledgments
The authors appreciate financial support from the National Natural
Science Foundation of China (81473155), the Natural Science
Fund Project of Guangdong Province (Grant No.2016A030312013), the Science and Technology Plan Projects ofGuangdong Province (Grant No. 2015B020232010), and the
Science and Technology Foundation Guangzhou (201707010103).
References
1Kresge C, Leonowicz ME, Roth WJ, Vartuli JC, Beck JS. Ordered
mesoporous molecular sieves synthesized by a liquid-crystal templatemechanism. Nature 1992; 359:710 –2.
2Li X, Chen Y, Wang M, Ma Y, Xia W, Gu H. A mesoporous silica
nanoparticle –PEI–fusogenic peptide system for siRNA delivery in
cancer therapy. Biomaterials 2013; 34:1391 –401.
3Benezra M, Penate-Medina O, Zanzonico PB, Schaer D, Ow H,
Burns A, et al. Multimodal silica nanoparticles are effective cancer-
targeted probes in a model of human melanoma. J Clin Investig
2011; 121:2768 –80.
4Ow H, Larson DR, Srivastava M, Baird BA, Webb WW, Wiesner U.
Bright and stable core-shell fluorescent silica nanoparticles. Nano Lett
2005; 5:113 –7.
5He Q, Shi J, Zhu M, Chen Y, Chen F. The three-stage in vitro
degradation behavior of mesoporous silica in simulated body fluid.
Microporous Mesoporous Mater 2010; 131:314 –20.
6Liu T, Li L, Teng X, Huang X, Liu H, Chen D, et al. Single and
repeated dose toxicity of mesoporous hollow silica nanoparticles in
intravenously exposed mice. Biomaterials 2011; 32:1657 –68.
7Fu C, Liu T, Li L, Liu H, Chen D, Tang F. The absorption,
distribution, excretion and toxicity of mesoporous silica nanoparticlesin mice following different exposure routes. Biomaterials
2013; 34:2565 –75.
8Vallet-Regi M, Rámila A, Del Real R, Pérez-Pariente J. A new
property of MCM-41: drug delivery system. Chem Mater
2001; 13:308 –11.
9Hauss DJ. Oral lipid-based formulations. Adv Drug Deliv Rev
2007; 59:667 –76.
10Jia Z, Lin P, Xiang Y, Wang X, Wang J, Zhang X, et al. A novel
nanomatrix system consisted of colloidal silica and pH-sensitive
polymethylacrylate improves the oral bioavailability of feno fibrate.
Eur J Pharm Biopharm 2011; 79:126 –34.
11Hu Y, Wang J, Zhi Z, Jiang T, Wang S. Facile synthesis of 3D cubic
mesoporous silica microspheres with a controllable pore size and their
application for improved delivery of a water-insoluble drug. J Colloid
Interface Sci 2011; 363:410 –7.
12Zhao P, Jiang H, Jiang T, Zhi Z, Wu C, Sun C, et al. Inclusion of
celecoxib into fibrous ordered mesoporous carbon for enhanced oral
bioavailability and reduced gastric irritancy. Eur J Pharm Sci
2012; 45:639 –47.
13Zhang Y, Jiang T, Zhang Q, Wang S. Inclusion of telmisartan in
mesocellular foam nanoparticles: drug loading and release property.Eur J Pharm Biopharm 2010; 76:17–23.Mesoporous silica nanoparticles for drug and gene delivery 9
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

14Hong EJ, Choi DG, Shim MS. Targeted and effective photodynamic
therapy for cancer using functionalized nanomaterials. Acta Pharm
Sin B 2016; 6:297 –307.
15Zhang Y, Wang J, Bai X, Jiang T, Zhang Q, Wang S. Mesoporous
silica nanoparticles for increasing the oral bioavailability and permea-
tion of poorly water soluble drugs. Mol Pharm 2012; 9:505 –13.
16Van Speybroeck M, Mellaerts R, Mols R, Thi TD, Martens JA, Van
Humbeeck J, et al. Enhanced absorption of the poorly soluble drugfenofibrate by tuning its release rate from ordered mesoporous silica.
Eur J Pharm Sci 2010; 41:623 –30.
17Kiekens F, Eelen S, Verheyden L, Daems T, Martens J, Van Den
Mooter G. Use of ordered mesoporous silica to enhance the oralbioavailability of ezetimibe in dogs. J Pharm Sci 2012; 101:1136 –44.
18Sliwinska-Bartkowiak M, Dudziak G, Sikorski R, Gras R, Radhak-
rishnan R, Gubbins KE. Melting/freezing behavior of a fluid con fined
in porous glasses and MCM-41: dielectric spectroscopy and mole-cular simulation. J Chem Phys 2001; 114:950 –62.
