Materials & Design 184 (2019) 108187

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Materials & Design

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Functionalised mesoporous silica nanoparticles with excellent

cytotoxicity against various cancer cells for pH-responsive and
controlled drug delivery
Sung Soo Park a, Moon Hyun Jung b, Young-Shin Lee b, Jae-Ho Bae b, Sun-Hee Kim b,
Chang-Sik Ha a, *
a
Department of Polymer Science and Engineering, Pusan National University, Busan 46241, Republic of Korea
b
Department of Biochemistry, School of Medicine, Pusan National University, Yangsan Hospital, Yangsan 50612, Republic of Korea

h i g h l i g h t s g r a p h i c a l a b s t r a c t

A mesoporous silica with carboxyl

groups was designed as a support for
loading of cisplatin.

The mesoporous silica was synthe-
sized hydrothermally using tetraethyl
orthosilicate and cetyl-
trimethylammonium tosylate.

The cisplatin as anticancer drug in
nanopores showed the controlled
release behavior by pH stimuli (pH
4.0 and 7.3).

The cisplatin-loaded hybrid (Pt/
COOH-MSNs) exhibited good anti-
cancer activity for three cells, i.e.
A549, A2780, and MCF-7.

Pt/COOH-MSNs could give more
generalised insights in developing
effective and universal nanocarrier of
an anticancer drug.

a r t i c l e i n f o a b s t r a c t

Article history: Mesoporous silica nanoparticles (MSNs) modified with Pt and carboxyl groups were designed and the
Received 4 April 2019 drug molecule-release behaviour was studied by loading cisplatin as a model anticancer drug. The MSNs
Received in revised form had a high surface area (342 m2 g1) and dual pores (3.3 and 33.4 nm) with a uniform size. The amount of
1 September 2019
cisplatin loaded in the nanopores was 74.9 mg g1. Drug release was approximately two times higher
Accepted 4 September 2019
Available online 5 September 2019
under acidic conditions (pH 4.0) than under neutral conditions (pH 7.3). The cell viability was tested
using three types of cancer cells (A549, A2780, and MCF-7). When the drug-free samples (Surfactant-
extracted MSNs, COOH-MSNs) were applied at a concentration of 500 mg ml1, the cancer cell death did
Keywords:
Mesoporous silica nanoparticles
not show any differences (Cell survival rate of approximately 82.7e85.7%). On the other hand, cancer cell
Cisplatin death was more pronounced with excellent performance when drug-loaded MSNs (Pt/COOH-MSNs)
pH-responsive were applied at the same concentration (Cell survival rate 3.6% for A549, 15.8% for A2780, 12.8% for
Drug delivery

* Corresponding author.
E-mail address: [email protected] (C.-S. Ha).

https://doi.org/10.1016/j.matdes.2019.108187
0264-1275/© 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2 S.S. Park et al. / Materials & Design 184 (2019) 108187

MCF-7, respectively). This result may give more generalised insights in developing effective and universal
nanocarrier of an anticancer drug by using multiple cell lines instead of using any single cancer cell line.
© 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction for exceptional capacity for drug storage [45e47]. The controlled
and sustained release of drug molecules from the ordered meso-
Cisplatin (cis-dichlorodiammineplatinum(II), CDDP) is one of porous structure can reduce the total dose that can cause side ef-
the most widely applied and effective anticancer drugs owing to its fects caused by overdosing of the drug and increase the efficiency of
potent activity of cross-linking DNA when entering cells in the the drug action by increasing the local drug concentration.
treatment of solid tumours [1,2]. The drug is used to treat a variety On the other hand, MSNs have biodegradation properties. Bein
of cancers, including sarcomas, some carcinomas (e.g., small cell et al. [48] reported bio-degradation of colloidal MSNs with
lung cancer, squamous cell carcinoma of the head and neck and regarding to the effect of surface functionalization with organo-
ovarian cancer), lymphomas, bladder cancer, cervical cancer, and silanes (phenyl-, chloropropyl- and aminopropyl groups) and
germ cell tumours [3]. Nevertheless, the advent of endogenous and poly(ethylene glycol) in Simulated Body Fluid (SBF) for a period of
acquired drug resistance limits its clinical use [4]. To overcome 1 month at 37  C. The fastest degradation kinetics were associated
resistance, high doses of CDDP are generally necessary for practical with the phenyl-functionalized sample and the slowest kinetics
clinical applications, but this can lead to systemic toxicity [5]. were observed for the PEGylated CMS nanoparticles. Braun et al.
Therefore, considerable efforts have been made to develop a new [49] reported the dissolution kinetics of MSNs in different SBFs. The
drug delivery system (DDS) to enhance the accumulation of CDDP observed silica dissolution rates followed the order of simulated
in cancer cells and reduce the risk of overdose [6e21]. lung fluid (SLF) > simulated body fluid (SBF) z phosphate-buffered
Generally, polymeric nanoparticles, which rely on the self- saline (PBS) [ simulated gastric juice (SGF). Palanikumar et al. [50]
assembly of amphipathic copolymers, have been widely used in reported on the biodegradable MSNs system as a simple, versatile
biomedical applications including drug delivery as well as cell and facile drug delivery platform utilizing noncovalent polymer
imaging because of their well designability, facile functionalization gatekeepers, which is capable of encapsulating hydrophilic drug,
and biocompatibility. Wei and coworkers [22e36] reported poly- doxorubicin hydrochloride (Dox) with high loading capacity, and
meric aggregation-induced emission dye-based fluorescent nano- that the decoration of hyaluronic acid (HA) facilitates the targeting
particles for cell imaging applications. The fluorescent organic capability to CD44 overexpressed cancer cells. Song et al. [51]
nanoparticles showed uniform size, high water dispersibility, studied on the gold nanorods/mesoporous silica/hydroxyapatite
strong fluorescence and excellent biocompatibility. They also re- (Au/SiO2/HAP) hybrid nanoparticles with gold nanorods (AuNRs)
ported a facile surface modification strategy for the fabrication of core and SiO2/HAP hybrid shell for multi-responsive drug delivery.
fluorescent silica nanoparticles with the aggregation-induced The results demonstrated that the prepared hybrid nanoparticles
emission dye through surface initiated cationic ring opening displayed great potentials in controllable drug delivery area owing
polymerisation [37]. Meanwhile, Wei and coworkers [38,39] also to their high drug loading efficiency, excellent pH-/NIR-sensitivity
reported facile preparation of fluorescent nanodiamond-based and biodegradability. Liu et al. [52] synthesised the Schiff base-
polymer composites for cellular imaging and drug delivery appli- embedded ultrasmall mesoporous organosilica nanoparticles (S-
cations. Pei et al. [40] synthesised Janus-like poly(methyl methac- MON) via rationally incorporating benzoiceimine bonds into sili-
rylate)-b-poly(ethylene glycol)-folic acid block copolymer-grafted cate frameworks. The S-MON based drug delivery system (DDS)
fluorescent carbon dots (CDs-PMMA-PEG-FA) for leakage-free tu- showed excellent stability in a neutral physiological environment
mor theranostic application. The cellular uptake result of the and facile degradation characterization under acidic conditions.
PMMA-PEG-FA grafted fluorescent carbon dots with doxorubicin Rao et al. [53] studied on the intracellularly degradable cystamine
(Dox) showed that the proposed fluorescent theranostic nano- integrated periodic mesoporous organosilica (PMO) nanoparticles
medicines could be effectively internalized into HepG2 cells and due to the degradation of disulfide bonds available in the frame-
release Dox into the cell nuclei. Recently, Marín et al. [41] reported work for cancer drug delivery. The results pave the way for the
the synthesis of magnetite nanoparticles/gelatin composite films development of cost-effective hybrid PMO nanoparticles possess-
for triggering drug release by an external magnetic field. Sirivat ing the combination of a high drug loading level and improved
et al. [42] synthesised the magnetite nanoparticles via the chemical specific delivery capabilities for intracellular degradable cancer
coprecipitation in a facile single step with gelatin as a biopolymer treatment.
coating for the cancer drug delivery. Yusop et al. [43] reported on In addition, the size and morphology of MSNs can be tuned
the effects of poly(lactic-co-glycolic acid) (PLGA) on structure, facilely to maximise the cellular uptake [6,54]. Therefore, MSNs
degradation, drug release and mechanical properties relationships have been exploited as excellent storage and nanocarriers for the
of iron-based drug eluting scaffolds. It is demonstrated that the controlled delivery of CDDP. On the other hand, although pure
PLGA played an important role to control the scaffold degradation MSNs contain silanol (Si-OH) groups on the surface of the pore
and curcumin release as well as enhancing the mechanical prop- walls, the low affinity between the pore walls and CDDP molecules
erties of the drug device as an integrated system for favorable usually results in a very limited loading and the explosive release of
scaffold-based drug design. Bang et al. [44] reported dysprosia the reloaded drug. To improve the CDDP loading capability and
aerogels as drug delivery systems. They carried out a comparative control its release profile, modification on the surface of pore
study with random and ordered mesoporous silicas with different channels and at the entrance of the pores using suitable functional
releasing time at pH 7.4. groups is generally necessary [55,56].
Mesoporous silica nanoparticles (MSNs) have been used suc- In previous studies [6,9,10], the carboxyl groups were coordi-
cessfully as drug carriers because of their distinctive properties nated with platinum atom to form a complex by replacing the
with a high surface area, uniform pore size, and large pore volume chloride ligands in CDDP. Therefore, a platinum-carboxyl complex
 S.S. Park et al. / Materials & Design 184 (2019) 108187 3

