In Situ Formation of Homogeneous Tellurium Nanodots in Paclitaxel-Loaded MgAl Layered Double Hydroxide Gated Mesoporous Silica Nanoparticles for Synergistic Chemo/PDT/PTT Trimode Combinatorial Therapy

Article abstract of DOI:10.1021/acs.inorgchem.8b02821

A folic acid (FA) functional drug delivery system (MT?L-PTX?FA) based on in situ formation of tellurium nanodots (Te NDs) in paclitaxel (PTX)-loaded MgAl layered double hydroxide (LDHs) gated mesoporous silica nanoparticles (MSNs) has been designed and fa

Full text of DOI:10.1021/acs.inorgchem.8b02821

Article
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/IC
In Situ Formation of Homogeneous Tellurium Nanodots in
Paclitaxel-Loaded MgAl Layered Double Hydroxide Gated
Mesoporous Silica Nanoparticles for Synergistic Chemo/PDT/PTT
Trimode Combinatorial Therapy
†
†
‡
†
†
,§
Jia Wen, Kui Yang, Xingcheng Ding, Hongjuan Li, Yongqian Xu, Fengyu Liu,*
,
†
and Shiguo Sun*
†Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University,
Yangling, Shaanxi 712100, People’s Republic of China
‡
Zhejiang Runtu Co., Ltd, Shangyu, Zhejiang, People’s Republic of China
§
State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, No.2 linggong Road, Ganjingzi
District, Dalian 116023, China
*
S Supporting Information
ABSTRACT: A folic acid (FA) functional drug delivery system (MT@L-
PTX@FA) based on in situ formation of tellurium nanodots (Te NDs) in
paclitaxel (PTX)-loaded MgAl layered double hydroxide (LDHs) gated
mesoporous silica nanoparticles (MSNs) has been designed and fabricated for
targeted chemo/PDT/PTT trimode combinatorial therapy. X-ray diffraction
(
XRD), X-ray photoelectron spectroscopy (XPS), scanning electron
microscopy (SEM), high-resolution transmission electron microscopy
(
HRTEM), N adsorption−desorption, Fourier transform infrared (FT-IR)
2
spectra, and UV−vis spectra were used to demonstrate the successful
fabrication of MT@L-PTX@FA. In particular, the in situ generated Te NDs
showed a homogeneous ultrasmall size. Reactive oxygen species (ROS)
generation, photothermal effects, and photostability evaluations indicated that
the in situ generated homogeneous Te NDs could serve as the photo-
therapeutic agent, converting the photon energy to ROS and heat under near-
infrared (NIR) irradiation efficiently. The drug-release test revealed that MT@L-PTX@FA showed an apparent sustained
release character in a pH-sensitive manner. In addition, cell imaging experiments demonstrated that MT@L-PTX@FA could
selectively enter into cancer cells owing to the function of FA and release of PTX efficiently for chemotherapy for the reason
2
+
3+
that the low intracellular pH would dissolve MgAl LDHs to Mg and Al . Cytotoxicity tests also indicated that MT@L-PTX@
FA exhibited enhanced therapeutic effect in cancer cells under NIR irradiation, benefiting from the synergy based on targeted
chemo/PDT/PTT trimode combinatorial therapy. The preliminary results reported here will shed new light on the future
design and applications of nanosystems for synergistic combinatorial therapy.
INTRODUCTION
Some researchers have utilized the combination of PDT or
PTT with chemotherapy to overcome the limitations of single
chemotherapy, gaining synergistic effects and reducing the
therapeutic doses of both phototherapeutic agents and
■
Chemotherapy still remains one of the best means to cure
1
−5
cancer.
However, after continuous treatment with a single
chemotherapeutic modality, cancer cells are able to bypass the
pathways affected by anticancer drugs and generate drug
resistance, leading to cancer recurrence and even the failure of
19−23
anticancer drugs, resulting in minimized side effects.
Unfortunately, the outcome remains suboptimal and unsat-
isfactory for completely curing cancer. Therefore, to further
enhance the therapeutic efficiency as well as minimize side
effects, triple or even more modes of combinatorial therapy are
highly desired.
6
−8
chemotherapy.
ment of other therapeutic modalities.
This deficiency has inspired the improve-
9
−12
Among them,
phototherapies such as photodynamic therapy (PDT) and
photothermal therapy (PTT), where the process mainly
includes delivery of phototherapeutic agents to tumors and
subsequently irradiation of the treated tumor site with specific
Tellurium (Te), a narrow band gap semiconductor widely
24−26
used in electrochemistry and optoelectronics applications,
1
3−15
light,
have gained considerable attention in recent years
due to their high tumor ablation efficiency, excellent spatial
resolution, and minimal side effects on normal tissue.
Received: October 4, 2018
16−18
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.8b02821
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
Scheme 1. Schematic Illustration of (a) L-PTX Preparation, (b) MT@L-PTX@FA Preparation, and (c) Intracellular Tri-Mode
Combination Therapy of MT@L-PTX@FA
has recently been reported to show great potential as a
formed MSNs and drug-loaded LDHs gatekeepers can be a
powerful stimuli-responsive DDS for targeted synergistic
trimode combinatorial therapy.
27−30
phototherapeutic agent in cancer therapy.
For example,
Te nanosheets have been synthesized via a facile liquid
31
exfoliation method for photoacoustic imaging guided PDT.