19Zhao Q, Wang T, Wang J, Zheng L, Jiang T, Cheng G, et al.
Fabrication of mesoporous hydroxycarbonate apatite for oral delivery
of poorly water-soluble drug carvedilol. J Non Cryst Solids
2012; 358:229 –35.
20Hu Y, Zhi Z, Wang T, Jiang T, Wang S. Incorporation of
indomethacin nanoparticles into 3-D ordered macroporous silica for
enhanced dissolution and reduced gastric irritancy. Eur J Pharm
Biopharm 2011; 79:544 –51.
21Gignone A, Manna L, Ronchetti S, Banchero M, Onida B. Incorpora-
tion of clotrimazole in ordered mesoporous silica by supercritical
CO
2.Microporous Mesoporous Mater 2014; 200:291 –6.
22He Y, Liang S, Long M, Xu H. Mesoporous silica nanoparticles as
potential carriers for enhanced drug solubility of paclitaxel. Mater Sci
Eng C 2017; 78:12–7.
23Ambrogi V, Perioli L, Pagano C, Marmottini F, Ricci M, Sagnella A,
et al. Use of SBA-15 for furosemide oral delivery enhancement. Eur J
Pharm Sci 2012; 46:43–8.
24Xu W, Riikonen J, Lehto VP. Mesoporous systems for poorly soluble
drugs. Int J Pharm 2013; 453:181 –97.
25Jia L, Shen J, Li Z, Zhang D, Zhang Q, Duan C, et al. Successfully
tailoring the pore size of mesoporous silica nanoparticles: exploitationof delivery systems for poorly water-soluble drugs. Int J Pharm
2012; 439:81–91.
26Zhu W, Wan L, Zhang C, Gao Y, Zheng X, Jiang T, et al.
Exploitation of 3D face-centered cubic mesoporous silica as a carrierfor a poorly water soluble drug: in fluence of pore size on release rate.
Mater Sci Eng C 2014; 34:78–85.
27Ahmadi E, Dehghannejad N, Hashemikia S, Ghasemnejad M,
Tabebordbar H. Synthesis and surface modi fication of mesoporous
silica nanoparticles and its application as carriers for sustained drugdelivery. Drug Deliv 2014; 21:164 –72.
28Geng H, Zhao Y, Liu J, Cui Y, Wang Y, Zhao Q, et al. Hollow
mesoporous silica as a high drug loading carrier for regulationinsoluble drug release. Int J Pharm 2016; 510:184 –94.
29Chen B, Wang Z, Quan G, Peng X, Pan X, Wang R, et al. In vitro and
in vivo evaluation of ordered mesoporous silica as a novel adsorbent
in liquisolid formulation. Int J Nanomed 2012; 7:199 –209.
30Hu L, Sun H, Zhao Q, Han N, Bai L, Wang Y, et al. Multilayer
encapsulated mesoporous silica nanospheres as an oral sustained drug
delivery system for the poorly water-soluble drug felodipine. Mater
Sci Eng C 2015; 47:313 –24.
31Wang Z, Chen B, Quan G, Li F, Wu Q, Dian L, et al. Increasing the
oral bioavailability of poorly water-soluble carbamazepine usingimmediate-release pellets supported on SBA-15 mesoporous silica.
Int J Nanomed 2012; 7:5807 –18.
32Hu Y, Dong X, Ke L, Zhang S, Zhao D, Chen H, et al. Poly-
saccharides/mesoporous silica nanoparticles hybrid composite hydro-gel beads for sustained drug delivery. J Mater Sci 2017; 52:3095 –109.33Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular
permeability and the EPR effect in macromolecular therapeutics: a
review. J Control Release 2000; 65:271 –84.
34Xiao K, Luo J, Fowler WL, Li Y, Lee JS, Xing L, et al. A self-
assembling nanoparticle for paclitaxel delivery in ovarian cancer.Biomaterials 2009; 30:6006 –16.
35Ren D, Kratz F, Wang SW. Protein nanocapsules containing
doxorubicin as a pH-responsive delivery system. Small
2011; 7:1051 –60.
36Dicheva BM, ten Hagen TL, Schipper D, Seynhaeve AL, Van Rhoon
GC, Eggermont AM, et al. Targeted and heat-triggered doxorubicindelivery to tumors by dual targeted cationic thermosensitive lipo-
somes. J Control Release 2014; 195:37–48.
37Qiu L, Qiao M, Chen Q, Tian C, Long M, Wang M, et al. Enhanced
effect of pH-sensitive mixed copolymer micelles for overcomingmultidrug resistance of doxorubicin. Biomaterials 2014; 35:9877 –87.