containing MSNs showed an improved loading capacity and best of our knowledge, this work is the first study to directly
controlled release profile with pH as the external stimulus. compare the anticancer effect of three different cancer cells of
Gu et al. [6] reported antitumor activity against both MCF-7 and functionalised MSNs, which could give more generalised insights in
HeLa cells using cisplatin-loaded MSNs with carboxyl groups by the developing effective and universal nanocarrier of an anticancer
co-condensation of tetraethoxy orthosilicate (TEOS) and carbox- drug by using multiple cell lines instead of using any single cancer
yethylsilanetriol sodium salt as the silica source. cell line. The results of the test revealed excellent cytotoxicity after
Mohapatra et al. [9] reported the synthesis of MSN, in which the cellular uptake to the three cancer cells. Therefore, it is believed
outer surface was modified chemically with carboxyl groups to that our novel pH-responsive cisplatin-loaded mesoporous silica
capture CDDP and had superparamagnetic CoFe2O4 nanoparticles (Pt/COOH-MSNs) with excellent cytotoxicity against various cancer
as cores. In addition, a hydrophobic anticancer drug (pemetrexed) cells can be an excellent candidate as the nanocarrier of an anti-
was loaded and the marker molecule, folic acid, and fluorescent cancer drug. Thus, the results of our study will be significantly
dye, rhodamine B isothiocyanate (RITC), were modified chemically. helpful to the researchers related to nanomedicines or materials
These dual drug-loaded nanospheres exhibited the enhanced chemistry for diverse biomedical applications in the near future.
cytotoxicity of HeLa cells compared to individual drugs.
Zhu et al. [10] also reported the synthesis of core-shell MSNs 2. Experimental
hollow spheres modified with carboxyl groups to grasp the CDDP
on the pore surfaces using Fe3O4 nanoparticles as cores. The ma- 2.1. Materials
terials exhibited enhanced antitumor efficiency against both A549
and MCF-7 cell lines. Cetyltrimethylammonium tosylate (CTATos), triethanolamine
Several research groups reported the synthesis of polymer- (TEAH3, 98%), tetraethyl orthosilicate (TEOS, 99%), (3-aminopropy)
coated MSNs, such as poly[(N-isopropylacrylamide)-co-(meth- triethoxysilane (APTES, 98%), toluene (Anhydrous, 99.8%), pyro-
acrylic acid)] {p(NIPAM-co-MA)} [8], polyethylene glycol (PEG) mellitic dianhydride (PMDA, 97%), cis-diammineplatinum(II)
[11,18,51,52], poly(acrylic acid) (PAA) [13,16], and polymers with a dichloride (cisplatin, CDDP, 99.9%), dimethyl sulfoxide (DMSO)
carboxyl group [17,19,21]. The polymer-coated MSNs with a CDDP were purchased from Sigma-Aldrich. Hydrochloric acid (HCl, 35% in
loading in the mesopores exhibited good cytotoxicity to Hep2, H2O) was obtained from Jusei Chemicals. All chemicals were used
A549, MCF-7, A357, and HeLa cells. Palanikumar et al. [12] syn- as received.
thesised the polymer-gatekeeper MSNs by noncovalent capping of
the pores of the drug (CDDP and doxorubicin)-loaded nano- 2.2. Synthesis of mesoporous silica nanoparticles (MSNs)
containers with disulfide cross-linkable polymers. The materials
showed high cytotoxicity to KB cells after release by intracellular MSNs were synthesised according to the method reported
reducing agents, such as glutathione (GSH). Ahn et al. [7] examined elsewhere [59]. A mixture of 3.37  102 mol of CTATos,
the cytotoxicity (Hela, A549, MCF-7) with the efficient therapeutic 1.86  102 mol of TEAH3 and 44.40 mol of deionised water was
cisplatin-drug delivery system using a Pt(IV) prodrug conjugated stirred at 80  C for 1 h, and 5.60  101 mol of TEOS was then added
on the surface of fluorescent MSNs. Tran et al. [20] synthesised quickly to the surfactant solution. The final mixture had a molar
multifunctional MSNs with internal fluorescent conjugates and composition: 1.0 SiO2:0.06 CTATos:0.026 TEAH3:80.0 H2O. The
external polydopamine (PDA) and graphene oxide (GO) layers. The mixture was stirred at 80  C for a further 2 h. The solids were
MSNs exhibited the stimuli (pH, NIR irradiation)-responsive filtered, washed and dried in an oven at 100  C for 24 h. The ob-
controlled release of drug molecules and high cytotoxicity to SH- tained product was labelled ‘As-synthesised MSNs’. Surfactants in
SY5Y cells. Zhang et al. [14] reported a drug delivery system the synthesised MSNs were removed using a solvent extraction
based on MSNs for codelivery of the cisplatin prodrug and chlorin process with 150 mL of EtOH containing 3 mL of 35 wt% HCl at 60  C
e6 (Ce6) to enable a combination chemophotodynamic dual ther- for 12 h and dried at 80  C for 12 h. This process was repeated twice.
apy against cisplatin-resistant cancer cells (A549R). The resulting product was labelled as ‘Surfactant-extracted MSNs’.
Recently, Tsai et al. [57] investigated the approach to target HCC
by combining conventional chemotherapeutic drug cisplatin to 2.3. Synthesis of aminosilane-functionalised mesoporous silica
target the bulk of tumor cells and differentiation therapy by nanoparticles (NH2-MSNs)
delivering the gene encoding HNF4a using polyethyleneimine-
modified mesoporous silica nanoparticles (PMSNs) as delivery ve- First, to remove the water bonded with surface silanol groups,
hicles. Han et al. [58] designed a pH-sensitive chemical drug Surfactant-extracted MSNs were degassed at 150  C over 12 h un-
loading nanoparticle system linked with a C-X-C motif chemokine der vacuum. For the aminosilane-functionalised MSNs, 1.0 g of
receptor 1 (CXCR1) targeting peptide. Cisplatin was loaded into the degassed MSNs was suspended in 100 ml of 0.1 M APTES solution in
pores of fluorescence-labelled magnetic iron oxide containing toluene and stirred at 80  C for 12 h under N2. The solid sample was
mesoporous silica nanoparticles (Fe3O4@MSNs) to enable detection filtered and washed several times with toluene and the sample was
via magnetic resonance (MR) imaging and an in vivo imaging sys- then dried at 60  C for 12 h in air. The obtained product was labelled
tem (IVIS). This system is expected to achieve synergistic antitumor as ‘NH2-MSNs’.
efficacy through precise targeting of CXCR1 on osteosarcoma (OS)
circulating tumor cells (CTCs) and cisplatin delivery via 2.4. Synthesis of carboxyl groups functionalised mesoporous silica
nanoparticles. nanoparticles (COOH-MSNs)
In this study, carboxyl group-functionalised MSNs (COOH-
MSNs) with large pores and a spherical morphology were designed A 1 g sample of NH2-MSNs was degassed at 80  C over 6 h under
and synthesised. Metal complexes were designed to form through vacuum. The degassed NH2-MSNs were suspended in 100 ml of
complexation between the platinum atom and carboxyl groups by 0.1 M PMDA solution in DMAc and stirred at room temperature for
replacing the chloride ion from the introduction of CDDP in the 12 h. The solid sample was filtered and washed several times with
functionalised MSNs. The cytotoxicity for three different types of DMAc. Deionised water (30 ml) was added and stirred at room
cancer cell lines (A549, A2780 and MCF-7 cell) of the cisplatin temperature for 2 h. After filtration, the solid sample was dried at
complex-functionalised MSNs (Pt/COOH-MSNs) were tested. To the 60  C for 12 h in air. The obtained product was labelled ‘COOH-
4 S.S. Park et al. / Materials & Design 184 (2019) 108187