Polysaccharide−protein complex modified Te nanorods have
As a proof of concept, in this study, a targeted nanosystem
based on in situ formation of Te NDs in MSNs has been
designed for chemo/PDT/PTT trimode combinatorial therapy
(Scheme 1). As designed, Te NDs were grown in situ within
the pores of carboxyl-functionalized MSNs (MSNs-COOH),
giving Te ND-doped MSNs-COOH (MT). Subsequently,
anticancer drug paclitaxel (PTX)-loaded MgAl LDHs (L-PTX)
were adsorbed on the surface of MT by electrostatic
interactions, yielding L-PTX gated MT (MT@L-PTX) to
avoid the premature leakage of Te NDs. To endow the
nanosystem with cancer selectivity, folic acid (FA) molecules,
which have high affinity to the overexpressed FA receptor on
the plasma membrane of most cancer cells, were covalently
attached onto the surface of MT@L-PTX, giving FA modified
MT@L-PTX (MT@L-PTX@FA). In this system, the in situ
formed homogeneous Te NDs served as the phototherapeutic
agent, converting the photon energy to reactive oxygen species
32
been used for chemo/PTT combination cancer therapy. In
particular, human serum albumin (HSA) has been utilized as a
size-limited nanoreactor to generate Te nanodots (Te NDs),
and certain synergistic anticancer efficacy was obtained since
the synthesized ultrasmall size Te NDs exhibited PDT and
33
PTT dual functions. Thus, Te NDs with dual functions can
be a good candidate for combinatorial therapy. Unfortunately,
the nanodot size and homogeneity are the two most crucial
factors to guarantee the efficiency and synergy of PDT and
3
3,34
PTT,
and the cavity size of HSA is not a good candidate to
control the proposed homogeneity.
In recent years, stimuli-responsive drug delivery systems
DDSs) based on mesoporous silica nanoparticles (MSNs)
(
have drawn much attention due to the unique properties of
MSNs such as stable porous structure, tunable pore size, good
3
5−39
(
ROS) and heat under near-infrared (NIR) irradiation, causing
biocompatibility, and high specific surface area.
In
damage to cancer cells. When the as-prepared MT@L-PTX@
FA selectively entered into cancer cells, the low intracellular
particular, the pore entrance size of MSNs can be controlled
precisely, which is just an ideal well-defined size-limited
reaction space for the in situ formation of homogeneous
ultrasmall Te NDs; thus, the aforementioned two most crucial
factors to guarantee the efficiency and synergy of PDT and
PTT from Te NDs could be achieved. Apart from providing
reaction space, MSNs can also endow therapeutic agents with
cancer cell targeting ability and precise release, in which MSNs
serve as controlled nanocarriers to avoid the side effects
2
+
3+
pH would dissolve MgAl LDHs to Mg and Al , thus leading
to the release of PTX for chemotherapy. Meanwhile, upon NIR
irradiation, Te NDs would convert the photon energy to ROS
and heat for PDT and PTT, simultaneously. The results
indicated that the chemo/PDT/PTT trimode combinatorial
therapy was more efficient to kill cancer cells in comparison to
either dual-mode combinatorial therapy or single therapy
alone. The preliminary results reported here will shed new light
on the future design and applications of nanosystems for
synergistic combinatorial therapy.
40−42
resulting from the premature release of drugs.
To avoid premature release and achieve targeted delivery,
the gatekeepers of MSNs, which respond to the specific
internal or external stimuli of cancer cells, play prominent and
crucial roles. Layered double hydroxides (LDHs), consisting of
positively charged brucite-type layers, are some of the
prominent members of MSNs benefiting from their good
biocompatibility, low cytotoxicity, pH-controlled degradation
properties in acidic environments, and ease of surface
EXPERIMENTAL SECTION
Reagents and Apparatus. Folic acid (FA), N-hydroxysuccini-
mide (NHS), 1-ethyl-3-(3-dimethylaminopropyl)carbodimide
■
(
(
(
EDC), tetraethoxysilane (TEOS), cetyltrimethylammonium bromide
CTAB), 3-aminopropyltrimethoxysilane (APTMS), 3-
triethoxysilyl)propylsuccinic anhydride (TPS), sodium dodecyl
4
3
modification. Especially, LDHs not only can act as pH-
sulfate (SDS), rhodamine B (RhB), 3-[4,5-dimethylthialzol-2-yl]-
2,5-diphenyltetrazolium bromide (MTT), paclitaxel (PTX), 1,3-
diphenylisobenzofuran (DPBF), and 2,7-dichlorodihydrofluorescein
controlled gatekeepers but also can act as nanocarriers
4
4
themselves. Therefore, the combination of Te ND in situ
B
DOI: 10.1021/acs.inorgchem.8b02821
Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
diacetate (DCFH-DA) were obtained from Sigma-Aldrich. All
1H), 1.69 (m, 3H), 1.31−1.19 (m, 5H), 1.14 (s, 3H), 0.86−0.75 (m,
9H), 0.53−0.35 (m, 6H).
aqueous solutions were prepared with ultrapure Milli-Q water (ρ >
−
1
1
8.0 MΩ cm ). Human cervical cancer cells HeLa and human
Synthesis of RhB-PTX. A solution of PTX-TES (50 mg, 0.05
mmol) and DMAP (1.22 mg, 0.01 mmol) in DCM was treated with
EDC (44.92 mg, 0.25 mmol) and RhB (119.75 mg, 0.25 mmol) for
embryonic kidney cells 293T were maintained in Dulbecco’s Modified
Eagle’s Medium (DMEM, Invitrogen) with 10 v/v% fetal bovine
serum (FBS) and 1 v/v% penicillin/streptomycin (complete DMEM)
18 h at room temperature. The mixture was then washed with H
× 5 mL). The organic solvent was dried over MgSO
O (3
and
2
in 5% CO at 37 °C. Human liver carcinoma cells HepG2 and human
4
2
normal liver cells HL7702 were cultured in 1640 medium containing
concentrated. The resulting residue was purified by silica gel column
chromatography (EA/hexanes (HEX) 1/2) to afford RhB-PTX-TES
as a red solid (yield 60%). Next, tetrabutylammonium fluoride
1
0% FBS and 1% penicillin/streptomycin (complete 1640) in 5%
CO at 37 °C.