38Hak S, Helgesen E, Hektoen HH, Huuse EM, Jarzyna PA, Mulder
WJ, et al. The effect of nanoparticle polyethylene glycol surface
density on ligand-directed tumor targeting studied in vivo by dual
modality imaging. ACS Nano 2012; 6:5648 –58.
39Asefa T, Tao Z. Biocompatibility of mesoporous silica nanoparticles.
Chem Res Toxicol 2012; 25:2265
–84.
40Gao Y, Chen Y, Ji X, He X, Yin Q, Zhang Z, et al. Controlled
intracellular release of doxorubicin in multidrug-resistant cancer cellsby tuning the shell-pore sizes of mesoporous silica nanoparticles. ACS
Nano 2011; 5:9788 –98.
41Ekkapongpisit M, Giovia A, Follo C, Caputo G, Isidoro C.
Biocompatibility, endocytosis, and intracellular traf ficking of meso-
porous silica and polystyrene nanoparticles in ovarian cancer cells:
effects of size and surface charge groups. Int J Nanomed
2012; 7:4147 –58.
42Vivero-Escoto JL, Slowing II, Trewyn BG, Lin VS. Mesoporous
silica nanoparticles for intracellular controlled drug delivery. Small
2010; 6:1952 –67.
43Hillaireau H, Couvreur P. Nanocarriers' entry into the cell: relevance
to drug delivery. Cell Mol Life Sci 2009; 66:2873 –96.
44Li ZX, Barnes JC, Bosoy A, Stoddart JF, Zink JI. Mesoporous silica
nanoparticles in biomedical applications. Chem Soc Rev
2012; 41:2590 –605.
45Yang H, Lou C, Xu M, Wu C, Miyoshi H, Liu Y. Investigation of
folate-conjugated fluorescent silica nanoparticles for targeting deliv-
ery to folate receptor-positive tumors and their internalizationmechanism. Int J Nanomed 2011; 6:2023 –32.
46Kim JS, Yoon TJ, Yu KN, Noh MS, Woo M, Kim BG, et al. Cellular
uptake of magnetic nanoparticle is mediated through energy-depen-
dent endocytosis in A549 cells. J Vet Sci 2006; 7:321 –6.
47Liu Q, Zhang J, Xia W, Gu H. Magnetic field enhanced cell uptake
efficiency of magnetic silica mesoporous nanoparticles. Nanoscale
2012; 4:3415 –21.
48Lu J, Liong M, Sherman S, Xia T, Kovochich M, Nel AE, et al.
Mesoporous silica nanoparticles for cancer therapy: energy-dependent
cellular uptake and delivery of paclitaxel to cancer cells. Nanobio-
technology 2007; 3:89–95.
49Chung TH, Wu SH, Yao M, Lu CW, Lin YS, Hung Y, et al. The
effect of surface charge on the uptake and biological function ofmesoporous silica nanoparticles in 3T3-L1 cells and human mesench-
ymal stem cells. Biomaterials 2007; 28:2959 –66.
50Morelli C, Maris P, Sisci D, Perrotta E, Brunelli E, Perrotta I, et al.
PEG-templated mesoporous silica nanoparticles exclusively targetcancer cells. Nanoscale 2011; 3:3198 –207.
51Slowing I, Trewyn BG, Lin VS. Effect of surface functionalization of
MCM-41-type mesoporous silica nanoparticles on the endocytosis by
human cancer cells. J Am Chem Soc 2006; 128:14792 –3.
52Chen Y, Chen H, Zeng D, Tian Y, Chen F, Feng J, et al. Core/shell
structured hollow mesoporous nanocapsules: a potential platform forYixian Zhou et al. 10
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

simultaneous cell imaging and anticancer drug delivery. ACS Nano
2010; 4:6001 –13.
53Ma M, Chen H, Chen Y, Wang X, Chen F, Cui X, et al. Au capped
magnetic core/mesoporous silica shell nanoparticles for combined
photothermo-/chemo-therapy and multimodal imaging. Biomaterials
2012; 33:989 –98.
54Chen Y, Chen H, Zhang S, Chen F, Zhang L, Zhang J, et al.
Multifunctional mesoporous nanoellipsoids for biological bimodal
imaging and magnetically targeted delivery of anticancer drugs. Adv
Funct Mater 2011; 21:270 –8.
55Lu J, Liong M, Zink JI, Tamanoi F. Mesoporous silica nanoparticles
as a delivery system for hydrophobic anticancer drugs. Small
2007; 3:1341 –6.
56Slowing II, Trewyn BG, Lin VS. Mesoporous silica nanoparticles for
intracellular delivery of membrane-impermeable proteins. J Am Chem
Soc2007; 129:8845 –9.
57Hao N, Li L, Zhang Q, Huang X, Meng X, Zhang Y, et al. The shape
effect of PEGylated mesoporous silica nanoparticles on cellularuptake pathway in Hela cells. Microporous Mesoporous Mater
2012; 162:14–23.