MSNs’. BarretteJoynereHalenda (BJH) method. The Fourier transform

infrared (FT-IR, Perkin Elmer) spectra of the samples were collected
2.5. Synthesis of cisplatin loaded mesoporous silica nanoparticles using KBr pellets. Thermogravimetric analysis (TGA, Perkin-Elmer
(Pt/COOH-MSNs) Pyris Diamond TG) was performed at a heating rate of 5  C min1
in air. Quantitative determination of Pt(II) was performed by
A 1 g sample of COOH-MSNs was suspended in 100 ml of a inductively coupled plasma-optical emission spectrometry (ICP-
2  102 M CDDP solution in DMSO and stirred at 45  C for 24 h in OES, AU/ICP72OES, Agilent technologies, USA). The isoelectric
the dark. The solid sample was filtered and washed several times points were measured using an electrophoretic light scattering
with DMSO and acetone and the sample was then dried at 45  C for spectrophotometer (ELS-8000). Particle size distribution curves
24 h in air. The resulting product was labelled ‘Pt/COOH-MSNs’. were measured using a dynamic light scattering spectrophotom-
eter (Zetasizer Nano, Malvern). The samples were made up in
2.6. Cell culture aqueous solutions with different pHs (pH 4.0, pH 5.4, and pH 7.3) at
a concentration of 1 mg/50 ml. X-ray photoelectron spectroscopy
Human lung carcinoma (A549) and human breast adenocarci- (XPS) was conducted using a VG Scientific ESCA lab 250 spec-
noma (MCF-7) cell lines were maintained in Dulbecco’s Modified trometer; Al Ka radiation at 1486.6 eV was used and the peak po-
Eagle’s Medium (DMEM, Welgene, Korea), and the human ovarian sitions were referenced internally to the C1s peak at 284.6 eV.
cancer cells (A2780) were maintained in Roswell Park Memorial
Institute medium (RPMI 1640, Welgene, Korea) supplemented with 3. Results and discussion
10% foetal bovine serum (FBS, Welgene, Korea) and 1%
penicillinestreptomycin (Welgene, Korea) at 37  C with 5% CO2 in a Scheme 1 presents a schematic illustration of the synthesis of
95% humidified atmosphere. Dulbecco’s phosphate buffered saline carboxyl group-functionalised MSNs and the releasing behaviour of
(DPBS) was purchased from Welgene (Korea). For the cell viability drug molecules with pH as the stimulus. Cisplatin complexes were
tests, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro- formed through complexation between the platinum atom and
mide (MTT) was purchased from Sigma-Aldrich (St. Louis, MO, carboxyl groups by replacing the chloride ion from the introduction
USA). of CDDP in the functionalised MSNs. On the other hand, the
cisplatin complex was dissociated under acidic conditions.
2.7. Cell proliferation assay Fig. 1 presents TEM images of (a) Surfactant-extracted MSNs, (b)
NH2-MSNs, (c) COOH-MSNs, and (d) Pt/COOH-MSNs. All samples
Cell proliferation was measured by counting the number of have a very uniform particle size (~120 nm) and uniform pore size.
viable cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5- After the modification of functional groups, the MSNs retained a
diphenyltetrazolium bromide (MTT) colorimetric dye-reduction uniform pore size and particle size without any loss of
method. Exponentially growing cells (1  104 cells/well) were mesostructure.
plated in a 96-well plate and incubated in a growth medium treated Fig. 2 shows N2 adsorptionedesorption isotherm curves (A) and
with the indicated concentration of samples and cisplatin at 37  C. pore size distributions (B) of (a) Surfactant-extracted, (b) NH2-
After 96 h, the medium was removed and the MTT-formazan MSNs, (c) COOH-MSNs, and (d) Pt/COOH-MSNs. Table 1 lists the
crystals were dissolved in 100 ml DMSO. The optical density of structural parameters, such as BET surface area, total pore volume
each sample at 570 nm was measured using an ELISA reader. The and pore diameter for Surfactant-extracted MSNs, NH2-MSNs,
optical density of the medium was proportional to the number of COOH-MSNs, and Pt/COOH-MSNs. The BET surface area, pore vol-
viable cells. The inhibition of proliferation was evaluated as the ume and pore diameter decreased after the surface modification of
percentage of control growth (no drug in the medium). All exper- mesopores. Surfactant-extracted MSNs have a dual pore size (3.3,
iments were repeated at least twice with triplicate determination. 33.4 nm), high surface area (342 m2 g1) and large pore volume
(0.65 cm3 g1). The decrease in BET surface area, pore volume and
2.8. Confocal fluorescence microscopy study pore diameter after the surface modification of mesopores can be
attributed to the presence of pendant groups on the mesopore
A549, A2780 and MCF-7 cells were seeded at 2  105 cells in surface of Surfactant-extracted MSNs that partially block the
confocal dishes. After 24 h incubation, 1e5 mM of cisplatin and adsorption of nitrogen molecules. In particular, the pore space was
200e400 mg ml1 of Pt/COOH-MSNs labelled with rhodamine B (Rh reduced significantly by the introduction of organic functional
B) were added to the respective dishes and incubated for 48 h. Each groups and cisplatin drug molecules on the surface of smaller pores
confocal dish was observed by confocal laser scanning microscopy. (approximately 3.3 nm) among the pores in the Surfactant-
The images were analysed using OLYMPUS FLUOVIEW ver. 4.2 extracted MSNs. Therefore, as shown in Fig. 2B, the pore size dis-
Viewer software. tribution curves around 3.3 nm (Fig. 2Bb, Bc and Bd) became flat
compared to the Surfactant-extracted MSNs (Fig. 2Ba), while the
2.9. Characterization pore size of the larger pores (33.4 nm) decreased to 25.6 nm. The
surface area, pore volume and pore diameter of Pt/COOH-MSNs
X-ray diffraction (XRD, Bruker AXS) was performed using Cu Ka obtained from the N2 sorption isotherm were determined to be
radiation (l ¼ 1.5418 Å) at 40 kV and 40 mA in the 2q range, 148 m2 g1, 0.36 cm3 g1, 25.6 nm, respectively.
0.5e10o. Transmission electron microscopy (TEM, JEOL 2010) im- Fig. 3 presents the FT-IR spectra of wide range (A) and selected
ages were obtained at an acceleration voltage of 200 kV. The range (B) of (a) As-synthesised MSNs, (b) Surfactant-extracted
adsorption/desorption isotherms of nitrogen at 196  C were MSNs, (c) NH2-MSNs, (d) COOH-MSNs, and (e) Pt/COOH-MSNs.
measured using a Nova 4000e surface area and pore size analyzer. The peaks at 2857 cm1 and 2926 cm1 (CH aliphatic), and
All samples were outgassed at 100  C for 12 h under vacuum 1478 cm1 (CeN) due to surfactants (CTATos) in the FT-IR spectrum
(p < 5  106 Torr) in the degas port of the adsorption analyzer. The disappeared, meaning that the surfactants in the as-synthesised
surface areas were determined using the BrunauereEmmetteTeller MSNs had been removed completely through a surfactant-
(BET) method. The pore size distribution curve was obtained extraction process (Fig. 3Ab). After modification of the mesopore
from an analysis of the adsorption branch using the surfaces with APTMS (Fig. 3Ac), the peak intensity of 965 cm1
 S.S. Park et al. / Materials & Design 184 (2019) 108187 5