2
X-ray diffraction (XRD) analysis was carried out with a D/
Max2550VB+/PC X-ray diffractometer with Cu Kα radiation (λ
(Bu NF; 30 μL, 0.03 mmol) was added to a solution of RhB-PTX-
4
TES (30 mg, 0.03 mmol) in tetrahydrofuran (THF) at room
temperature and stirred for 2 h at room temperature. The solution
was diluted with EA (100 mL) and washed with water (3 × 10 mL)
0
.15406 nm), using an operating voltage and current of 40 kV and 30
mA, respectively. The composition of the products was determined by
X-ray photoelectron spectroscopy (XPS, Thermo ESCALAB 250).
The dynamic light scattering (DLS) and zeta potential were
characterized using a zetasizer instrument (Nano ZS, Malvern
Instruments, U.K.). The absorption and emission spectra were
collected using a Shimadzu 1750 UV−vis spectrometer and an RF-
and brine (3 × 10 mL). The organic solvent was dried over MgSO
4
and concentrated, and the residue was purified by silica gel column
chromatography (EA/HEX = 3/2) to afford RhB-PTX as a red solid
1
(
yield 95%). The product was characterized by H NMR, MS,
1
fluorescence, and UV−vis spectra (Figures S3−S5). H NMR (500
MHz, CDCl ): δ 9.06 (d, J = 7.2 Hz, 1H), 8.18−8.13 (m, 2H), 8.09−
5
301 fluorescence spectrometer (Japan), respectively. Fourier trans-
3
7
5
1
1
7
4
1
1
1
0
.99 (m, 3H), 7.76−7.56 (m, 4H), 7.51 (m, 7.1 Hz, 5H), 7.33 (m,
H), 7.25 (s, 1H), 7.19 (dd, J = 7.4, 1.1 Hz, 1H), 7.10 (t, J = 7.4 Hz,
H), 6.98 (d, J = 9.4 Hz, 1H), 6.76 (m, 3H), 6.69 (dd, J = 9.6, 2.4 Hz,
H), 6.24 (s, 1H), 6.08 (s, 1H), 5.98 (t, J = 8.4 Hz, 1H), 5.58 (d, J =
.1 Hz, 1H), 5.51 (t, J = 7.3 Hz, 1H), 5.40 (dd, J = 10.6, 7.0 Hz, 1H),
.94 (d, J = 7.2 Hz, 1H), 4.76 (d, J = 8.5 Hz, 1H), 4.22 (d, J = 8.4 Hz,
H), 4.11 (d, J = 8.4 Hz, 1H), 3.63−3.52 (m, 8H), 3.34−3.25 (m,
H), 2.33 (s, 3H), 2.02 (s, 3H), 1.82 (s, 1H), 1.79−1.73 (m, 6H),
.71 (m, 3H), 1.30 (t, J = 7.1 Hz, 12H), 1.10 (m, J = 15.6 Hz, 5H),
form infrared (FT-IR) spectra were obtained on a Brucher
EQUINX55 FTIR spectrophotometer by a standard KBr disk method
−
1
in the range 400−4000 cm . A Quanta 200 environmental scanning
electron microscope (SEM) was used to observe the morphologies of
the obtained materials. High-resolution transmission electron micro-
scope (HRTEM) images and the element mapping were recorded
with a JEM-3010 transmission electron microscope operating at 200
kV. Specimens were prepared through dispersing the samples into
alcohol via ultrasonic treatment and dropped on carbon−copper grids
for observation. The nitrogen adsorption and desorption isotherms
were measured at liquid N2 temperature using a Quantachrom
Autosorb-iQ instrument, after degassing samples for 12 h at 120 °C.
Surface area was calculated according to the conventional Brunauer−
Emmett−Teller (BET) method, and then the adsorption branches of
the isotherms were used to calculate the pore parameters using the
BJH method. Inductively coupled plasma mass spectrometry (ICP-
MS, Agilent 7700X, Agilent Technologies, USA) was utilized to
.96 (m, J = 7.4 Hz, 3H). MS (RhB-PTX): calcd M for
+
(C H N O ) 1279.44, found 1279.06.
75 80
3
16
Preparation of MgAl Layered Double Hydroxides (MgAl
LDHs). MgAl LDHs were prepared by coprecipitation and subsequent
46
hydrothermal treatment. Mg(NO ) ·6H O (0.56 g, 1.5 mmol) and
3
2
2
Al(NO ) ·9H O (0.77 g, 3.0 mmol) were dissolved in 60 mL of
3
3
2
water, and the solution mixture was titrated with NaOH solution
−
1
(
0.175 mol L , 60 mL) to pH 10 ± 0.5 with vigorous stirring within
1
30 min, followed by treatment at 100 °C for 16 h under a N
2
analyze the element concentration of nanomaterials. H NMR and
13
atmosphere. The solid was centrifuged and washed with water.
Finally, the solid was dried at room temperature under high vacuum.