58Tao Z, Toms B, Goodisman J, Asefa T. Mesoporous silica micro-
particles enhance the cytotoxicity of anticancer platinum drugs. Acs
Nano 2010; 4:789 –94.
59Sarkar A, Ghosh S, Chowdhury S, Pandey B, Sil PC. Targeted
delivery of quercetin loaded mesoporous silica nanoparticles to thebreast cancer cells. Biochim Biophys Acta 2016; 1860 :2065 –75.
60Lu J, Li Z, Zink JI, Tamanoi F. In vivo tumor suppression ef ficacy of
mesoporous silica nanoparticles-based drug-delivery system:
enhanced ef ficacy by folate modi fication. Nanomedicine
2012; 8:212 –20
.
61Kne ževićNŽ, Mranovi J, Bori šev I, Milenkovi S, Janakovi D, Cunin
F, et al. Hydroxylated fullerene-capped, vinblastine-loaded folic acid-functionalized mesoporous silica nanoparticles for targeted anticancertherapy. RSC Adv 2016; 6:7061 –5.
62Prasad R, Aiyer S, Chauhan DS, Srivastava R, Selvaraj K. Bior-
esponsive carbon nano-gated multifunctional mesoporous silica forcancer theranostics. Nanoscale 2016; 8:4537 –46.
63Geng H, Chen W, Xu ZP, Qian G, An J, Zhang H. Shape-controlled
hollow mesoporous silica nanoparticles with multifunctional capping
forin vitro cancer treatment. Chemistry 2017; 23:10878 –85.
64Brevet D, Gary-Bobo M, Raehm L, Richeter S, Hocine O, Amro K,
et al. Mannose-targeted mesoporous silica nanoparticles for photo-
dynamic therapy. Chem Commun 2009; 2009 :1475 –7.
65Gary-Bobo M, Mir Y, Rouxel C, Brevet D, Basile I, Maynadier M,
et al. Mannose-functionalized mesoporous silica nanoparticles for
efficient two-photon photodynamic therapy of solid tumors. Angew
Chem Int Ed Engl 2011; 50:11425 –9.
66Chen F, Hong H, Zhang Y, Valdovinos HF, Shi S, Kwon GS, et al.
In vivo tumor targeting and image-guided drug delivery with anti-
body-conjugated, radiolabeled mesoporous silica nanoparticles. ACS
Nano 2013; 7:9027 –39.
67Dréau D, Moore LJ, Alvarez-Berrios MP, Tarannum M, Mukherjee P,
Vivero-Escoto JL. Mucin-1-antibody-conjugated mesoporous silica
nanoparticles for selective breast cancer detection in a mucin-1transgenic murine mouse model. J Biomed Nanotechnol
2016; 12:2172 –84.
68Niemela E, Desai D, Nkizinkiko Y, Eriksson JE, Rosenholm JM.
Sugar-decorated mesoporous silica nanoparticles as delivery vehiclesfor the poorly soluble drug celastrol enables targeted induction ofapoptosis in cancer cells. Eur J Pharm Biopharm 2015; 96:11–21.
69Gary-Bobo M, Mir Y, Rouxel C, Brevet D, Hocine O, Maynadier M,
et al. Multifunctionalized mesoporous silica nanoparticles for thein vitro treatment of retinoblastoma: drug delivery, one and two-
photon photodynamic therapy. Int J Pharm 2012; 432:99–104.
70Dai L, Li J, Zhang B, Liu J, Luo Z, Cai K. Redox-responsive
nanocarrier based on heparin end-capped mesoporous silica nano-particles for targeted tumor therapy in vitro andin vivo .Langmuir
2014; 30:7867 –77.71Liu Y, Ding X, Li J, Luo Z, Hu Y, Liu J, et al. Enzyme responsive
drug delivery system based on mesoporous silica nanoparticles for
tumor therapy in vivo .Nanotechnology 2015; 26:145102 .
72Ma M, Chen H, Chen Y, Zhang K, Wang X, Cui X, et al. Hyaluronic
acid-conjugated mesoporous silica nanoparticles: excellent colloidal
dispersity in physiological fluids and targeting ef ficacy. J Mater
Chem 2012; 22:5615 –21.
73Wu X, Han Z, Schur RM, Lu Z. Targeted mesoporous silica
nanoparticles delivering arsenic trioxide with environment sensitive
drug release for effective treatment of triple negative breast cancer.ACS Biomater Sci Eng 2016; 2:501 –7.
74Chen X, Sun H, Hu J, Han X, Liu H, Hu Y. Transferrin gated
mesoporous silica nanoparticles for redox-responsive and targeted
drug delivery. Colloids Surf B Biointerfaces 2017; 152:77–84.
