Dual pH-responsive mesoporous silica nanoparticles for efficient combination of chemotherapy and photodynamic therapy

Article abstract of DOI:10.1039/c5tb00256g

A kind of dual pH-responsive mesoporous silica nanoparticle (MSN)-based drug delivery system, which can respond to the cancer extracellular and intercellular pH stimuli, has been fabricated for synergistic chemo-photodynamic therapy. By grafting histidine onto the silica surface, the acid sensitive PEGylated tetraphenylporphyrin zinc (Zn-Por-CA-PEG) can be used as a gatekeeper to block the nanopores of MSNs by the metallo-supramolecular-coordinated interaction between Zn-Por and histidine. This gatekeeper is stable enough to prevent the loaded drug from leaching out in healthy tissue. However, at cancer extracellular pH (～6.8) the conjugated acid sensitive cis-aconitic anhydride (CA) between Zn-Por and PEG will cleave and the surface of Zn-Por will be amino positively charged to facilitate cell internalization. Furthermore, the metallo-supramolecular-coordination will disassemble in intracellular acidic microenvironments (～5.3) to release the carried drug and Zn-Por due to the removal of the gatekeeper. The photosensitivity of Zn-Por further makes it possible to combine chemotherapy and photodynamic therapy. This dual pH-sensitive MSN-based drug delivery system showed higher in vitro cytotoxicity than the single chemotherapy of free DOX or photodynamic therapy of Zn-Por, presenting its great potential for cancer treatment to overcome the challenges in efficient delivery in the site and ideal anti-cancer efficacy.

Full text of DOI:10.1039/c5tb00256g

View Article Online
View Journal
Journal of
Materials Chemistry B
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Chen, X. Yao, X.
Chen, C. He and X. Chen, J. Mater. Chem. B, 2015, DOI: 10.1039/C5TB00256G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/materialsB

Page 1 of 9
Journal of Materials Chemistry B
Dynamic Article Links ►
Journal of Materials
Chemistry B
View Article Online
DOI: 10.1039/C5TB00256G
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Dual pH-Responsive Mesoporous Silica Nanoparticles for Efficient Combination of
Chemotherapy and Photodynamic Therapy
a
a
b
a*
b
Xuemei Yao , Xiaofei Chen , Chaoliang He , Li Chen , Xuesi Chen
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A kind of dual pHꢀresponsive mesoporous silica nanoparticles (MSNs)ꢀbased drug delivery system, which can respond to the cancer
extracellular and intercellular pH stimuli, has been fabricated for synergistic chemoꢀphotodynamic therapy. By grafting histidine onto the
silica surface, the acid sensitive PEGylated tetraphenylporphyrin zinc (ZnꢀPorꢀCAꢀPEG) can be acted as gatekeeper to block the
nanopores of MSNs by the metalloꢀsupramolecularꢀcoordinated interaction between ZnꢀPor and histidine. This gatekeeper is stable
enough to prevent loadedꢀdrug from leaching out at health tissue. However, at cancer extracellular pH (∼6.8) the conjugated acid
sensitive cisꢀaconitic anhydride (CA) between ZnꢀPor and PEG will cleave and the surface of ZnꢀPor will be amino positively charged to
facilitate cell internalization. Furthermore, the metalloꢀsurprmolecularꢀcoordination will disassemble at intracellular acidic
microenvironments (~5.3) to release the carried drug and ZnꢀPor due to the removal of gatekeeper. The photosensitivity of ZnꢀPor further
make it possible to combine chemotherapy and photodynamic therapy. This dual pHꢀsensitive MSNsꢀbased drug delivery system has
showed higher in vitro cytotoxicity than the single chemotherapy of free DOX or photodynamic therapy of ZnꢀPor, presenting its great
potential for cancer treatments to overcome the challenges of efficient delivery in site and ideal antiꢀcancer efficacy.
1
0
1
5
16
17
18
19
nanovalves, proteins, polymers or nucleic acids are used as
gatekeepers to fabricate pHꢀcontrolled MSN release systems. For
example, Zhou had reported a kind of pHꢀresponsive natural
gelatin capped mesoporous silica nanoparticles (MSN@Gelatin)
as intracellular drug delivery. The gelatin capping layer could
effectively prohibit the release of loaded drug molecules in
5
0
1
Introduction
Advancement
in
nanotechnology
provides
enormous
2
2
3
3
0
5
0
5
opportunities to cancer therapeutics. With nontoxic nature, easily
modifiable surface and good biocompatibility, uniform
mesoporous silica nanoparticles (MSNs), as a leading kind of 55 neutral pH environment. While the slightly acidic environment
1
ꢀ3
nanocontainer, have attracted tremendous interest. Due to the
controllable mesoporous structure, high specific surface area and
large pore volume, MSNs present high drug loading capacity4,
smart drug release behavior, and coꢀdelivery capability.
would enhance the electrostatic repulsion between the gelatin and
MSN, giving rise to uncapping and the subsequent controlled
20
release of the entrapped drug. Che and coꢀworkers had reported
a novel coordination polymers (CPs)ꢀcoated MSN drug delivery,
Mesoporous silica sustained drug delivery systems, which can 60 which capped by the CPs of zinc and 1,4ꢀbis (imidazolꢀ1ꢀ
pack drug molecules into the channels of mesoporous silica
materials by simple physical adsorption, will cause immediate
drug release after administration.
effect and enhance the antiꢀcancer efficacy, it is highly desirable
to design stimuliꢀresponsive controlled drug delivery systems, in
which the caps can be closed in normal conditions and opened in
demand. In this kind of system, the mesopores loaded with drug
can be capped by various stimuliꢀresponsive “gatekeepers”.
ylmethyl) benzene (BIX) grown on the MSNs surfaces, serving as
a pHꢀresponsive nanocarrier for efficient targeted drug delivery to
5
, 6
21
To reduce the severe sideꢀ
cancer cells.