Delamination of MgAl LDHs. The delamination of MgAl LDHs
was performed according to the previously reported method. Briefly,
MgAl LDHs (1.0 g) were dispersed in 200 mL of formamide (0.05%,
w/v) with magnetic stirring, and the resulting dispersion was
C NMR spectra were recorded on a Bruker 500 AVANCE III
spectrometer with chemical shifts reported in ppm at room
1
13
temperature (500 MHz for H NMR and 125 MHz for C NMR,
Germany). Mass spectrum (MS) was obtained with a Thermo Fisher
LCQ Fleet mass spectrometer (USA). Cell culture was carried out in
47
an incubator with a humidified atmosphere of 5% CO at 37 °C. Cell
−1
2
sonicated until it became transparent to provide a 5 mg mL
formamide dispersion of MgAl LDH nanosheets.
toxicity tests were tested by a microplate reader (KHB ST-360). The
confocal laser microscope data were acquired using a confocal
fluorescence microscope (Nikon A1R).
All of the experiments were performed in compliance with the
relevant laws and institutional guidelines and were approved by
Northwest A&F University.
Preparation of PTX-Loaded MgAl LDHs (L-PTX). A
48
coassembly route was used to synthesize L-PTX. Briefly, a 0.01 M
SDS aqueous solution was prepared by dissolving SDS (0.34 g) in
deionized water (120 mL). A solution of PTX in chloroform (1.0 g
−1
L ) was also prepared by dissolving PTX (120 mg) in chloroform
Synthesis of RhB Conjugated PTX (RhB-PTX). RhB-PTX was
(120 mL). The chloroform PTX solution was then added to the as-
4
5
synthesized according to our previous work. The synthesis
procedure of RhB-PTX is shown in Figure S1 in the Supporting
Information.
prepared SDS aqueous solution (0.01 M) with continuous stirring,
and the resulting system was stirred under N2 to allow for the
evaporation of the chloroform to give a PTX-loaded micelle mixture.
Synthesis of PTX-TES. PTX (100 mg, 0.12 mmol) and
chlorotriethylsilane (TESCl) (19.4 mg, 0.13 mmol) were dissolved
in pyridine at room temperature. The solution was stirred at 25 °C for
−1
A 120 mL portion of the 5 mg mL MgAl LDH dispersion was then
added to the micelle mixture with continuous stirring. The suspension
was centrifuged and washed sequentially with deionized water and
anhydrous ethanol using a redispersion/centrifugation process. The
resulting solid sample, denoted as L-PTX, was dried with a vacuum
freeze-dryer overnight. The loading amount of PTX was measured by
UV−vis spectroscopy at 250 nm.
3
h and then diluted with ethyl acetate (EA; 50 mL) and washed with
water (3 × 5 mL) and brine (3 × 5 mL). The organic solvent was
dried over MgSO and concentrated, and the residue was purified by
4
silica gel column chromatography (petroleum ether (PE)/dichloro-
methane (DCM) 4/1 to 2/1) to afford PTX-TES as a white solid
The loading of RhB-PTX was according to the above-mentioned
method and named as L- RhB-PTX.
1
(
yield 80%). The product was characterized by H NMR (Figure S2).
1
H NMR (500 MHz, CDCl ): δ 8.16−8.10 (m, 2H), 7.77−7.71 (m,
3
Preparation of Carboxyl-Functionalized MSNs (MSNs-
2
6
2
H), 7.54 (m, 4H), 7.43−7.32 (m, 6H), 7.12 (d, J = 8.9 Hz, 1H),
.32−6.21 (m, 2H), 5.71 (m, 2H), 5.02−4.93 (m, 1H), 4.70 (d, J =
.1 Hz, 1H), 4.43 (t, J = 7.3 Hz, 1H), 4.32 (d, J = 8.4 Hz, 1H), 4.22
COOH). MSNs-COOH was synthesized according to a previous
49
report with slight modification. Briefly, 1.0 g of CTAB and 3.5 mL
of sodium hydroxide (2.0 M) were dissolved into 480 mL of double-
distilled water and heated to 80 °C in 30 min. Then, 5.0 g of TEOS
was added dropwise and the mixture stirred vigorously for 2 h to
(
d, J = 8.5 Hz, 1H), 3.83 (d, J = 7.1 Hz, 1H),2.62−2.46 (m, 5H), 2.23
(
s, 2H), 2.19−2.12 (m, 1H), 2.04 (s, 1H), 1.89 (m, 5H), 1.78 (br,
C
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Article
obtain MSNs. Next, 1 mL of TPS was dripped into the solution and
further stirred at 80 °C for another 4 h. After that, the precipitant was
collected by vacuum filtration and washed with double-distilled water
and methanol for 6 times each, respectively. Finally, the sample was
dried with a vacuum oven at 80 °C overnight to yield MSNs-COOH.
The surfactant was removed by an extraction method as in a previous
study. The crude product was refluxed with a solution composed of
DMPO (500 mM) with 100 μL of MT@L-PTX@FA. Then the
−
2
samples were irradiated at 785 nm at 2 W cm for 5 min, followed by
ESR analysis. The ESR spectrum of MT@L-PTX@FA in the presence
of DMPO without irradiation was collected as a control.
Evaluation of Photothermal Effect and Photostability. To
evaluate the photothermal effect of MT@L-PTX@FA, the solutions
−2
of MT@L-PTX@FA (2 mL) were irradiated (785 nm, 2 W cm ) for
−
1
7
h.
.0 mL of HCl (37.4 wt %) and 120.0 mL of methanol at 60 °C for 24
5 min at different concentrations (0.5, 1, and 2 mg mL ) and the
temperature was measured every 30 s using a digital thermometer.
−
1
Preparation of Tellurium Nanodot (Te-ND) Doped MSNs-
Further, the solutions of MT@L-PTX@FA (2 mg mL , 2 mL) were
COOH (MT). Te-NDs were synthesized using MSNs-COOH as a
nanoreactor. A 200.0 mL portion of 5.0 mg mL− MSNs-COOH was
added dropwise to 40.0 mL of 20.0 mM Na TeO with stirring. Next,
irradiated (785 nm) under different light intensities (0.5, 1, and 2 W
1
−2
cm ) for 5 min and the temperature was measured using the same
method.