Scheme 1. Schematic diagram of the synthesis of carboxyl group-functionalised MSNs and the releasing behavior of drug molecules with pH as the stimulus.

Fig. 1. TEM images of (a) Surfactant-extracted MSNs, (b) NH2-MSNs, (c) COOH-MSNs, and (d) Pt/COOH-MSNs.
6 S.S. Park et al. / Materials & Design 184 (2019) 108187

Fig. 2. A, N2 adsorptionedesorption isotherm curves and B, pore size distributions of (a) Surfactant-extracted MSNs, (b) NH2-MSNs, (c) COOH-MSNs, and (d) Pt/COOH-MSNs.

Table 1 compositions of Surfactant-extracted MSNs, NH2-MSNs, and

Textural properties determined from the nitrogen adsorptionedesorption experi- COOH-MSNs were determined by X-ray photoelectron spectros-
ments of samples. copy (XPS). (Table 2) Chemical composition of Surfactant-extracted
Sample SBETa (m2 g1) VTotalb (cm3 g1) Dc (nm) MSNs was 37.7% of Si and 62.3% of O. The contents of Si (30.4%) and
O (48.7%) were decreased in the modified amine group, and
Surfactant-extracted MSNs 342 0.65 3.3, 33.4
NH2-MSNs 200 0.45 2.8, 25.6 showed 18.5% of C and 2.4% of N, respectively. And the element
COOH-MSNs 144 0.37 25.6 contents of the carboxyl group modified samples were 30.4% of Si,
Pt/COOH-MSNs 148 0.36 25.6 48.7% of O, 18.5% of C, and 2.4% of N. These results indicate that the
a
SBET (m2 g1): Total BET surface area. organic moieties were successfully modified on MSNs pore sur-
b
Vtotal (cm3 g1): Total pore volume. faces, which is also shown by IR spectra and TGA results.
c
D (Å): Pore diameter. TGA was performed to examine the content of the modified
moieties in the functionalised MSNs (Fig. 4). TGA of the samples
exhibited the first weight loss below 100  C due to the desorption of
decreased remarkably compared to Surfactant-extracted MSNs.
physisorbed water (1.3% for Surfactant-extracted MSNs, 1.5% for
This is because the silanol (Si-OH) groups had been consumed by
NH2-MSNs, 1.2% for COOH-MSNs, 1.2% for Pt/COOH-MSNs, respec-
the reaction between silanol groups and aminosilane (APTMS)
tively). The next decrease in weight occurred between 200 and
molecules on the pore surfaces [60]. In addition, the characteristic
800  C; this weight loss was assigned to the loss of organic func-
peaks for NH2-MSNs appeared at 1062 cm1 (eSieOeSie),
tional groups on the mesopore walls. During this process, water
1478 cm1 (CeN), 1554 cm1 (eNH2), and 2857 cm1 and
molecules may also form through the condensation of SieOH units
2926 cm1 (CH aliphatic) (Fig. 3Ac, Bc) [60]. As shown in Fig. 3Ad
in the pore walls. The total weight loss of the samples was 8.8% for
and Bd, the main characteristic peaks for COOH-MSNs appeared at
the Surfactant-extracted MSNs, 14.5% for the NH2-MSNs, 18.5% for
1062 cm1 (eSieOeSie), 1563 cm1 (eCHNe in amide I),
the COOH-MSNs, and 21.7% for the Pt/COOH-MSNs. In addition, the
1599 cm1 (eC¼Ce in benzene ring), 1620 cm1 (eC¼Oe in amide
amount of cisplatin loaded in the nanopores was confirmed to be
I), 1714 cm1 (eC¼Oe in COOH), and 2857 cm1 and 2926 cm1 (CH
74.9 mg g1 by an analysis of the mother solution after the
aliphatic) [6,60]. After loading cisplatin in the COOH-MSNs (Pt/
adsorption of a cisplatin solution with COOH-MSNs using the ICP-
COOH-MSNs), the sample exhibited the main characteristic peaks
OES technique.
at 1062 cm1 (eSieOeSie), 1314 cm1 and 1625 cm1 (NH3), and
The hydrodynamic diameters and zeta potentials of samples
2857 cm1 and 2926 cm1 (CH aliphatic) [60,61]. The results of the
were measured in aqueous solutions with various pHs for the po-
FT-IR spectra showed the successful modification of functional
tential application in the biomedical areas of pristine MSNs (Sur-
groups and the introduction of CDDP into MSNs. Chemical
factant-extracted MSNs) and modified MSNs (NH2-MSNs, COOH-