In current clinical therapy, administering single drug or
exploring single treatment is not successful as expected. A
combination of multiple anticancer agents or different types of
therapy has been widely explored to enhance clinical anticancer
efficiency, such as the combination of chemotherapy with
65
22
23
It is known that the biological microenvironment in cancer
phototherapy or photothermal therapy. Photodynamic therapy
tissues is different from that in physiologically normal cells and 70 (PDT) is a type of phototherapy, which is based on the concept of
tissues. Up to now, several sophisticated stimuliꢀresponsive drug
delivery systems based on MSNs have been described. In these
systems, the efficient release of drug form MSNs are regulated by
photosensitizers. When photosensitizers were exposed to light of
specific wavelength, the generated cytotoxic reactive oxygen
species (ROS) is capable of killing cancer cells.
Metalloporphrins, as a type of photosensitizer, have been widely
Among these stimuli, pHꢀtrigged release is a 75 used in clinical photodynamic therapy for the effective generation
2
4, 25
4
0
7
, 8
9, 10
11, 12
biological stimuli, such as redox, pH,
temperature
and
13, 14
enzyme.
particularly attractive option since certain tissues of the body,
such as cancers and inflammatory tissues (pH ≈ 6.8), endosomal
and lysosomal cell compartments (pH ≈ 5.5), have a more acidic
pH than blood or healthy tissues (pH ≈ 7.4). These pHꢀsensitive
human systems and tissues provide an efficient way to control the 80 delivery systems for porphyrins or their derivatives such as
drug release behavior by pHꢀstimuli. Generally, supramolecular
of ROS. However, most of porphyrins and their derivatives are
hydrophobic. The lipophilic nature makes them undispersed and
4
5
unstable in an aqueous medium, which greatly limits their
1
5
26, 27
applications in vivo.
To overcome these problems, the
liposomes, polymeric particles, hydrophilic polymer, or
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Journal of Materials Chemistry B
Page 2 of 9
View Article Online
DOI: 10.1039/C5TB00256G
2
8ꢀ
amphiphilic polymerꢀporphyrin conjugates have been designed.
which charge switching is pH dependent, presenting considerable
potential as a new class of photosensitizers for photodynamic
cancer therapy.
3
1
Lee and coworkers had reported a waterꢀsoluble, chargeꢀ
switchable, fourꢀarmed polymeric photosensitizer (C4PꢀPS), in
5
32
Fig. 1 Schematic illustration of DOX loading and in vivo microenvironmentꢀtriggered release from DOXꢀloaded MSNsꢀPorꢀCAꢀPEG and photodynamic
10
therapy
Herein, to overcome the limitation of porphyrins, reduce the
severe sideꢀeffect and enhance the antiꢀcancer efficacy, we
designed a kind of dual pHꢀresponsive mesoporous silica
nanoparticles (MSNs)ꢀbased drug delivery system (MSNsꢀDDS)
for synergistic chemoꢀphotodynamic therapy, which can respond
to the cancer extracellular and intercellular pH stimuli (Fig. 1).
Firstly, cisꢀaconitic anhydride (CA) was explored to prepare acid
sensitive PEGylated tetraphenylporphyrin zinc (ZnꢀPorꢀCAꢀPEG).
Secondly, the surface of MSNs was modified by histidine
Sinopharm Chemical Reagent Co., Ltd.
.2 Synthesis of 5, 10, 15-tris(4-aminophenyl)-20-
2
phenylporphyrin (Por-NH2)
1
2
2
3
3
5
0
5
0
5
33
PorꢀNH was prepared as previous literature. Firstly, sodium
2
5
5
nitrite (660 mg, 9.57 mmol) was added to mesoꢀ
tetraphenylporphyrin (160 mg, 0.261 mmol) solution in TFA (10
mL). After stirring at room temperature for 55 min, the reaction
was quenched with water (100 mL) and the mixture extracted
with dichloromethane. The organic layers were washed once with
(MSNsꢀHis), and then ZnꢀPorꢀCAꢀPEG was used as gatekeeper to
cap the nanopores of MSNsꢀHis by the metalloꢀsupramolecularꢀ
coordinated interaction between ZnꢀPor and histidine to fabricate
dual pHꢀsenstive MSNsꢀbased drug delivery system (MSNsꢀPorꢀ
CAꢀPEG). At the normal biological condition of pH ~7.4, drug
can be loaded in the nanopores and cannot leach out due to being
blocked. While the conjugated amide group of ZnꢀPorꢀCAꢀPEG
would break at cancer extracellular pH (∼6.8), which resulted
that the surface of ZnꢀPor had positive charge to facilitate cell
internalization and promote drugꢀloaded MSNs accumulation at
60
saturated aqueous NaHCO and once with water before being
3
dried
over
anhydrous
Na SO .
were
Then,
recrystallize
mesoꢀtris(4ꢀ
from
2
4
nitrophenyl)phenylporphyrin
dichloromethane.
Secondly, mesoꢀtris(4ꢀnitrophenyl)phenylporphyrin (100 mg,
0.163 mmol) was dissolved in hydrochloric acid (50 mL) and
tin(II) chloride (540 mg, 2.39 mmol) was carefully added with
65
o
stirring. The final mixture was heated to 65 C for 1 h under
argon before being poured into cold water (100 mL). The aqueous
solution was neutralized with ammonium hydroxide until pH 8.
And then the aqueous solution was extracted with
dichloromethane until colorless. The organic layer was then
concentrated under vacuum and the residue purified on a plug of
alumina using dichloromethane for elution. The final obtained
residue was recrystallized from petroleum ether.
the
cancer
site.
Furthermore,
metalloꢀsupramolecular
coordination would disassemble at intracellular pH (~5.3) and the
loadedꢀdrug and ZnꢀPor would be released due to the removal of
gatekeeper. In addition, ZnꢀPor as photosensitizier, can response
to light and produce highly reactive oxygen species resulting in
toxicity to targeted tissues. This MSNsꢀDDS can efficiently load
drug and combine chemotherapy and PDT, hoping as drug
delivery for enhancing anticancer efficiency.