2
3
1
6.0 mL of 100.0 mM NaBH as the reductant was further added to
To evaluate the photostability for temperature elevation, MT@L-
4
−
1
the mixture. Then, the reduction reaction was performed in the
mixture at 55 °C for 4 h with vigorous stirring, followed by the
formation of Te-NDs. Subsequently, the precipitant was collected by
centrifugation and purified through the dialysis against distilled water.
Finally, the sample was dried with a vacuum freeze-dryer overnight to
yield MT.
PTX@FA (2 mg mL , 2 mL) was subjected to 785 nm irradiation at
−
2
2 W cm for 5 min and then cooled to room temperature. Afterward,
an additional four irradiation/cooling cycles were repeated. During
these cycles, the temperature was monitored.
Cell Imaging. HepG2 cells and HL7702 cells were used for cell
imaging. Cells were seeded in 35 mm plastic-bottomed μ-dishes for 24
h. The medium was replaced with a fresh one. The cells were then
incubated with free RhB-PTX (40 μM) and MT@L-RhB-PTX@FA
To obtain free Te NDs, MT was added to a solution of Na CO
2
3
(
470 mg, 5 mL) and stirred at 60 °C for 16 h. Subsequently, the
−
1
precipitant was washed three times by ultrapure water, collected by
centrifugation, and dried with a vacuum freeze-dryer overnight to
yield free Te NDs.
(800 μg mL ) with equivalent PTX concentrations, respectively.
After incubation for 4 h, the medium was removed and the cells were
washed with PBS (pH 7.4) three times. To analyze the target ability of
FA, HepG2 cells were first incubated with FA (100 μM) for 30 min.
The cells were then incubated with MT@L-RhB-PTX@FA for 4 h.
The red fluorescence of RhB-PTX was observed by a confocal
scanning microscope (CLSM, Nikon A1R) with an excitation
wavelength of 488 nm.
Preparation of L-PTX Gated MT (MT@L-PTX). To gate the
pores of MSNs-COOH, MT and L-PTX were dispersed ultrasonically
in formamide (0.05%, w/v) and stirred for 20 min. The solid MT@L-
PTX was centrifuged, and washed with water.
L-RhB-PTX gated MT was fabricated according to the afore-
mentioned method and denoted as MT@L-RhB-PTX.
Preparation of FA Conjugated MT@L-PTX (MT@L-PTX@FA).
First, toluene (33 mL), methanol (1.6 mL), APTMS (0.25 mL), and
MT@L-PTX (50 mg) were mixed rigorously for 6 h under N . The
5
ROS Detection in Cells. HepG2 cells (1 × 10 ) were seeded in
35 mm plastic-bottomed μ-dishes for 24 h. The medium was replaced
with a fresh one. Next, the cells were treated with MT@L-PTX@FA
−
1
(800 μg mL ) for 4 h and irradiated by a NIR laser (785 nm, 2 W
2
−
2
product was washed several times by centrifugation at 3500 rpm to
remove excess APTMS in the suspension and dried with a vacuum
freeze-dryer overnight to yield APTMS conjugated MT@L-PTX
cm ) for 5 min irradiation. Then the medium containing 10 μM
DCFH-DA was refreshed. After 20 min incubation, the cells were
washed with PBS and then observed under a CLSM.
50
(
MT@L-PTX-APTMS). A mixture of FA (0.24 g), EDC (0.12 g),
Flow Cytometry. For flow cytometry studies, HepG2 cells (1 ×
6
and NHS (0.08 g) in dimethyl sulfoxide (DMSO, 40 mL) was stirred
for 0.5 h at room temperature. Then, MT@L-PTX-APTMS (0.20 g)
was added. The resulting mixture was stirred for 24 h at room
temperature. The product was dialyzed by SPECTRUM molecular
porous membrane tubing (1000 Da), collected by centrifugation, and
then dried with a vacuum freeze-dryer overnight to yield MT@L-
PTX@FA.
10 ) were seeded in six-well culture plates and grown overnight. The
cells were then treated with MT@L-RhB-PTX@FA for 0 h, 15 min,
30 min, 1 h, 2 h, and 4 h (for FA-preincubation groups, cells were first
incubated with FA (100 μM) for 30 min). A single cell suspension
was prepared consecutively by trypsinization, washing with PBS, and
filtration through a nylon mesh filter (300 mesh). Then, the cells were
analyzed using a flow cytometer (PE) for RhB.
Cytotoxicity Evaluation. HepG2 and HL7702 cells were
FA conjugated L-RhB-PTX was fabricated according to the
aforementioned method and denoted as MT@L- RhB-PTX@FA.
In Vitro PTX Release Kinetics. To determine the kinetics of PTX
release from MT@L-PTX@FA, MT@L-PTX@FA (4 mg) was
incubated in 2 mL of phosphate buffer solution (PBS, pH 5.8, 0.02
M), which contained a 1/1 (v/v) mixture of water and methanol to
increase the solubility of PTX, for different periods of time. The
supernatant was collected by centrifugation at predetermined time
points. PTX release was determined by measuring the absorption
intensity at 250 nm by a UV−vis spectrometer.
cultured in complete 1640 medium in 5% CO at 37 °C. HeLa and
2
2
3
93T cells were cultured in complete DMEM medium in 5% CO at
2
7 °C. The relative cytotoxicities of MT@L-PTX@FA, MT@L, and
free PTX were evaluated in vitro by MTT assays, respectively. The
4
cells were seeded in 96-well plates at a density of 1 × 10 cells per well
in 100 μL of complete medium. In particular, after 4 h of growth at 37
°
C, HepG2 and HeLa cells incubated with MT@L-PTX@FA and
−
2
MT@L were irradiated by a NIR laser (785 nm, 2 W cm ) for 5 min
irradiation. Subsequently, all groups of cells were incubated for
another 44 h. The cells were washed, and the fresh medium
For comparison, the release profile of PTX from MT@L-PTX@FA
in PBS (pH 7.4, 0.02 M) and 10% FBS was conducted by the same
procedure.