Fig. 3. FT-IR spectra of wide range (A) and selected range (B) of (a) As-synthesised MSNs, (b) Surfactant-extracted MSNs, (c) NH2-MSNs, (d) COOH-MSNs, and (e) Pt/COOH-MSNs.
 S.S. Park et al. / Materials & Design 184 (2019) 108187 7

Table 2 Table 3
Chemical compositions of Surfactant-extracted MSNs, NH2-MSNs, and COOH-MSNs Hydrodynamic diameters and Zeta potentials of Surfactant-extracted MSNs, NH2-
by X-ray photoelectron spectroscopy (XPS). MSNs, and COOH-MSNs in aqueous solutions with various pHs.

Sample Atomic % Sample Hydrodynamic Zeta potential

diameter (mV)
Si O C N
(nm)
Surfactant-extracted MSNs 37.7 62.3 e e
pH 4.0 pH 5.4 pH 7.3 pH 4.0 pH 5.4 pH 7.3
NH2-MSNs 30.4 48.7 18.5 2.4
COOH-MSNs 27.4 46.2 23.9 2.6 Surfactant-extracted MSNs 295.1 253.5 232.2 3.66 4.36 5.21
NH2-MSNs 199.5 202.3 222.5 22.4 10.87 2.96
COOH-MSNs 207.3 184.1 109.1 10.32 18.07 28.7

MSNs) (Table 3). The zeta potential values for samples showed less
absolute values at lower pH value. This is due to the protonation of
functional groups present on the pore surface of MSNs. In partic-
ular, samples with modified carboxyl groups have large negative
values. On the other hand, the smaller particle size was observed
with the larger absolute value of the zeta potential of samples. The
result may be due to the repulsive force of the nanoparticle surface.
Fig. 5 shows the time-dependent release kinetics of cisplatin
from Pt/COOH-MSNs in a PBS buffer at (a) pH 7.3, (b) 5.4, and (c) 4.0
at 37  C. CDDP in Pt/COOH-MSNs was released continuously for up
to 42 h, as shown in Fig. 5b and c. CDDP release in currently syn-
thesised Pt/COOH-MSNs proceeds via ligand exchange reactions
between the carboxylic groups within Pt/COOH-MSNs and chloride
in PBS [6]. Drug release was also strongly dependent on the acidity.
CDDP was released from the Pt/COOH-MSNs significantly faster at
lower pH. The more rapid release under the acidic condition may be
due to the protonation of carboxylic groups within Pt/COOH-MSNs,
which weakens the coupling of the drug with nanoparticles and
Fig. 5. Time-dependent release kinetics of cisplatin from Pt/COOH-MSNs in a PBS
makes the drug more replaceable by chloride in PBS [6]. After a
solution at (a) pH 7.3, (b) 5.4, and (c) 4.0 at 37  C.
release time of 92 h, the amount of CDDP released at lower pH
(pH ¼ 5.4, 4.0) was more than double that at higher pH (7.3, i.e.
neutral conditions). respectively). Pt/COOH-MSNs showed approximately six and two
Fig. 6 presents the in vitro cytotoxicity of Surfactant-extracted times higher cytotoxicity for A549 and MCF-7 cells, respectively,
MSNs, NH2-MSNs, COOH-MSNs, and Pt/COOH-MSNs with various than pristine cisplatin while the cytotoxicity of Pt/COOH-MSNs was
cancer cells of (a) A549, (b) A2780 and (c) MCF-7. When the drug- comparable to cisplatin for A2780 cells.
free samples (Surfactant-extracted MSNs, COOH-MSNs) were The internalisation of Pt drugs by Pt/COOH-MSNs into cancer
applied at a concentration of 500 mg ml1, there was no significant cells was checked by confocal laser scanning electron microscopy
difference in cancer cell death (Cell survival rate of approximately (CLSM) after incubation of various cancer cells, such as A549, A2780
82.7e85.7%). These results suggest that drug-free samples (Sur- and MCF-7 as the model cancer cell. Fig. 7 shows bright field, dark
factant-extracted MSNs, COOH-MSNs) are biocompatible. On the field and merged CLMS images of A549, A2780 and MCF-7 cells
other hand, when the sample containing the drug (Pt/COOH-MSNs) after 24 h incubation with 400 mg ml1 of Pt/COOH-MSNs labelled
was applied at the same concentration, the extent of cancer cell with rhodamine B (Rh B). The images of all cancer cells showed
death was more pronounced with excellent performance (Cell strong red fluorescence due to the Rh B-labelled Pt/COOH-MSNs
survival rate 3.6% for A549, 15.8% for A2780, and 12.8% for MCF-7, nanoparticles. The well-matched locations of the cancer cells and
nanoparticles in the merged images of bright field and dark field
images for all cancer cells indicated that Rh B-labelled Pt/COOH-
MSNs nanoparticles had been taken up successfully into the cells.
Therefore, the results of cytotoxicity test in vitro in Fig. 6 as well as
the internalisation test in Fig. 7 prove that the cisplatin-loaded
mesoporous silica (Pt/COOH-MSNs) is an excellent candidate as
an anticancer agent. In our next work, detailed degradability
studies on the Pt/COOH-MSNs will be further carried out.

4. Conclusions

Mesoporous silica nanoparticles with high surface area

(342 m2 g1) and dual pores (3.3 and 33.4 nm) were designed and
synthesised via a hydrothermal process using tetraethyl orthosili-
cate (TEOS) as the silica source and cetyltrimethylammonium
tosylate (CTATos) as structure directing agent. The mesoporous
silica nanoparticles modified with carboxyl groups were designed
and synthesised by a post-synthesis method, and the drug mole-
Fig. 4. TGA curves of (a) As-synthesised MSNs, (b) Surfactant-extracted MSNs, (c) NH2- cule release was studied by loading cisplatin as a model anticancer
MSNs, (d) COOH-MSNs, and (e) Pt/COOH-MSNs. drug. The amount of cisplatin loaded in the nanopores was
8 S.S. Park et al. / Materials & Design 184 (2019) 108187

Fig. 6. In vitro cytotoxicity of Surfactant-extracted MSNs, NH2-MSNs, COOH-MSNs, and Pt/COOH-MSNs with various cancer cells: (a) A549, (b) A2780 and (c) MCF-7.