70
75
2.3 Synthesis of 5, 10, 15-tris(4-aminophenyl)-20-
phenylporphyrin zinc (Zn-Por-NH2)
2
. Materials and methods
PorꢀNH (100 mg, 0.15 mmol) and Zn(Ac) ·2H O (100 mg, 0.45
2
2
2
40
2.1 Reagents and materials
mmol) were dissolved in CHCl (40 mL). Then the above mixture
3
o
Tetraethylorth osilicate (TEOS), (3ꢀaminopropyl)triethoxysilane
was heated to 65 C and stirred for 2 h. The resulting mixture was
(APTES),
Nꢀ(3ꢀdimethylaminopropyl)ꢀN‘ꢀethylcarbodiimide 80 cooled with cold water. The aqueous solution was extracted with
hydrochloride (EDC·HCl), Nꢀhydroxysuccinimide (NHS), cisꢀ
aconitic anhydride (CA), succinic anhydride (SA), 3ꢀ(4,5)ꢀ
dimethylthiahiazo (ꢀzꢀy1)ꢀ3,5ꢀdiꢀphenytetrazoliumromide (MTT),
PEG (Mn 2000) were purchased from SigmaꢀAldrich. Nꢀ
Cetyltrimethylammonium bromide (CTAB) was purchased from
Alfa Aesar (Tianjin, China). Doxorubicin hydrochloride
dichloromethane until colorless. The organic layer was then
concentrated under vacuum.
45
2
.4 Synthesis of cis-aconitic anhydride modified Zn-Por-NH2
(Zn-Por-CA) and succinic anhydride modified Zn-Por-NH2
85
(Zn-Por-SA)
(DOX·HCl) was purchased from Zhejiang Hisun Pharmaceutical
ZnꢀPorꢀCA and ZnꢀPorꢀSA was, respectively, synthesized through
50
Co., Ltd. All the other reagents and solvents were purchased from
the ringꢀopening reaction between ZnꢀPorꢀNH and SA or CA
2
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 9
Journal of Materials Chemistry B
View Article Online
DOI: 10.1039/C5TB00256G
with triethylamine as catalyst. For typical synthesis procedure of
investigated in PBS (pH 5.3, 6.8 or 7.4). The preꢀweighed freezeꢀ
dried DOX loaded MSNs were suspended in 4 mL of release
medium and transferred into a dialysis bag (MWCO 3500 Da).
ZnꢀPorꢀCA, ZnꢀPorꢀNH (100 mg, 0.14 mmol) and CA (84 mg,
2
0
.54 mmol) were dissolved in 10.0 mL of anhydrous DMF in a
dried flask, and then 74 ꢁL of anhydrous triethylamine was added.
The mixture was stirred under a nitrogen environment at room 65 dialysis bag into 50 mL of release medium at 37 C with
The release experiment was initiated by placing the endꢀsealed
o
5
temperature for 24 h. After that, the solution was mixed with
00.0 mL of cold ethyl acetate, and then the mixture was washed
with cold acidic saturated sodium chloride solution (pH 2−3) and
continuous shaking at 70 rpm. At predetermined intervals, 2 mL
of external release medium was taken out and an equal volume of
fresh release medium was replenished. The amount of released
DOX was determined by using fluorescence measurement. The
1
finally with normal saturated solution (pH 7.4). The organic layer
1
0
was collected and dried with anhydrous sodium sulfate overnight. 70 release experiments were conducted in triplicate.
After filtration, the filtrate was dried under vacuum at room
2
.9 Intracellular drug release
temperature to obtain product. ZnꢀPorꢀSA was synthesized with
the same approach as ZnꢀPorꢀCA.
The cellular uptake and intracellular release behaviors of DOXꢀ
loaded MSNs were assessed by confocal laser scanning
microscopy (CLSM) and flow cytometric analyses on HeLa cells.
2
.5 Synthesis of PEGylated Zn-Por-CA (Zn-Por-CA-PEG)
1
5
and PEGylated Zn-Por-SA (Zn-Por-SA-PEG)
75
2.9.1 CLSM
ZnꢀPorꢀCAꢀPEG and ZnꢀPorꢀSAꢀPEG were separately
synthesized through the condensation reaction between PEG and
ZnꢀPorꢀCA or ZnꢀPorꢀSA with EDC·HCl and DMAP as
condensing agent and catalyst, respectively. For example, PEG
(500 mg, 0.25 mmol) was dissolved in DMF, and then ZnꢀPorꢀCA
For CLSM study, HeLa cells were seeded in 6ꢀwell plates at a
density of 10 cells per well in 2.0 mL of complete Dulbecco’s
5
modified Eagle’s medium (DMEM) containing 10 % fetal bovine
ꢀ
1
ꢀ1
2
0
serum, supplemented with 50 IU mL penicillin and 50 IU mL
(
(
72 mg, 0.1 mmol), EDC·HCl (39 mg, 0.2 mmol), and DMAP 80 streptomycin. After incubation for 24 h, the culture media were
2.4 mg, 0.02 mmol) were added to the solution. The mixture was
withdrawn and culture media containing MSNꢀPorꢀCAꢀPEG or
MSNꢀPorꢀSAꢀPEG were supplemented (final ZnꢀPor
concentration: 9 mg L ). The cells were incubated for another 2
stirred at room temperature for 48 h. Then, ZnꢀPorꢀCAꢀPEG was
obtained through a dialysis method (molecular weight cutoff
(MWCO) = 3500 Da) against deionized water for 48 h. ZnꢀPorꢀ
−1
o
o
2
5
h at 37 C and 4 C. After washed with PBS five times, the cells
SAꢀPEG was synthesized with the similar approach as ZnꢀPorꢀ 85 were then fixed in 4% paraformaldehyde for 20 min and washed
CAꢀPEG.
with PBS five times. For staining the nuclei, the cells were
incubated with 4′,6ꢀdiamidinoꢀ2ꢀphenylindole (DAPI, blue) for 2
min. The images of cells were observed using a laser scanning
confocal microscope (Olympus FluoView 1000).
2
.6 Synthesis of histidine modified mesoporous silica
nanoparticles (MSN-His)
34
3
0
MSNꢀNH was synthesized as our team previous works. MSN–
2
90
2.9.2 Flow cytometric analyses
NH (0.03 g) was dispersed in 70 mL of anhydrous DMSO, and
2
5
then BOCꢀhistidine (2.55 g, 0.01 mol), EDC·HCl (3.94 g, 0.02
mol) and NHS (2.76 g, 0.024 mol) were added into the solution.