−
1
containing MTT (0.5 mg mL ) was added into each plate. The cells
were incubated for another 4 h. After that, the medium containing
MTT was removed and DMSO (100 μL) was added to each well to
dissolve the formazan crystals. Finally, the plate was gently shaken for
10 min and the absorbance at 490 nm was recorded with a microplate
reader.
Evaluation of ROS. A solution of DPBF (300 μM) in DMSO
(
500 μL) was added to a solution of MT@L-PTX@FA (0.125, 0.25,
−1
and 0.5 mg mL ) in PBS buffer (pH 5.8, 2 mL). The resulting
solutions containing 1.5 mg MT@L-PTX@FA and 75 μM DPBF
were photoirradiated with 785 nm irradiation (2 W cm ) for
different periods of time. Changes in the UV−vis spectra of DPBF
were recorded.
To distinguish the type of ROS, the electron spin resonance (ESR)
technique was employed to monitor ROS signals from MT@L-PTX@
FA upon 785 nm irradiation using 5,5-dimethyl-1-pyrroline N-oxide
−
2
RESULTS AND DISCUSSION
■
Synthesis and Characterization of MT@L-PTX@FA.
MgAl LDHs, L-PTX, MSNs-COOH, MT, MT@L-PTX, and
MT@L-PTX@FA were first prepared step by step as illustrated
in Scheme 1, and their physical/chemical properties were
characterized in detail. On one hand, MgAl LDHs were
33
(
DMPO) as the spin-trapping agent of superoxide radicals. Spectra
of spin-trapped superoxide radicals were acquired by mixing 5 μL of
D
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Article
Figure 4. SEM images of (a) MSNs-COOH, (b) MT, (c) MT@L-
PTX, and (d) MT@L-PTX@FA (scale bar 100 nm).
fabricated using a hydrothermal method according to the
43
literature. As shown in Figure 1, MgAl LDHs exhibited
nearly hexagonal platelets with a lateral size, which is the
43
typical morphology of LDH samples. The typical XRD
pattern and XPS also indicated the successful synthesis of
43
MgAl LDHs. Further, PTX was loaded into MgAl LDHs via
48
a coassembly route, in which PTX was initially incorporated
into the micelles of the negatively charged surfactant SDS. The
resulting negatively charged PTX-loaded micelles and the
positively charged delaminated MgAl LDHs were then
coassembled together obtaining L-PTX. HRTEM and SEM
gave the morphology of L-PTX. The decreased zeta potential
Figure 1. (a, b) HRTEM images of MgAl LDHs and L-PTX (scale
bar 200 nm). (insets are images with high magnification; scale bar 5
nm). (c, d) SEM images of MgAl LDHs and L-PTX (scale bar 200
nm). (e) XRD pattern of MgAl LDHs; (f) XPS analysis of MgAl
LDHs.
(
from 38.1 to 15.4 mV) of L-PTX confirmed the intercalation
of PTX-loaded micelles into MgAl LDHs (Figure 2). The PTX
loading amount of the L-PTX was calculated to be 4.2% by
UV−vis spectroscopy.
On the other hand, MSNs-COOH were first prepared by a
49
sol−gel method, and then Te-NDs were synthesized in situ
using the pores of MSNs-COOH as nanoreactors yielding
MT. The successful fabrication of the nanomaterials was
confirmed by HRTEM (Figure 3) and SEM (Figure 4) images,
XRD (Figure 5a), XPS (Figure 5b,c), BET surface values
33
(
(
Figure 5d), pore volumes (Figure 5e), and the pore size
Figure 5f). HRTEM and SEM images revealed that Te-NDs
were generated in situ in the pores of MSNs-COOH. The
XRD pattern of MT exhibited the characteristic Bragg peaks at
Figure 2. Zeta potential of MgAl LDHs, L-PTX, MSNs-COOH, MT,
MT@L-PTX, and MT@L-PTX@FA.
(
011) and (102) facets that confirmed the generation of Te-
33
0
NDs. XPS also suggested the composition of Te element.
Moreover, BET surface values, pore volumes, and the pore size
calculated from the N adsorption−desorption isotherms for
2
MT showed a significant decrease in comparison to that of
MSNs-COOH, which is typical of mesoporous systems with
filled pores, indicating that Te-NDs were generated in situ in
the pores of MSNs-COOH. In addition, free Te NDs
obtaining via the etching of MSNs showed a homogeneous
diameter of about 3 nm, benefiting from the well-defined pore
entrances of MSNs (Figure S6). Next, the as-prepared L-PTX
nanosheets were adsorbed on the surface of MT spheres by
electrostatic interactions to encapsulate the Te NDs inside the
pores of the MSNs-COOH, giving MT@L-PTX. HRTEM
images showed that, for the sample of MT@L-PTX, L-PTX
nanosheets were randomly packed on the surface of MT
spheres. The appearance of the Mg 1s peak component and the
Al 2p peak component in the XPS of MT@L-PTX also
Figure 3. (a−c) HRTEM images of MSNs-COOH, MT and MT@L-
PTX@FA. (d) TEM image and element mapping (Si, Te, Mg, Al, and
merged image of Si, Te, Mg, Al) of MT@L-PTX@FA (scale bar 100
nm).