Fig. 7. Bright field, dark field and merged confocal laser scanning microscopy (CLSM) images of A549, A2780 and MCF-7 cells after 24 h incubation with 400 mg ml1 of Pt/COOH-
MSNs labelled with rhodamine B (Rh B).
 S.S. Park et al. / Materials & Design 184 (2019) 108187 9

74.9 mg g1 according to ICP-OES. Drug release was approximately Y. Wei, Direct surface grafting of mesoporous silica nanoparticles with
phospholipid choline-containing copolymers through chain transfer free
two times higher under acidic conditions (pH 4.0) than under
radical polymerization and their controlled drug delivery, J. Colloid Interface
neutral conditions (pH 7.3). The cell viability was tested using three Sci. 508 (2017) 396e404.
different types of cancer cells (A549, A2780 and MCF-7). The [18] L. Huang, M. Liu, L. Mao, D. Xu, Q. Wan, G. Zeng, Y. Shi, Y. Wen, X. Zhang,
cisplatin-loaded sample (Pt/COOH-MSNs) exhibited excellent per- Y. Wei, Preparation and controlled drug delivery applications of mesoporous
silica polymer nanocomposites through the visible light induced surface-
formance of anticancer with cell death 96.4% for A549, 84.2% for initiated ATRP, Appl. Surf. Sci. 412 (2017) 571e577.
A2780 and 87.2% for MCF-7, respectively, while the drug-free [19] L. Huang, M. Liu, L. Mao, Q. Huang, H. Huang, Q. Wan, J. Tian, Y. Wen, X. Zhang,
samples (Surfactant-extracted MSNs, COOH-MSNs) exhibited cell Y. Wei, Surface PEGylation of mesoporous silica materials via surface-initiated
chain transfer free radical polymerization: characterization and controlled
survival rate of approximately 82.7e85.7%. Overall, the cisplatin- drug release, Mater. Sci. Eng. C 81 (2017) 57e65.
loaded mesoporous silica nanoparticles (Pt/COOH-MSNs) are an [20] L. Huang, M. Liu, L. Mao, Q. Huang, H. Huang, G. Zeng, J. Tian, Y. Wen, X. Zhang,
excellent candidate as an anticancer agent. In addition, the results Y. Wei, A facile FeBr3 based photoATRP for surface modification of meso-
porous silica nanoparticles for controlled delivery cisplatin, Appl. Surf. Sci. 434
obtained from the present work may pave the way to develop (2018) 204e210.
effective and universal nanocarrier of an anticancer drug by using [21] A.-V. Tran, K. Shim, T.-T.V. Thi, J.-K. Kook, S.S.A. An, S.-W. Lee, Targeted and
multiple cell lines instead of using any single cancer cell line. controlled drug delivery by multifunctional mesoporous silica nanoparticles
with internal fluorescent conjugates and external polydopamine and gra-
phene oxide layers, Acta Biomater. 74 (2018) 397e413.
Acknowledgements [22] X. Zhang, X. Zhang, B. Yang, M. Liu, W. Liu, Y. Chen, Y. Wei, Polymerisable
aggregation-induced emission dye-based fluorescent nanoparticles for cell
imaging applications, Polym. Chem. 5 (2014) 356e360.
The work was supported by the National Research Foundation of [23] X. Zhang, X. Zhang, B. Yang, M. Liu, W. Liu, Y. Chen, Y. Wei, Fabrication of
Korea (NRF) Grant funded by the Ministry of Science and ICT, Korea aggregation induced emission dye based fluorescent organic nanoparticles via
{Mid-Career Researchers Program (NRF-2017R1A2B3012961); In- emulsion polymerisation and their cell imaging applications, Polym. Chem. 5
(2014) 399e404.
dividual Basic Research Program (NRF-2017R1D1A1B03034414); [24] X. Zhang, K. Wang, M. Liu, X. Zhang, L. Tao, Y. Chen, Y. Wei, Polymeric AIE-
Brain Korea 21 Plus Program (21A2013800002)}. based nanoprobes for biomedical applications: recent advances and per-
spectives, Nanoscale 7 (2015) 11486e11508.
[25] Z. Long, M. Liu, K. Wang, F. Deng, D. Xu, L. Liuc, Y. Wan, X. Zhang, Y. Wei, Facile
References synthesis of AIE-active amphiphilic polymers: self-assembly and biological
imaging applications, Mater. Sci. Eng. C 66 (2016) 215e220.
[1] L. Galluzzi, L. Senovilla, I. Vitale, J. Michels, I. Martins, O. Kepp, M. Castedo, [26] J. Tian, R. Jiang, P. Gao, D. Xu, L. Mao, G. Zeng, M. Liu, F. Deng, X. Zhang, Y. Wei,
G. Kroemer, Molecular mechanisms of cisplatin resistance, Oncogene 31 Synthesis and cell imaging applications of amphiphilic AIE-active poly(amino
(2012) 1869e1883. acid)s, Mater. Sci. Eng. C 79 (2017) 563e569.
[2] S. Khiati, D. Luvino, K. Oumzil, B. Chauffert, M. Camplo, P. Barthelemy, [27] Z. Long, M. Liu, R. Jiang, Q. Wan, L. Mao, Y. Wan, F. Deng, X. Zhang, Y. Wei,
Nucleoside lipid-based nanoparticles for cisplatin delivery, ACS Nano 5 (2011) Preparation of water soluble and biocompatible AIE-active fluorescent organic
8649e8655. nanoparticles via multicomponent reaction and their biological imaging
[3] S. Dasari, P.B. Tchounwou, Cisplatin in cancer therapy: molecular mechanisms capability, Chem. Eng. J. 308 (2017) 527e534.
of action, Eur. J. Pharmacol. 740 (2014) 364e378. [28] Q.-Y. Cao, R. Jiang, M. Liu, Q. Wan, D. Xu, J. Tian, H. Huang, Y. Wen, X. Zhang,
[4] X.H. Peng, Y.Q. Wang, D.H. Huang, Y.X. Wang, H.J. Shin, Z.J. Chen, M.B. Spewak, Y. Wei, Preparation of AIE-active fluorescent polymeric nanoparticles through
H. Mao, X. Wang, Y. Wang, Z. Chen, S.M. Nie, D.M. Shin, Targeted delivery of a catalyst-free thiol-yne click reaction for bioimaging applications, Mater. Sci.
cisplatin to lung cancer using ScFvEGFR-heparin-cisplatin nanoparticles, ACS Eng. C 80 (2017) 411e416.
Nano 5 (2011) 9480e9493. [29] Q.-Y. Cao, R. Jiang, M. Liu, Q. Wan, D. Xu, J. Tian, H. Huang, Y. Wen, X. Zhang,
[5] N. Graf, D.R. Bielenberg, N. Kolishetti, C. Muus, J. Banyard, O.C. Farokhzad, Y. Wei, Microwave-assisted multicomponent reactions for rapid synthesis of