The reaction mixture was stirred at 25 C for 48 h. After the
reaction, the mixture was centrifuged (9500 rpm, 10 min), and
washed twice with methanol and dried under vacuum overnight.
HeLa cells were placed into 6ꢀwell plates (2 × 10 cells/well) and
cultured in 2.0 mL of complete DMEM for 24 h. The culture
media were then withdrawn and culture media with MSNꢀPorꢀ
CAꢀPEG or MSNꢀPorꢀSAꢀPEG were supplemented at a final Znꢀ
o
3
5
−1
95 Por concentration of 9 mg L . The cells were incubated for
additional 2 h, followed by washing with PBS three times and
trypsinized. Then, 1.0 mL of PBS was added, and the solutions
were centrifuged for 4 min at 3000 rpm and the cells were
2
.7 Synthesis of Zn-Por-CA-PEG or Zn-Por-SA-PEG caped
MSNs (MSN-Por-CA-PEG or MSN-Por-SA-PEG)
MSNꢀHis (0.03 g) and ZnꢀPorꢀCAꢀPEG (0.35 g) were dissolved
resuspended in 0.3 mL of PBS. The analysis was performed by
o
4
4
0
in 10 mL of DMSO. The mixture was stirred at 25 C for 72 h. 100 flow cytometer (Beckman, California, U.S.A.) for 1 × 10 cells.
Then, MSNꢀPorꢀCAꢀPEG was obtained by centrifugation (9500
2
.10 Cell viability assays
rpm, 10 min), and washed six times with methanol and dried
under vacuum overnight. MSNꢀPorꢀSAꢀPEG was got as similar
way with MSNꢀPorꢀCAꢀPEG.
The relative cytotoxicities of MSNꢀPorꢀCAꢀPEG or MSNꢀPorꢀ
SAꢀPEG in the dark against HeLa and MCFꢀ7 cells were
evaluated in vitro by a standard MTT assay. The cells were
4
5
2.8 In vitro drug loading and release
4
1
05 seeded in 96ꢀwell plates at 1 × 10 cells per well in 200.0 ꢁL of
Doxorubicin (DOX) was used as a model drug for in vitro drug
loading and release. DOX loaded MSNꢀPorꢀCAꢀPEG were
prepared by a simple dialysis technique. Typically, MSNꢀHis
complete DMEM and incubated at 37 °C in 5 % CO atmosphere
2
for 24 h. The culture medium was then removed and MSNꢀPorꢀ
CAꢀPEG or MSNꢀPorꢀSAꢀPEG solutions in complete DMEM at
ꢀ
1
(14.0 mg), ZnꢀPorꢀCAꢀPEG (117 mg) and drug (30 mg) were
different concentrations (0ꢀ10 g L ) were added. The cells were
5
0
mixed in 10 mL of DMSO. The mixture was stirred at room 110 subjected to MTT assay after being incubated for additional 48 h.
temperature for 24 h and then added dropwise into 50.0 mL of
PBS at pH 7.4. The DMSO was removed by dialysis against
water at pH 7.4 for 24 h. The dialysis medium was refreshed four
times and the whole procedure was performed in the dark. After
removing the blank particles by centrifugation, the supernatant
The absorbance of the solution was measured on a BioꢀRad 680
microplate reader at 490 nm. Cell viability (%) was calculated
based on eqn (1):
Cell viability (%) = Asample /Acontrol × 100
(1)
5
5
was measured by UVꢀVis spectrophotometer. According to a 115 where, Asample and Acontrol represent the absorbances of the sample
standard curve obtained from DOX/DMSO solutions at a series
of DOX concentrations, we obtained drug loading content. DOXꢀ
loaded MSNꢀPorꢀSAꢀPEG was got as similar way.
and control wells, respectively.
The cytotoxicities of DOXꢀloaded MSNs against HeLa and
MCFꢀ7 cells were also evaluated in vitro by a MTT assay.
Similarly, cells were seeded into 96ꢀwell plates at 7 × 10 cells
3
6
0
In vitro drug release profiles of drugꢀloaded MSNs were
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Journal of Materials Chemistry B
Page 4 of 9
View Article Online
DOI: 10.1039/C5TB00256G
per well in 200.0 ꢁL of complete DMEM and further incubated
for 24 h. After washing cells with PBS, 180.0 ꢁL of complete
DMEM and 20.0 ꢁL of DOXꢀloaded MSNꢀPorꢀCAꢀPEG and 50 2928 cm ascribed to C–H confirmed the successful modification
vibration confirmed the successful synthesis of MSN–NH . The
2
ꢀ
1
peaks appeared at 1667 cm assigned to the imine bond and at
ꢀ
1
MSNꢀPorꢀSAꢀPEG and free DOX solutions in PBS were added to
form culture media with different DOX concentrations (0ꢀ10.0
mg L DOX). The cells were subjected to MTT assay after being
incubated for 24 and 48 h under light irradiation (2mW, 400ꢀ700
nm). The absorbance of the solution was measured on a BioꢀRad
of histidine on the surface of MSNꢀNH . The adsorption peaks at
2
ꢀ
1
5
2880 cm , which assigned to C–H deformation vibration in PEG,
indicated the successful block of ZnꢀPorꢀCAꢀPEG as a gatekeeper
to prepare MSNꢀPorꢀCAꢀPEG.
ꢀ
1
5
5
According to the TGA curves of MSNꢀNH and MSNꢀHis (Fig.
2
6
80 microplate reader at 490 nm. Cell viability (%) was also
S2), the grafted ratio of His on the surface of MSN was 33 % wt,
just as expected. Shown in Fig. S2, the loss weight of MSNꢀZnꢀ
PorꢀCAꢀPEG is more than that of MSNꢀHis, indicating the
presence of gate keeper. According to Fig.S2, the graft ratio of
His on the surface of MSN coordinated with PEGꢀCAꢀZnꢀPor
was 19%.
1
0
calculated based on eqn (1).