75Sun H, Meng F, Cheng R, Deng C, Zhong Z. Reduction-responsive
polymeric micelles and vesicles for triggered intracellular drug
release. Antioxid Redox Signal 2014; 21:755 –67.
76Cheng W, Nie J, Xu L, Liang C, Peng Y, Liu G, et al. pH-sensitive
delivery vehicle based on folic acid-conjugated polydopamine-mod-
ified mesoporous silica nanoparticles for targeted cancer therapy. ACS
Appl Mater Interfaces 2017; 9:18462 –73.
77Gurka MK, Pender D, Chuong P, Fouts BL, Sobelov A, McNally
MW, et al. Identi fication of pancreatic tumors in vivo with ligand-
targeted, pH responsive mesoporous silica nanoparticles by multi-
spectral optoacoustic tomography. J Control Release 2016; 231:60–7.
78Hakeem A, Zahid F, Duan R, Asif M, Zhang T, Zhang Z, et al.
Cellulose conjugated FITC-labelled mesoporous silica nanoparticles:
intracellular accumulation and stimuli responsive doxorubicin release.
Nanoscale 2016; 8:5089 –97.
79Li ZY, Hu JJ, Xu Q, Chen S, Jia HZ, Sun YX, et al. A redox-
responsive drug delivery system based on RGD containing
peptide-capped mesoporous silica nanoparticles. J Mater Chem B
2015; 3:39–44.
80Zhao Q, Liu J, Zhu W, Sun C, Di D, Zhang Y, et al. Dual-stimuli
responsive hyaluronic acid-conjugated mesoporous silica for targeted
delivery to CD44-overexpressing cancer cells. Acta Biomater
2015; 23:147 –56.
81Jiao J, Liu C, Li X, Liu J, Di D, Zhang Y, et al. Fluorescent carbon
dot modi fied mesoporous silica nanocarriers for redox-responsive
controlled drug delivery and bioimaging. J Colloid Interface Sci
2016; 483:343 –52.
82Xiao D, Hu JJ, Zhu JY, Wang SB, Zhuo RX, Zhang XZ. A redox-
responsive mesoporous silica nanoparticle with a therapeutic peptideshell for tumor targeting synergistic therapy. Nanoscale
2016; 8:16702 –9.
83Tamarov K, Xu W, Osminkina L, Zinovyev S, Soininen P,
Kudryavtsev A, et al. Temperature responsive porous silicon nano-particles for cancer therapy –spatiotemporal triggering through
infrared and radiofrequency electromagnetic heating. J Control
Release 2016; 241:220 –8.
84Yu Z, Li N, Zheng P, Pan W, Tang B. Temperature-responsive DNA-
gated nanocarriers for intracellular controlled release. Chem Commun
2014; 50:3494 –7.
85De La Torre C, Agostini A, Mondragón L, Orzáez M, Sancenón F,
Martínez-Máñez R, et al. Temperature-controlled release by changesin the secondary structure of peptides anchored onto mesoporous
silica supports. Chem Commun 2014; 50
:3184 –6.
86Yu Gu Z, Ottewell T, Yu C. Silica-based nanoparticles for therapeutic
protein delivery. J Mater Chem B 2017; 5:3241 –52.
87Cheng YJ, Luo GF, Zhu JY, Xu XD, Zeng X, Cheng DB, et al.
Enzyme-induced and tumor-targeted drug delivery system based on
multifunctional mesoporous silica nanoparticles. ACS Appl Mater
Interfaces 2015; 7:9078 –87.
88Qian HS, Guo HC, Ho PC, Mahendran R, Zhang Y. Mesoporous-
Silica-coated up-conversion fluorescent nanoparticles for photody-
namic therapy. Small 2009; 5:2285 –90.
89Shen S, Tang H, Zhang X, Ren J, Pang Z, Wang D, et al. Targeting
mesoporous silica-encapsulated gold nanorods for chemo-Mesoporous silica nanoparticles for drug and gene delivery 11
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

photothermal therapy with near-infrared radiation. Biomaterials
2013; 34:3150 –8.
90Huang IP, Sun SP, Cheng SH, Lee CH, Wu CY, Yang CS, et al.
Enhanced chemotherapy of cancer using pH-sensitive mesoporous
silica nanoparticles to antagonize p-glycoprotein-mediated drug
resistance. Mol Cancer Ther 2011; 10:761 –9.
91Shen J, He Q, Gao Y, Shi J, Li Y. Mesoporous silica nanoparticles
loading doxorubicin reverse multidrug resistance: performance and
mechanism. Nanoscale 2011; 3:4314 –22.