E
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Figure 5. (a) XRD patterns of MSNs-COOH and MT. (b) XPS analysis of MT. (c) XPS analysis of MT@L. (d) BET surface areas of MSNs-
COOH, MT, and MT@L. (e) Pore volumes of MSNs-COOH, MT, and MT@L. (f) Pore sizes of MSNs-COOH, MT, and MT@L.
Figure 6. (a) Release kinetics of PTX from MT@L-PTX@FA in PBS (pH 5.8) and stability of MT@L-PTX@FA in PBS (pH 7.4) and 10% FBS.
−
2
(
b) Concentration-dependent ROS generation from MT@L-PTX@FA under 785 nm irradiation at 2 W cm using DPBF as a probe. Inset:
−
2
magnification of one segment. (c) Concentration-dependent temperature elevation of MT@L-PTX@FA under 785 nm irradiation at 2 W cm .
d) Light-intensity-dependent temperature elevation of MT@L-PTX@FA (2 mg mL ) under 785 nm irradiation. Inset: temperature elevation of
−
1
(
−1
MT@L-PTX@FA (2 mg mL ) under five irradiation/cooling cycles.
confirmed the existence of the L-PTX coating. Moreover, the
estimated weight percentage of L-PTX in MT@L-PTX
obtained from ICP-MS was about 39.6% (Figure S7). Finally,
FA molecules were conjugated onto MT@L-PTX, and the final
nanosystem MT@L-PTX@FA was obtained (Figure S8
revealed that the hydrodynamic size of MT@L-PTX@FA
obtained from DLS was about 250 nm). As shown in Figure
S9, the FT-IR spectra of MT@L-PTX@FA exhibited addi-
−
1
tional absorption bands at 1639 and 1401 cm in comparison
with that of MT@L-PTX, which were assigned to the
symmetrical ν (CO) and asymmetric ν (CO) vibrations
s
as
51
of FA, respectively, indicating the successful conjugation of
FA.
F
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Figure 9. DCF fluorescence images in HepG2 cells treated with
−
2
Figure 7. CLSM images of HepG2 cells incubated with MT@L-RhB-
PTX@FA for 4 h: (a) without FA preincubation and (b) with FA
preincubation, respectively. (c) HL7702 cells incubated with MT@L-
RhB-PTX@FA for 4 h (scale bar 20 μm).
MT@L-RhB-PTX@FA under 785 nm irradiation (2 W cm ) for (a)
min and (b) 5 min (scale bar 20 μm).
0
probe molecule. The photo-oxidation of DPBF was monitored
−
2
In Vitro Drug Release of MT@L-PTX@FA. The feasibility
of pH-triggered drug release of the nanosystem in vitro was
then investigated. MT@L-PTX@FA was added into PBS (pH
for 40 min under 785 nm light irradiation (2 W cm ). As
shown in Figure 6b, in the presence of MT@L-PTX@FA, the
DPBF absorption decreased continuously over the course of
light irradiation, confirming the generation of ROS. In
addition, MT@L-PTX@FA also exhibited a concentration
dependent ROS generation. Further, the ESR technique was
employed, indicating that the main type of ROS generated
from MT@L-PTX@FA under irradiation was superoxide
5
.8, 0.02 M), which contained a 1/1 (v/v) mixture of water
and methanol to increase the solubility of PTX, and the release
efficiency was evaluated by recording the absorbance at 250
nm. As shown in Figure 6a, approximately 70% PTX was
released from MT@L-PTX@FA at pH 5.8, which mimics the
acidic environment of tumor sites, because of the degradation
of MgAl-LDHs. In comparison, MT@L-PTX@FA showed
very high stability under physiological conditions of PBS (pH
33
radicals (Figure S10). These results indicate that this
nanosystem has a good capacity for potential PDT.
We next proceeded to investigate the photothermal effect of
MT@L-PTX@FA in vitro. As shown in Figure 6c,d, MT@L-
PTX@FA had a concentration-dependent as well as light-
intensity-dependent temperature increase under irradiation
(785 nm), while water showed no significant temperature
elevation. All of these results indicated that MT@L-PTX@FA
7
.4) and 10% FBS. Hence, MT@L-PTX@FA exhibited pH-
responsive drug release.
ROS Generation, Photothermal Effect, and Photo-
stability of MT@L-PTX@FA. To assess the capability of ROS
generation of MT@L-PTX@FA, DPBF was employed as a
Figure 8. Flow cytometry analysis of HepG2 cells incubated with (a) MT@L-RhB-PTX@FA for 0 h, 15 min, 30 min, 1 h, 2 h, and 4 h, (b) RhB-
PTX for 0 h, 15 min, 30 min, 1 h, 2 h, and 4 h, and (c) MT@L-RhB-PTX@FA for 0, 2, and 4 h (group 1, without FA preincubation; group 2, with
FA preincubation).
G
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Figure 10. Cytotoxicity of MT@L-PTX@FA with or without irradiation, MT@L with irradiation, and free PTX at different concentrations on (a)
HepG2 cells and (c) HeLa cells for 48 h. Cytotoxicity of MT@L-PTX@FA without irradiation and free PTX at different concentrations on (b)
HL7702 cells and (d) 293T cells for 48 h.
had a strong ability to generate potent hyperthermia. To
further confirm the photostability, we evaluated the ability of
MT@L-PTX@FA to maintain temperature elevation under
irradiation. The solutions of MT@L-PTX@FA suffered from 5
min irradiation (785 nm) at 2 W cm− and then were cooled to
room temperature in the absence of irradiation for 5 min,
followed by another four cycles of irradiation/cooling. As
shown in the inset of Figure 6d, MT@L-PTX@FA had a
temperature elevation of 47.0 °C after the first irradiation/
cooling cycle and exhibited no significant change in temper-
ature elevation after five cycles, suggesting that MT@L-PTX@
FA had a good resistance to photobleaching.