3
. Results and discussion
3
.1 Synthesis of Zn-Por-CA-PEG
60
The acid sensitive PEGylated ZnꢀPor (ZnꢀPorꢀCAꢀPEG) was
synthesized as the route shown in Scheme S1 and S2. Firstly, Znꢀ
PorꢀCA was prepared by the ringꢀopening reaction between Znꢀ
PorꢀNH2 and CA, which conjugated with an amide bond. To
improve the biocompatibility and stability in vivo, ZnꢀPorꢀCA
was further PEGylated by condensation between the hydroxyl
group of PEG and the carboxyl group of ZnꢀPorꢀCA. The
There were three diffraction peaks associated with the 100,110,
and 200 reflections of hexagonal symmetry in the XRD pattern of
MSNꢀNH2 (Fig.3A), implying a similar ordered hexagonal
mesostructure. TEM images of MSNꢀNH2 particles presented
uniform spherical with a mean diameter of approximately 145 nm.
Besides, an array of ordered mesoporous network could be
clearly observed shown in Fig.3B. After Capping, the size
became bigger about 230 nm (Fig. S3). TEM of MSNꢀZnꢀPorꢀ
CAꢀPEG presented similar result (Fig. S4).
1
2
2
3
5
0
5
0
65
1
HNMR spectra shown in Fig.S1 strongly confirmed the
successful synthesis of ZnꢀPorꢀCAꢀPEG. The peaks at ꢀ2.7 ppm (a)
assigned to –NH2 and at 4.05 ppm (b) belonged to –NHꢀ
70
demonstrated the successful synthesis of PorꢀNH in Fig.S1A.
2
Then, the peaks at ꢀ2.7 ppm disappeared after coordination
between PorꢀNH2 and Zinc, implying ZnꢀPorꢀNH2 gained
successfully (Fig.S1B). Shown in Fig.S1C, the disappearance of
the peaks at 4.05 ppm and following the appearance of the peak
at 1.5 ppm indicated the successful conjugate of ZnꢀPorꢀNH and
2
CA. Then, the peak at 3.5 ppm (d) belonged to –OCH CH Oꢀ and
2
2
the peak at 11.8 ppm assigned to –COOH demonstrated the
successful synthesis of ZnꢀPorꢀCAꢀPEG (Fig.S1D).
3
.2 Synthesis of MSN-Por-CA-PEG
Fig. 3 Lowꢀangle Xꢀray diffraction (XRD) pattern of MSN–NH
2
powders
(
A) and TEM image of MSN–NH (B)
2
The surface area and pore size of MSNꢀNH and MSNꢀPorꢀ
2
75
CAꢀPEG was examined by BrunauerꢀEmmettꢀTeller (BET) and
BarrettꢀJoynerꢀHalenda (BJH) analyses. The BET surface areas of
2
2
nanoparticles reduced from 1197 m /g to 418.5 m /g after the
blocking of PorꢀCAꢀPEG to the MSN’s nanopores by the metalloꢀ
supramolecularꢀcoordination between ZnꢀPorꢀCAꢀPEG and
histidine (Fig. 4). The BJH pore sizes of nanoparticles also
reduced from 2.32 nm to 1.97 nm. These results suggest that the
mesopores were successfully capped by ZnꢀPorꢀCAꢀPEG.
80
Fig. 2 FTIR spectra of MSNꢀPorꢀCAꢀPEG (a), MSNꢀHis (b), MSNꢀNH
2
35
(c) and MSNꢀCTAB (d).
In this paper, MCMꢀ41 type MSNs with an average diameter of
40 nm was used as a scaffold. To realize the histidine
1
modification, MSNꢀNH was prepared firstly. And then, ZnꢀPorꢀ
2
CAꢀPEG was used as a gatekeeper to block the nanopores of
MSNꢀHis by the metalloꢀsupramolecularꢀcoordinated interaction
between ZnꢀPor and histidine. The FTꢀIR spectra of MSNꢀCTAB,
40
MSNꢀNH , MSNꢀHis and MSN–PorꢀCAꢀPEG were shown in Fig.
2
ꢀ
1
2
. The characteristic C–H peaks at 2928, 2850 and 1474 cm
were ascribed to a large amount of CTAB existing in the channels,
implying the successful synthesis of MSNꢀCTAB. The
disappearance of these peaks attributed to the removal of CTAB.
45
2
Fig. 4 Nitrogen adsorption–desorption isotherms of MSNꢀNH (a) and
MSNꢀPorꢀCAꢀPEG
85
ꢀ
1
Moreover, the peak appeared at 1629 cm belonged to N–H
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 9
Journal of Materials Chemistry B
View Article Online
DOI: 10.1039/C5TB00256G
3
.3 In vitro DOX loading and triggered release
Metalloporphyrins have attracted enormous attention, not only
because of its protential ability as photosensitizer but also as
fluorescent probe (red). So confocal laser scanning microscopy
(CLSM) and flow cytometric analyses were employed to explore
the cellular uptake of MSNꢀPorꢀCAꢀPEG and MSNꢀPorꢀSAꢀPEG
by HeLa cells.
Generally, due to high specific surface area and large pore
volume, MSNs present high drug loading capacity. The DOX
loading content of DOXꢀloaded MSNꢀPorꢀCAꢀPEG was
calculated and as high as to be 11.2 wt%. Then in vitro release
behaviors of DOXꢀloaded MSNꢀPorꢀCAꢀPEG were investigated
at pH 5.3, 6.8 and 7.4, respectively, which were mimicking the
physiological pH in late endosome, cancer extracellular
50
5
o
After incubation with MSNs for 2 h in 37 or 4 C, their cellular
distribution was evaluated by CLSM analysis. As indicated in Fig.