92Jia L, Li Z, Shen J, Zheng D, Tian X, Guo H, et al. Multifunctional
mesoporous silica nanoparticles mediated co-delivery of paclitaxeland tetrandrine for overcoming multidrug resistance. Int J Pharm
2015; 489:318 –30.
93Meng H, Mai WX, Zhang H, Xue M, Xia T, Lin S, et al. Codelivery
of an optimal drug/siRNA combination using mesoporous silica
nanoparticles to overcome drug resistance in breast cancer in vitro
andin vivo .ACS Nano 2013; 7:994 –1005 .
94Meng H, Liong M, Xia T, Li Z, Ji Z, Zink JI, et al. Engineered design
of mesoporous silica nanoparticles to deliver doxorubicin and
p-glycoprotein siRNA to overcome drug resistance in a cancer cell
line. ACS Nano 2010; 4:4539 –50.
95Chen AM, Zhang M, Wei D, Stueber D, Taratula O, Minko T, et al.
Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica
nanoparticles enhances the ef ficacy of chemotherapy in multidrug-
resistant cancer cells. Small 2009; 5:2673 –7.
96Liu J, Li Q, Zhang J, Huang L, Qi C, Xu L, et al. Safe and effective
reversal of cancer multidrug resistance using sericin-coated mesopor-
ous silica nanoparticles for lysosome-targeting delivery in mice. Small
2017; 13:1602567 .
97Pan L, Liu J, He Q, Wang L, Shi J. Overcoming multidrug resistance
of cancer cells by direct intranuclear drug delivery using TAT-
conjugated mesoporous silica nanoparticles. Biomaterials
2013; 34:2719 –30
.
98Pan L, He Q, Liu J, Chen Y, Ma M, Zhang L, et al. Nuclear-targeted
drug delivery of TAT peptide-conjugated monodisperse mesoporous
silica nanoparticles. J Am Chem Soc 2012; 134:5722 –5.
99Pan L, Liu J, He Q, Shi J. MSN-mediated sequential vascular-to-cell
nuclear-targeted drug delivery for ef ficient tumor regression. Adv
Mater 2014; 26:6742 –8.
100 Kim MH, Na HK, Kim YK, Ryoo SR, Cho HS, Lee KE, et al. Facile
synthesis of monodispersed mesoporous silica nanoparticles with
ultralarge pores and their application in gene delivery. ACS Nano
2011; 5:3568 –76.
101 Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the
use of viral vectors for gene therapy. Nat Rev Genet 2003; 4:346 –58.
102 Marshall E. Viral vectors still pack surprises. Science 2001; 294:1640 .
103 De Smedt SC, Demeester J, Hennink WE. Cationic polymer based
gene delivery systems. Pharm Res 2000; 17:113 –26.
104 Arı́s A, Villaverde A. Modular protein engineering for non-viral gene
therapy. Trends Biotechnol 2004; 22:371 –7.
105 Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and
gene delivery to cells and tissue. Adv Drug Deliv Rev 2012; 64:61–71.
106 Zhang M, Kim YK, Cui P, Zhang J, Qiao J, He Y, et al. Folate-
conjugated polyspermine for lung cancer-targeted gene therapy. Acta
Pharm Sin B 2016; 6:336 –43.
107 Zhang XQ, Chen M, Lam R, Xu X, Osawa E, Ho D. Polymer-
functionalized nanodiamond platforms as vehicles for gene delivery.
ACS Nano 2009; 3:2609 –16.
108 Lv H, Zhang S, Wang B, Cui S, Yan J. Toxicity of cationic lipids
and cationic polymers in gene delivery. J Control Release
2006; 114:100 –9.
109 Tao C, Zhu Y, Xu Y, Zhu M, Morita H, Hanagata N. Mesoporous
silica nanoparticles for enhancing the delivery ef ficiency of immu-
nostimulatory DNA drugs. Dalton Trans 2014; 43:5142 –50.
110 Kim TH, Kim M, Eltohamy M, Yun YR, Jang JH, Kim HW. Ef ficacy
of mesoporous silica nanoparticles in delivering BMP-2 plasmid DNAforin vitro osteogenic stimulation of mesenchymal stem cells. J
Biomed Mater Res A 2013; 101A :1651 –60.111 Yang H, Zheng K, Zhang Z, Shi W, Jing S, Wang L, et al. Adsorption
and protection of plasmid DNA on mesoporous silica nanoparticlesmodified with various amounts of organosilane. J Colloid Interface
Sci2012; 369:317 –22.
112 Zheng K, Yang H, Wang L, Jing S, Huang H, Xu J, et al. Amino-
functionalized mesoporous silica nanoparticles: adsorption and pro-
tection for pcDNA3.1( ț)-PKB-HA. J Porous Mater 2013; 20:1003 –8.