S.J. Lippard, aVb3 integrin-targeted PLGA-PEG nanoparticles for enhanced anti- AIE-active fluorescent polymeric nanoparticles by post-polymerization
tumor efficacy of a Pt(IV) prodrug, ACS Nano 6 (2012) 4530e4539. method, Mater. Sci. Eng. C 80 (2017) 578e583.
[6] J. Gu, J. Liu, Y. Li, W. Zhao, J. Shi, One-pot synthesis of mesoporous silica [30] Z. Long, L. Mao, M. Liu, Q. Wan, Y. Wan, X. Zhang, Y. Wei, Marrying multi-
nanocarriers with tunable particle sizes and pendent carboxylic groups for component reactions and aggregation-induced emission (AIE): new directions
cisplatin delivery, Langmuir 29 (2013) 403e410. for fluorescent nanoprobes, Polym. Chem. 8 (2017) 5644e5654.
[7] B. Ahn, J. Park, K. Sigha, H. Park, W.J. Kim, Mesoporous silica nanoparticle- [31] R. Jiang, M. Liu, C. Li, Q. Huang, H. Huang, Q. Wan, Y. Wen, Q.-Y. Cao, X. Zhang,
based cisplatin prodrug delivery and anticancer effect under reductive Y. Wei, Facile fabrication of luminescent polymeric nanoparticles containing
cellular environment, J. Mater. Chem. B 1 (2013) 2829e2836. dynamic linkages via a one-pot multicomponent reaction: synthesis,
[8] X. Liu, Dan Yu, C. Jin, X. Song, J. Cheng, X. Zhao, X. Qi, G. Zhang, A dual aggregation-induced emission and biological imaging, Mater. Sci. Eng. C 80
responsive targeted drug delivery system based on smart polymer coated (2017) 708e714.
mesoporous silica for laryngeal carcinoma treatment, New J. Chem. 38 (2014) [32] H. Huang, D. Xu, M. Liu, R. Jiang, L. Mao, Q. Huang, Q. Wan, Y. Wen, X. Zhang,
4830e4836. Y. Wei, Direct encapsulation of AIE-active dye with b cyclodextrin terminated
[9] S. Mohapatra, S.R. Rout, R. Narayan, T.K. Maiti, Multifunctional mesoporous polymers: self-assembly and biological imaging, Mater. Sci. Eng. C 78 (2017)
hollow silica nanocapsules for targeted co-delivery of cisplatin-pemetrexed 862e867.
and MR imaging, Dalton Trans. 43 (2014) 15841e15850. [33] Y. Liu, L. Mao, X. Liu, M. Liu, D. Xu, R. Jiang, F. Deng, Y. Li, X. Zhang, Y. Wei,
[10] X. Zhu, J. Gu, Y. Li, W. Zhao, J. Shi, Magnetic core-mesoporous shell nano- A facile strategy for fabrication of aggregation-induced emission (AIE) active
carriers with drug anchorages suspended in mesopore interior for cisplatin fluorescent polymeric nanoparticles (FPNs) via post modification of synthetic
delivery, Microporous Mesoporous Mater. 196 (2014) 115e121. polymers and their cell imaging, Mater. Sci. Eng. C 79 (2017) 590e595.
[11] C. Rejeeth, R. Vivek, S. Kannan, A novel magnetic drug delivery nanocomplex [34] R. Jiang, H. Liu, M. Liu, J. Tian, Q. Huang, H. Huang, Y. Wen, Q.-Y. Cao, X. Zhang,
with a cisplatin-conjugated Fe3O4 core and a PEG functionalized mesoporous Y. Wei, A facile one-pot Mannich reaction for the construction of fluorescent
silica shell for enhancing cancer drug delivery efficiency, RSC Adv. 5 (2015) polymeric nanoparticles with aggregation-induced emission feature and their
94534e94538. biological imaging, Mater. Sci. Eng. C 81 (2017) 416e421.
[12] L. Palanikumar, E.S. Choi, J.Y. Cheon, S.H. Joo, J.-Y. Ryu, Noncovalent polymer- [35] Q. Wan, Q. Huang, M. Liua, D. Xu, H. Huang, X. Zhang, Y. Wei, Aggregation-
gatekeeper in mesoporous silica nanoparticles as a targeted drug delivery induced emission active luminescent polymeric nanoparticles: non-covalent
platform, Adv. Funct. Mater. 25 (2015) 957e965. fabrication methodologies and biomedical applications, Appl. Mater. Today
[13] H. Li, H. Yu, C. Zhu, J. Hu, M. Du, F. Zhang, D. Yang, Cisplatin and doxorubicin 9 (2017) 145e160.
dual-loaded mesoporous silica nanoparticles for controlled drug delivery, RSC [36] R. Jiang, M. Liu, H. Huang, L. Mao, Q. Huang, Y. Wen, Q.-Y. Cao, J. Tian, X. Zhang,
Adv. 6 (2016) 94160e94169. Y. Wei, Facile fabrication of organic dyed polymer nanoparticles with
[14] W. Zhang, J. Shen, H. Su, G. Mu, J.-H. Sun, C.-P. Tan, X.-J. Liang, L.-N. Ji, Z.- aggregation-induced emission using an ultrasound-assisted multicomponent
W. Mao, Co-delivery of cisplatin prodrug and chlorin e6 by mesoporous silica reaction and their biological imaging, J. Colloid Interface Sci. 519 (2018)
nanoparticles for chemo-photodynamic combination therapy to combat drug 137e144.
resistance, ACS Appl. Mater. Interfaces 8 (2016) 13332e13340. [37] L. Huang, S. Yang, J. Chen, J. Tian, Q. Huang, H. Huang, Y. Wen, F. Deng,
[15] M.P. alvarez-Berríos, J.L. Vivero-escoto, In vitro evaluation of folic acid- X. Zhang, Y. Wei, A facile surface modification strategy for fabrication of
conjugated redox-responsive mesoporous silica nanoparticles for the de- fluorescent silica nanoparticles with the aggregation-induced emission dye
livery of cisplatin, Int. J. Nanomedicine 11 (2016) 6251e6265. through surface initiated cationic ring opening polymerization, Mater. Sci.
[16] C. Rejeeth, R. Vivek, V. NipunBabu, A. Sharma, X. Ding, K. Qian, Cancer Eng. C 94 (2019) 270e278.
nanomedicine: from PDGF targeted drug delivery, MedChemComm 8 (2017) [38] J. Chen, M. Liu, Q. Huang, L. Huang, H. Huang, F. Deng, Y. Wen, J. Tian, X. Zhang,
2055e2059. Y. Wei, Facile preparation of fluorescent nanodiamond-based polymer com-
[17] L. Huang, J. Wu, M. Liu, L. Mao, H. Huang, Q. Wan, Y. Dai, Y. Wen, X. Zhang, posites through a metal-free photo-initiated RAFT process and their cellular
10 S.S. Park et al. / Materials & Design 184 (2019) 108187