o
microenvironment, and blood and normal tissue. About 80% of 55 6B, MSNꢀPorꢀCAꢀPEG was remarkably internalized at 4 C and
1
1
2
2
0
5
0
5
DOX was released from DOXꢀloaded MSNs during first 24 h in
PBS at pH 5.3 shown in Fig. 5. Compared with pH 5.3, the DOX
release rate accordingly reduced in pH 7.4. These different
release behaviors were likely to be resulted from the acidꢀ
distributed intensively in the cytoplasm, which was rarely
observed in the cells incubated with the identical MSNꢀPorꢀCAꢀ
PEG at 4 C (Fig. 6A). Moreover, the sample incubated with
o
MSNꢀPorꢀCAꢀPEG showed the strongest influorescence intensity
o
triggered dissociation of coordinate bond between ZnꢀPor and 60 at 37 C. As show in Fig. 7, the fluorescence intensity form high
histidine, leading to the removal of the capped ZnꢀPor from the
nanoparticle surface. Noticeably, the release ratio of DOX from
DOXꢀloaded MSNꢀPorꢀCAꢀPEG was only nearly 45% and 30%
at pH 6.8 and 7.4, respectively, which resulted from the blocking
of gatekeeper ZnꢀPorꢀCAꢀPEG to the nanopores of MSN. Being 65 fluorescence intensity.).
blocked, drug release from the mesoporous silica more slowly
than from MSN without capping (Fig. S5). So this intermediate
pHꢀsensitive gatekeeper has the ability to enhance DOX loading
content and to effectively control drug holding or rapidly release
at different pH environment. Therefore, this pHꢀsensitive DOXꢀ
loaded MSNꢀPorꢀCAꢀPEG is potential as effective drug delivery
system for future use.
to low in flow cytometric analyses was in the following order:
o
o
MSNꢀPorꢀCAꢀPEG in 37 C (817) > MSNꢀPorꢀSAꢀPEG in 37 C
o
(346) > MSNꢀPorꢀCAꢀPEG in 4 C (255) > MSNꢀPorꢀSAꢀPEG
(186) in 4 C, respectively (the value means the average
o
These phenomena could ascribed to disconjugation of PEG and
ZnꢀPor responsed to pH 6.8, presenting positive charges and then
promoting the nanoparticles enter into the cell. The results
demenstrated that MSNꢀPorꢀCAꢀPEG could be efficiently
internalized by cancer cells.
70
Fig. 5 In vitro DOX release behaviors of DOXꢀloaded MSNꢀPorꢀCAꢀPEG
o
in PBS at pH 5.3, 6.8 and 7.4 at 37 C
3
0
3.4 Intracellular Endocytosis
In our designed MSNsꢀbased drug delivery system, cisꢀaconitic
anhydride conjugation between ZnꢀPor and PEG present pHꢀ
sensitive and the amide bond formed between an amino of ZnꢀPor
Fig. 6 Representative CLSM images of HeLa cells incubated with MSNꢀ
o
o
PorꢀSAꢀPEG (A) at 4 C, MSNꢀPorꢀCAꢀPEG (B) at 4 C, MSNꢀPorꢀSAꢀ
o
o
PEG (C) at 37 C, and MSNꢀPorꢀCAꢀPEG (D) at 37 C for 2 h. For each
and CA is cleavable under slightly acidic condition such as pH 75 panel, the images from left to right show differential interference contrast
(
DIC) image, cell nuclei stained by DAPI (blue), ZnꢀPor fluorescence in
3
5
6.8. After cleaving of amide bond, the surface of ZnꢀPor becomes
amino positively charged. Generally the cell membranes are
negatively charged, this positively charged MSNꢀZnꢀPor will
easily uptake by cancer cells to enhance their internalization.
cells (red), and overlays of the three images.
3
.5 In Vitro anti-cancer eficacy
For a drug delivery, the biocompatibility is a key factor for their
application. The in vitro cytotoxicity of MSNꢀPorꢀCAꢀPEG and
MSNꢀPorꢀSAꢀPEG against HeLa and MCFꢀ7 cells in the dark
was examined by a MTT assay (Fig. S9 and S10). Free MSNs
without irradiation present no obvious cytotoxicity at different
To demonstrate whether MSNꢀPorꢀCAꢀPEG can be more
efficiently internalized by cancer cells, MSNꢀPorꢀSAꢀPEG was
synthesized as a control (Scheme S3, Fig. S6-S8). Differently,
the amide bond of MSNꢀPorꢀSAꢀPEG is uncleavable because the
linkage succinic anhydride cannot respond to pH 6.8. The
HNMR and FTꢀIR spectra demonstrated the successful synthesis
of MSNꢀPorꢀSAꢀPEG. MSNꢀPorꢀSAꢀPEG also could efficiently
load DOX with a drug loding conten (DLC) of 11.4 wt%.
8
0
4
0
−1
concentrations, up to 10.0 g L , indicating the excellent
biocompatibility of MSNs itself as a drug carrier.
1
85
4
5
In particular, some metalloporphrins, such as ZnꢀPor, have
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Journal of Materials Chemistry B
Page 6 of 9
View Article Online
DOI: 10.1039/C5TB00256G
been used as a kind of photosensitizer in clinical photodynamic 55 (Fig.8C and D), the similar results were presented, in which the
therapy because of the effective generation of cytotoxic reactive
oxygen species, such as singlet oxygen. However, most of
porphyrins and their derivatives are hydrophobic. The lipophilic
nature makes them undispersed and unstable in an aqueous
medium, which greatly limits their applications in vivo. Taking
advantage of the metalloꢀsupramolecularꢀcoordinated interaction,
we realized not only the blocking of the nanopores of MSNs but
also the coꢀdelivery of anticancer drug and photosensitizer to
enhance the water solubility and stability of them. By coꢀdelivery
and pHꢀcontrolled coꢀrelease of drug and photosensitizer “on
demand”, it presents an effective way to combine chemotherapy
and photodynamic therapy.
lowest cell viability was 40% incubated for 24 h and 20%
incubated for 48 h, respectively.