113 Ganguly A, Ganguli AK. Anisotropic silica mesostructures for DNA
encapsulation. Bull Mater Sci 2013; 36:329 –32.
114 Chang FP, Kuang LY, Huang CA, Jane WN, Hung Y, Hsing YIC,
et al. A simple plant gene delivery system using mesoporous silicananoparticles as carriers. J Mater Chem B 2013; 1:5279 –87.
115 Solberg SM, Landry CC. Adsorption of DNA into mesoporous silica.
J Phys Chem B 2006; 110:15261 –8.
116 Xia T, Kovochich M, Liong M, Meng H, Kabehie S, George S, et al.
Polyethyleneimine coating enhances the cellular uptake of mesopor-
ous silica nanoparticles and allows safe delivery of siRNA and DNA
constructs. ACS Nano 2009; 3:3273 –86.
117 Wang M, Li X, Ma Y, Gu H. Endosomal escape kinetics of
mesoporous silica-based system for ef ficient siRNA delivery. Int J
Pharm 2013; 448:51–7.
118 Park IY, Kim IY, Yoo MK, Choi YJ, Cho MH, Cho CS. Mannosy-
lated polyethylenimine coupled mesoporous silica nanoparticles for
receptor-mediated gene delivery. Int J Pharm 2008; 359:280 –7.
119 Zhang L, Wang T, Li L, Wang C, Su Z, Li J. Multifunctional
fluorescent-magnetic polyethyleneimine functionalized Fe 3O4-meso-
porous silica yolk-shell nanocapsules for siRNA delivery. Chem
Commun 2012; 48:8706 –8.
120 Cebrián V, Yagüe C, Arruebo M, Martín-Saavedra FM, Santamaría J,
Vilaboa N. On the role of the colloidal stability of mesoporous
silica nanoparticles as gene delivery vectors. J Nanopart Res
2011; 13:4097 –108.
121 Shen J, Kim HC, Su H, Wang F, Wolfram J, Kirui D, et al.
Cyclodextrin and polyethylenimine functionalized mesoporous silica
nanoparticles for delivery of siRNA cancer therapeutics. Theranostics
2014; 4:487 –97.
122 Zhu Y, Meng W, Gao H, Hanagata N. Hollow mesoporous silica/poly
(L-lysine) particles for codelivery of drug and gene with enzyme-
triggered release property. J Phys Chem C 2011; 115:13630 –6.
123 Hartono SB, Gu W, Kleitz F, Liu J, He L, Middelberg AP, et al.
Poly- L-lysine functionalized large pore cubic mesostructured silica
nanoparticles as biocompatible carriers for gene delivery. ACS Nano
2012; 6:2104 –17.
124 Kar M, Tiwari N, Tiwari M, Lahiri M, Sen Gupta S. Poly- L-arginine
grafted silica mesoporous nanoparticles for enhanced cellular uptake
and their application in DNA delivery and controlled drug release.
Part Part Syst Charact 2013; 30:166 –79.
125 Radu DR, Lai CY, Jeftinija K, Rowe EW, Jeftinija S, Lin VS. A
polyamidoamine dendrimer-capped mesoporous silica nanosphere-
based gene transfection reagent. J Am Chem Soc 2004; 126:13216 –7.
126 Boussif O, Lezoualc'h F, Zanta MA, Mergny MD, Scherman D,
Demenix B, et al. A versatile vector for gene and oligonucleotide
transfer into cells in culture and in vivo: polyethylenimine. Proc Natl
Acad Sci U S A 1995; 92:7297 –301.
127 Yamazaki Y, Nango M, Matsuura M, Hasegawa Y, Hasegawa M,
Oku N. Polycation liposomes, a novel nonviral gene transfer system,
constructed from cetylated polyethylenimine. Gene Ther
2000; 7:1148 –55.
128 Godbey WT, Wu KK, Hirasaki GJ, Mikos AG. Improved packing of
poly(ethylenimine)/DNA complexes increases transfection ef ficiency.
Gene Ther 1999; 6:1380 –8.
129 Kircheis R, Wightman L, Wagner E. Design and gene delivery
activity of modi fied polyethylenimines. Adv Drug Deliv Rev
2001; 53:341 –58.
130 Zhang X, Oulad-Abdelghani M, Zelkin AN, Wang Y, Haîkel Y,
Mainard D, et al. Poly( L-lysine) nanostructured particles for gene
delivery and hormone stimulation. Biomaterials 2010; 31:1699 –706.Yixian Zhou et al. 12
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007

131 Incani V, Lin X, Lavasanifar A, Uluda ǧH. Relationship between the
extent of lipid substitution on poly( L-lysine) and the DNA delivery
efficiency. ACS Appl Mater Interfaces 2009; 1:841 –8.