imaging, Chem. Eng. J. 337 (2018) 82e90. mesoporous silica coated gold nanorods with improved degradability as a
[39] H. Huang, M. Liu, R. Jiang, J. Chen, L. Mao, Y. Wen, J. Tian, N. Zhou, X. Zhang, multi-responsive drug delivery platform, Mater. Sci. Eng. C 83 (2018) 90e98.
Y. Wei, Facile modification of nanodiamonds with hyperbranched polymers [52] L. Liu, C. Kong, M. Huo, C. Liu, L. Peng, T. Zhao, Y. Wei, F. Qian, J. Yuan, Schiff
based on supramolecular chemistry and their potential for drug delivery, base interaction tuned mesoporous organosilica nanoplatforms with pH-
J. Colloid. Interface Sci. 513 (2018) 198e204. responsive degradability for efficient anti-cancer drug delivery in vivo,
[40] M. Pei, X. Jia, P. Liu, Design of Janus-like PMMA-PEG-FA grafted fluorescent Chem. Commun. 54 (2018) 9190e9193.
carbon dots and their nanoassemblies for leakage-free tumor theranostic [53] K. Madhusudana Rao, S. Parambadath, A. Kumar, C.-S. Ha, S.S. Han, Tunable
application, Mater. Des. 155 (2018) 288e296. intracellular degradable periodic mesoporous organosilica hybrid nano-
[41] T. Marín, P. Montoya, O. Arnache, R. Pinal, J. Caldero n, Development of particles for doxorubicin drug delivery in cancer cells, ACS Biomater. Sci. Eng.
magnetite nanoparticles/gelatin composite films for triggering drug release by 4 (2018) 175e183.
an external magnetic field, Mater. Des. 152 (2018) 78e87. [54] X. Du, X. Li, L. Xiong, X. Zhang, F. Kleitz, S.Z. Qiao, Mesoporous silica nano-
[42] A. Sirivat, N. Paradee, Facile synthesis of gelatin-coated Fe3O4 nanoparticle: particles with organo-bridged silsesquioxane framework as innovative plat-
effect of pH in single-step co-precipitation for cancer drug loading, Mater. Des. forms for bioimaging and therapeutic agent delivery, Biomaterials 91 (2016)
181 (2019), 107942, https://doi.org/10.1016/j.matdes.2019.107942. 90e127.
[43] A.H. Yusop, M.N. Sarian, F.S. Januddi, Q.U. Ahmed, M.R. Kadir, D. Hartanto, [55] Z. Wang, P. Wu, Z. He, H. He, W. Rong, J. Li, D. Zhou, Y. Huang, Mesoporous
H. Hermawan, H. Nur, Structure, degradation, drug release and mechanical silica nanoparticles with lactose-mediated targeting effect to deliver plati-
properties relationships of iron-based drug eluting scaffolds: the effects of num(IV) prodrug for liver cancer therapy, J. Mater. Chem. B 5 (2017)
PLGA, Mater. Des. 160 (2018) 203e217. 7591e7597.
[44] A. Bang, A.G. Sadekar, C. Buback, B. Curtin, S. Acar, D. Kolasinac, W. Yin, [56] M. Varache, I. Bezverkhyy, G. Weber, L. Saviot, R. Chassagnon, F. Baras,
D.A. Rubenstein, H. Lu, N. Leventis, C. Sotiriou-Leventis, Evaluation of dys- F. Bouyer, Loading of cisplatin into mesoporous silica nanoparticles: effect of
prosia aerogels as drug delivery systems: a comparative study with random surface functionalization, Langmuir 35 35 (2019) 8984e8995.
and ordered mesoporous silicas, ACS Appl. Mater. Interfaces 6 (2014) [57] P.-H. Tsai, M.-L. Wang, J.-H. Chang, A.A. Yarmishyn, P.N.N. Nguyen, W. Chen,
4891e4902. Y. Chien, T.-I. Huo, C.-Y. Mou, S.-H. Chiou, Dual delivery of HNF4a and cisplatin
[45] S.S. Park, M.S. Moorthy, C.-S. Ha, Periodic mesoporous organosilicas for by mesoporous silica nanoparticles inhibits cancer pluripotency and tumori-
advanced applications, NPG Asia Mater 6 (e96) (2014) 1e21. genicity in hepatoma-derived CD133-expressing stem cells, ACS Appl. Mater.
[46] M. Vallet-Regí, M. Colilla, I. Izquierdo-Barba, M. Manzano, Mesoporous silica Interfaces 11 (2019) 19808e19818.
nanoparticles for drug delivery: current insights, Molecules 23 (47) (2018) [58] X.-G. Han, S.-B. Yang, H.-M. Mo, M.-Q. Wang, F. Zhou, H.-J. Li, H. Qiao, J.-T. Mei,
1e19. Y.-J. Wang, Y.-W. Cheng, X.-Q. Liu, L. Du, Y. Dong, T.-T. Tang, Targeting of
[47] J.G. Croissant, Y. Fatieiev, A. Almalik, N.M. Khashab, Mesoporous silica and CXCR1 on osteosarcoma circulating tumor cells and precise treatment via
organosilica nanoparticles: physical chemistry, biosafety, delivery strategies, cisplatin nanodelivery, Adv. Funct. Mater. 29 (2019), 1902246, https://doi.org/
and biomedical applications, Adv. Healthc. Mater. 7 (1700831) (2018) 1e75. 10.1002/adfm.201902246.
[48] V. Cauda, A. Schlossbauer, T. Bein, Bio-degradation study of colloidal meso- [59] K. Zhang, L.-L. Xu, J.-G. Jiang, N. Calin, K.-F. Lam, S.-J. Zhang, H.-H. Wu, G.-
porous silica nanoparticles: effect of surface functionalization with organo- D. Wu, B. Albela, L. Bonneviot, Peng Wu, Facile large-scale synthesis of
silanes and poly(ethylene glycol), Microporous Mesoporous Mater. 132 monodisperse mesoporous silica nanospheres with tunable pore structure,
(2010) 60e71. J. Am. Chem. Soc. 135 (2013) 2427e2430.
[49] K. Braun, A. Pochert, M. Beck, R. Fiedler, J. Gruber, M. Linden, Dissolution ki- [60] S.S. Park, M.S. Moorthy, H.-J. Song, C.-S. Ha, Functionalized mesoporous silicas
netics of mesoporous silica nanoparticles in different simulated body fluids, with crown ether moieties for selective adsorption of lithium ions in artificial
J. Sol-Gel Sci. Technol. 79 (2016) 319e327. sea water, J. Nanosci. Nanotechnol. 14 (11) (2014) 8845e8851.
[50] L. Palanikumar, J. Kim, J. Yong Oh, H. Choi, M.-H. Park, C. Kim, J.-H. Ryu, Hy- [61] Y. Wang, Q. Liu, L. Qiu, T. Wang, H. Yuan, J. Lin, S. Luo, Molecular structure, IR
aluronic acid-modified polymeric gatekeepers on biodegradable mesoporous spectra, and chemical reactivity of cisplatin and transplatin: DFT studies, basis
silica nanoparticles for targeted cancer therapy, ACS Biomater. Sci. Eng. 4 set effect and solvent effect, Spectrochim. Acta A Mol. Biomol. Spectrosc. 150
(2018) 1716e1722. (2015) 902e908.
[51] Z. Songa, Y. Liub, J. Shia, T. Maa, Z. Zhanga, H. Ma, S. Cao, Hydroxyapatite/