5
1
0
To study the anticancer efficiency of chemotherapy and PDT,
we investigated thoroughly the anticancer activity in vitro. Firstly,
singlet oxygen generated by MSNs was examined by a chemical
method involving the photoꢀoxidation of 9,10ꢀanthracenediylꢀ
bis(methylene)dimalonic acid (ABDA) (Fig.S11) . The data
indicated that during the light illumination in the presence of
MSNs the absorption value of ABDA gradually decreased,
suggesting the production of singlet oxygen. Under the same
experiment condition, the amout of singlet oxygen produced by
MSNꢀPorꢀCAꢀPEG is little more than that produced by MSNꢀ
PorꢀSAꢀPEG. To rule out the potential effect induced by light
15
20
25
3
5
Fig. 7 Flow cytometric profiles of HeLa cells blank (a) and incubated
o
o
irradiation, HeLa and MCFꢀ7 cells were irradiated directly. As 60 with MSNꢀPorꢀSAꢀPEG (b) at 37 C, MSNꢀPorꢀCAꢀPEG (c) at 37 C,
shown in Fig.S12, irradiation single was no harm to cells.
o
o
MSNꢀPorꢀSAꢀPEG (d) at 4 C, and MSNꢀPorꢀCAꢀPEG (e) at 4 C for 2 h
Subsequently, MTT assays twards HeLa and MCFꢀ7 cells were
employed to investigate the infulence of light irradiatiton (0.12
W/cm , 400ꢀ700 nm) on the cytotoxicity of cells in vitro. HeLa
4. Conclusion
2
In summary, the dual pHꢀresponsive capped MSNs was
successfully prepared by the metalloꢀsupramolecularꢀcoordinated
interaction between acid sensitive PEGylated ZnꢀPor and
histidine, which can respond to both extracellular and
intracellular pH environments to simultaneously enhance cellular
uptake and promote acidꢀtriggered intracellular drug release.
Because the gatekeeper ZnꢀPorꢀCAꢀPEG can be used as
photosensitiser in PDT, MSNꢀPorꢀCAꢀPEG could realize the
combination of chemical therapy and PDT. The in vitro
experiments indicated that MSNs had good biocompatibility and
no toxicity towards the normal cells. Compared with the single
chemotherapy of free DOX or photodynamic therapy of ZnꢀPor
in MSNs, DOXꢀloaded MSN with irradiation showed higher in
vitro anticancer therapeutic activity, potential for synergistic
treatments of cancer.
30
35
40
45
50
85
and MCFꢀ7 cells were treated with a gradient concentrations of
MSNꢀPorꢀCAꢀPEG, MSNꢀPorꢀSAꢀPEG, DOXꢀloaded MSNꢀPorꢀ
CAꢀPEG, MSNꢀPorꢀSAꢀPEG and free DOX under or without
light irradiation for 5 min after incubation for 4 h, and then
treated with MTT after 24 h. The data of cell viability were
presented in Fig.8A and C. For simplicity, only the data in the
case of 10.0 mg/L DOX and 9 mg/mL ZnꢀPor were simplified.
Compared with free DOX or MSNꢀPorꢀCAꢀPEG with irradiation,
DOXꢀloaded MSNꢀPorꢀCAꢀPEG with irradiation showed the
highest cytotoxicity with the lowest cell viability, indicating the
successful combination of DOX and ZnꢀPor, realizing synergistic
chemoꢀphotodynamic therapy to enhance the anticancer efficacy.
Moreover, the cell viability of MSNꢀPorꢀCAꢀPEG was lower than
that of MSNꢀPorꢀSAꢀPEG, indicating that MSNꢀPorꢀCAꢀPEG
was easier to enter into cancer cells because the amino positively
charged MSNꢀZnꢀPor more easily enter into the negatively
charged cell membranes. Furthermore, free DOX and DOXꢀ
6
7
7
5
0
5
Acknowledgements
This research was financially supported by the National Natural
loaded MSN without light irradiation exhibited comparable 80 Science Foundation of China (Projects 21474012, 51273037 and
cytotoxicity, implying that single encapsulation of DOX in MSN
would not obviously improve the anticncer efficacy. The cell
viability towards HeLa and MCFꢀ7 cells incubated for 48 h were
also investigated, similarly, DOXꢀloaded MSNꢀPorꢀCAꢀPEG with
irradiation showed the highest anticancer efficacy as shown in
Fig.8B and D. Moreover, the anticancer efficacy could be
improved by prolong the irradiation time. For MCFꢀ7 cells
50903012),
Jilin
Science
and
Technology
Bureau
(20130206074GX, International Cooperation Project 20120729),
Jilin Human Resources and Social Security Bureau(201125020),
Jilin Environmental Protection Bureau (201127).
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 9
Journal of Materials Chemistry B
View Article Online
DOI: 10.1039/C5TB00256G
Fig. 8 Cytotoxicities of free DOX (a), MSNꢀPorꢀCAꢀPEG with irradiation (b), MSNꢀPorꢀSAꢀPEG with irradiation (c), DOXꢀloaded MSNꢀPorꢀCAꢀPEG
d), DOXꢀloaded MSNꢀPorꢀSAꢀPEG (e), DOXꢀloaded MSNꢀPorꢀCAꢀPEG with irradiation (f) and DOXꢀloaded MSNꢀPorꢀSAꢀPEG with irradiation (g)
toward HeLa cells for 24 h (A), 48 h (B), and MCFꢀ7 cells for 24 h (C), 48 h (D).
(
1
1
1
0. X. Ji, J. Chen, X. Chi and F. Huang, ACS Macro Letters, 2014, 3,
110ꢀ113.
5
Notes and references
35
40
45
1. W. Wu, W. Driessen and X. Jiang, J Am Chem Soc, 2014, 136, 3145ꢀ
a
Department
of
Chemistry,
Northeast
Normal
University,
3
155.
Changchun130024, P. R. China.
Tel.: +86 431 85099667. Fax: +86 431 85099668. E-mail:
2. E. Aznar, L. Mondragon, J. V. RosꢀLis, F. Sancenon, M. D. Marcos,
R. MartinezꢀManez, J. Soto, E. PerezꢀPaya and P. Amoros, Angew.
Chem. (Inter. in English), 2011, 50, 11172ꢀ11175.
*
chenl686@nenu.edu.cn
b
1
0
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
1
1
3. P. D. Thornton and A. Heise, Am Chem Soc, 2010, 132, 2024ꢀ2028.
4. E. Secret, S. J. Kelly, K. E. Crannell and J. S. Andrew, ACS Appl.
Mater. Interfaces, 2014, 6, 10313ꢀ10321.
Changchun 130022, P. R. China.
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
15. M. Chen, X. He, K. Wang, D. He, S. Yang, P. Qiu and S. Chen, J
Mater Chem B, 2014, 2, 428ꢀ436.