132 Itoh Y, Matsusaki M, Kida T, Akashi M. Time-modulated release of
multiple proteins from enzyme-responsive multilayered capsules.
Chem Lett 2008; 37:238 –9.
133 Wang Z, Qian L, Wang X, Zhu H, Yang F, Yang X. Hollow DNA/
PLL microcapsules with tunable degradation property as ef ficient dual
drug delivery vehicles by α-chymotrypsin degradation. Colloids Surf
A Physicochem Eng Asp 2009; 332:164 –71.
134 Qin F, Zhou Y, Shi J, Zhang YA. DNA transporter based on
mesoporous silica nanospheres mediated with polycation poly(allyla-
mine hydrochloride) coating on mesopore surface. J Biomed Mater
Res A 2009; 90A:333 –8.
135 Zhang Y, Wang Z, Zhou W, Min G, Lang M. Cationic poly( ɛ-
caprolactone) surface functionalized mesoporous silica nanoparticles
and their application in drug delivery. Appl Surf Sci 2013; 276:
769–75.
136 Bhattarai SR, Muthuswamy E, Wani A, Brichacek M, Castañeda AL,
Brock SL, et al. Enhanced gene and siRNA delivery by polycation-
modified mesoporous silica nanoparticles loaded with chloroquine.
Pharm Res 2010; 27:2556 –68.
137 Brevet D, Hocine O, Delalande A, Raehm L, Charnay C, Midoux P,
et al. Improved gene transfer with histidine-functionalized mesopor-
ous silica nanoparticles. Int J Pharm 2014; 471:197 –205.
138 Ashley CE, Carnes EC, Epler KE, Padilla DP, Phillips GK, Castillo
RE, et al. Delivery of small interfering RNA by peptide-targeted
mesoporous silica nanoparticle-supported lipid bilayers. ACS Nano
2012; 6:2174 –88.
139 Dengler EC, Liu J, Kerwin A, Torres S, Olcott CM, Bowman BN,
et al. Mesoporous silica-supported lipid bilayers (protocells) for DNA
cargo delivery to the spinal cord. J Control Release 2013; 168:209 –24.140 Li LL, Yin Q, Cheng J, Lu Y. Polyvalent mesoporous silica
nanoparticle-aptamer bioconjugates target breast cancer cells. Adv
Healthc Mater 2012; 1:567 –72.
141 Hom C, Lu J, Liong M, Luo H, Li Z, Zink JI, et al. Mesoporous silica
nanoparticles facilitate delivery of siRNA to shutdown signaling
pathways in mammalian cells. Small 2010; 6:1185 –90.
142 Gao F, Botella P, Corma A, Blesa J, Dong L. Monodispersed
mesoporous silica nanoparticles with very large pores for enhanced
adsorption and release of DNA. J Phys Chem B 2009; 113:1796 –804.
143 Mou CY, Lin HP. Control of morphology in synthesizing mesoporous
silica. Pure Appl Chem 2000; 72:137 –46.
144 Meka AK, Niu Y, Karmakar S, Hartono SB, Zhang J, Lin CX, et al.
Facile synthesis of large-pore bicontinuous cubic mesoporous silica
nanoparticles for intracellular gene delivery. Chemnanomat
2016; 2:220 –5.
145 Li J, Wang Y, Zhu Y, Oupický D. Recent advances in delivery of
drug –nucleic acid combinations for cancer treatment. J Control
Release 2013; 172:589 –600.
146 Taratula O, Garbuzenko OB, Chen AM, Minko T. Innovative strategy
for treatment of lung cancer: targeted nanotechnology-based inhala-
tion co-delivery of anticancer drugs and siRNA. J Drug Target
2011; 19:900 –14.
147 Ashley CE, Carnes EC, Phillips GK, Padilla D, Durfee PN, Brown
PA, et al. The targeted delivery of multicomponent cargos to cancer
cells by nanoporous particle-supported lipid bilayers. Nat Mater
2011; 10:389 –97.
148 Zhang J, Sun W, Bergman L, Rosenholm JM, Lindén M, Wu G, et al.
Magnetic mesoporous silica nanospheres as DNA/drug carrier. Mater
Lett2012; 67:379 –82.
149 Yiu HH, McBain SC, Lethbridge ZA, Lees MR, Dobson J. Prepara-
tion and characterization of polyethylenimine-coated Fe 3O4-MCM-48
nanocomposite particles as a novel agent for magnet-assisted transfec-tion. J Biomed Mater Res A 2010; 92A:386 –92.Mesoporous silica nanoparticles for drug and gene delivery 13
Please cite this article as: Zhou Yixian, et al. Mesoporous silica nanoparticles for drug and gene delivery. Acta Pharmaceutica Sinica B (2018), https:
//doi.org/10.1016/j.apsb.2018.01.007