1
5
1
6. X. Huang and X. Du, ACS Appl. Mater. Interfaces, 2014, 6, 20430ꢀ
1
2
.
.
N. Niu, F. He, P. Ma, S. Gai, G. Yang, F. Qu, Y. Wang, J. Xu and P.
Yang, ACS Appl. Mater. Interfaces, 2014, 6, 3250ꢀ3262.
20436.
17. S. Wu, Q. Deng, X. Huang and X. Du, ACS Appl. Mater. Interfaces,
2014, 6, 15217ꢀ15223.
J. Croissant and J. I. Zink, J Am Chem Soc, 2012, 134, 7628ꢀ7631.
2
2
3
0
5
0
3. M. Frasconi, Z. Liu, J. Lei, Y. Wu, E. Strekalova, D. Malin, M. W. 50 18. Q. Zhao, H. Geng, Y. Wang, Y. Gao, J. Huang, Y. Wang, J. Zhang
Ambrogio, X. Chen, Y. Y. Botros, V. L. Cryns, J. P. Sauvage and J.
F. Stoddart, J Am Chem Soc, 2013, 135, 11603ꢀ11613.
S. Sahu, N. Sinha, S. K. Bhutia, M. Majhi and S. Mohapatra, J Mater
Chem B, 2014, 2, 3799ꢀ3808.
and S. Wang, ACS Appl. Mater. Interfaces, 2014, 6, 20290ꢀ20299.
19. Q. Yuan, Y. Zhang, T. Chen, D. Lu, Z. Zhao, X. Zhang, Z. Li, C.ꢀH.
Yan and W. Tan, ACS Nano, 2012, 6, 6337ꢀ6344.
4
.
20. Z. Zou, D. He, X. He, K. Wang, X. Yang, Z. Qing and Q. Zhou,
Langmuir, 2013, 29, 12804ꢀ12810.
5. M. Colilla, B. Gonzalez and M. ValletꢀRegi, Biomater. Sci., 2013, 1,
14ꢀ134.
55
1
21. L. Xing, H. Zheng, Y. Cao and S. Che, Adv. Mater., 2012, 24, 6433ꢀ
6437.
6
7
.
.
P. Yang, S. Gai and J. Lin, Chem Soc Rev, 2012, 41, 3679ꢀ3698.
R. Hernandez, H. R. Tseng, J. W. Wong, J. F. Stoddart and J. I. Zink,
J Am Chem Soc, 2004, 126, 3370ꢀ3371.
22. T. Wang, L. Zhang, Z. Su, C. Wang, Y. Liao and Q. Fu, ACS Appl.
Mater. Interfaces, 2011, 3, 2479ꢀ2486.
8. R. Liu, X. Zhao, T. Wu and P. Feng, J Am Chem Soc, 2008, 130, 60 23. Y. Wang, K. Wang, J. Zhao, X. Liu, J. Bu, X. Yan and R. Huang, J
1
4418ꢀ14419.
C. Park, K. Oh, S. C. Lee and C. Kim, Angew. Chem. Inter. Ed.,
007, 46, 1455ꢀ1457.
Am Chem Soc, 2013, 135, 4799ꢀ4804.
24. B. C. Wilson and M. S. Patterson, Physics in Medicine and Biology,
2008, 53, R61ꢀ109.
9
.
2
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Journal of Materials Chemistry B
Page 8 of 9
View Article Online
DOI: 10.1039/C5TB00256G
2
5. A. Juarranz, P. Jaen, F. SanzꢀRodriguez, J. Cuevas and S. Gonzalez,
Clinical & translational oncology : official publication of the
Federation of Spanish Oncology Societies and of the National
Cancer Institute of Mexico, 2008, 10, 148ꢀ154.
15 30. X. Liang, X. Li, X. Yue and Z. Dai, Angew. Chem. Inter.Ed., 2011,
50, 11622ꢀ11627.
31. D. Ma, Z. H. Liu, Q. Q. Zheng, X. Y. Zhou, Y. Zhang, Y. F. Shi, J. T.
Lin and W. Xue, Macromol. Rapid Commun., 2013, 34, 548ꢀ552.
32. C. S. Lee, W. Park, Y. U. Jo and K. Na, Chem. Commun., 2014, 50,
5
26. G. Oenbrink, P. Jurgenlimke and D. Gabel, Photochem. and
Photobio., 1988, 48, 451ꢀ456.
20
4354ꢀ4357.
2
7. U. Isele, K. Schieweck, R. Kessler, P. van Hoogevest and H. G.
Capraro, J. Pharma. Sci., 1995, 84, 166ꢀ173.
33. R. Luguya, L. Jaquinod, F. R. Fronczek, M. G. H. Vicente and K. M.
Smith, Tetrahedron, 2004, 60, 2757ꢀ2763.
34. X. Chen, X. Yao, Z. Zhang and L. Chen, RSC Advances, 2014, 4,
49137ꢀ49143.
2
8. D. Veres, B. BocskeiꢀAntal, I. Voszka, K. Modos, G. Csik, A. D.
Kaposi, J. Fidy and L. Herenyi, J Phys. Chem. B, 2012, 116, 9644ꢀ
10
9
652.
25 35. H.ꢀL. Tu, Y.ꢀS. Lin, H.ꢀY. Lin, Y. Hung, L.ꢀW. Lo, Y.ꢀF. Chen and
2
9. K. Nawalany, A. Rusin, M. Kepczynski, P. Filipczak, M. Kumorek,
B. Kozik, H. Weitman, B. Ehrenberg, Z. Krawczyk and M.
Nowakowska, Inter.J Pharma., 2012, 430, 129ꢀ140.
C.ꢀY. Mou, Adv. Mater., 2009, 21, 172ꢀ177.
30
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 9 of 9
Journal of Materials Chemistry B
View Article Online
DOI: 10.1039/C5TB00256G
Graphical Abstract
By the metallo-supramolecular coordinated interaction between Zn-Por and histidine,
a dual pH-responsive mesoporous silica nanoparticles (MSNs)-based drug delivery
system has been fabricated for synergistic chemo-photodynamic therapy, which can
respond to the tumor extracellular and intercellular pH stimuli.
TOC