Intracellular Imaging. These encouraging results in
solution prompted us to evaluate the feasibility of MT@L-
PTX@FA as an anticancer agent in cells. First, the selective
cellular internalization of MT@L-PTX@FA was tested by cell
imaging using CLSM and flow cytometry. RhB conjugated
PTX (RhB-PTX) was used instead of PTX here (the synthesis
procedure and characterizations of RhB-PTX are shown in the
Supporting Information), and the corresponding nanosystem
was denoted as MT@L-RhB-PTX@FA. As shown in Figure 7a,
MT@L-RhB-PTX@FA showed obvious red fluorescence after
Thereafter, the ROS production of MT@L-RhB-PTX@FA
was performed with HepG2 cells using DCFH-DA as a probe
molecule. HepG2 cells were incubated with MT@L-RhB-
PTX@FA (800 μg mL ) for 4 h and then with or without 785
nm light irradiation for 5 min. The cells were then stained with
10 μM DCFH-DA for 10 min. As shown in Figure 9, after light
irradiation, green fluorescence generated from DCFH-DA can
be seen clearly, indicating that MT@L-RhB-PTX@FA can be
used as a promising candidate for PDT in living cells.
−
1
2
In Vitro Cytotoxicity. To further evaluate the anticancer
efficacy of the nanosystem in vitro, an MTT assay was used to
assess the cell viability after the cells were treated with MT@L-
PTX@FA with and without light irradiation. In addition, cells
treated with MT@L and free PTX were used as a comparison.
As shown in Figure 10, the cell viabilities of HepG2 cells
(Figure 10a) incubated with MT@L-PTX@FA with irradiation
were much lower than those incubated with MT@L under the
same conditions, MT@L-PTX@FA without irradiation, and
free PTX, which was ascribed to the chemo/PDT/PTT
trimode therapeutic synergy of as-prepared MT@L-PTX@FA.
However, the cell viabilities of HL7702 cells (Figure 10b)
incubated with MT@L-PTX@FA without irradiation were
much higher than those incubated with free PTX. In addition,
HepG2 cells and HL7702 cells incubated with free PTX
exhibited similar cytotoxicities. These results indicate that
MT@L-PTX@FA had a highly selective toxicity for cancer
cells thanks to the targeting ability of FA but also showed
enhanced therapeutic effects upon light irradiation inside cells
based on chemo/PDT/PTT trimode combinatorial therapy.
To provide further evidence, human cervical cancer cells HeLa
(Figure 10c) and human embryonic kidney cells 293T (Figure
10d) were used to repeat the experiments and consistent
results were obtained.
4
h incubation in human liver cancer cells HepG2 that was
focused mainly in the cytoplasm, which was also stronger than
that of free RhB-PTX (Figure S11a). In comparison, for
HepG2 cells preincubated with FA (Figure 7b), a sharp
decrease in fluorescence was observed. In addition, for human
normal liver cells HL7702 incubated with MT@L-RhB-PTX@
FA, an obvious decrease of fluorescence was also observed
(Figure 7c). However, the fluorescence intensity of HL7702
cells incubated with free RhB-PTX was almost the same as that
of HepG2 cells (Figure S11b). The results of flow cytometry
were consistent with those of CLSM (Figure 8). All of these
can be ascribed to the targeting ability of FA, which remarkably
enhances the cancer cellular internalization of MT@L-RhB-
PTX@FA in comparison with free RhB-PTX.
Moreover, the synergistic effect between PDT and PTT was
verified using MT@L under irradiation. The ROS scavenger
vitamin C (Vc) was used to scavenge intracellular ROS from
H
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MT@L under irradiation and thus to inhibit photodynamic
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NIR enhanced drug release from gold nanocages possesses high
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activity, while cells were temporarily incubated at ∼4 °C
29
during irradiation to avoid photothermal damage. As shown
in Figure S12, in comparison with the group incubated with
MT@L under irradiation, the relative cell viability of MT@L
was increased in the presence of 10 mM Vc, indicating that
their cytotoxicity from PTT alone was distinctly decreased in
the absence of ROS. Moreover, at ∼4 °C incubation, much
higher cell viability was observed, indicating a much lower
cytotoxicity caused by PDT alone. Therefore, MT@L
exhibited a synergistic effect between PDT and PTT.
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In summary, a FA-functioned targeted nanosystem based on in
situ formation of Te NDs in PTX-loaded MgAl LDH gated
MSNs has been successfully synthesized. The obtained
nanosystem MT@L-PTX@FA exhibited an efficient in vitro
PDT and PTT activity as well as intracellular pH-responsive
drug release. Moreover, MT@L-PTX@FA could target cancer
cells due to the function of FA. In particular, cytotoxicity tests
indicated that, under NIR irradiation, more efficient
therapeutic effects could be achieved using MT@L-PTX@
FA, benefiting from therapeutic synergy based on chemo/
PDT/PTT trimode combinatorial therapy, which provides a
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Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.8b02821.
■
Liu, W.; Tang, Y. Self-assembled upconversion nanoparticle clusters
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AUTHOR INFORMATION
Corresponding Authors
E-mail for F.L.: liufengyu@dlut.edu.cn
E-mail for S.S.: sunsg@nwsuaf.edu.cn.
■
(13) Zhu, H.; Cheng, P.; Chen, P.; Pu, K. Recent progress in the
development of near-infrared organic photothermal and photo-
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ORCID
Recent advances in functional nanomaterials for light−triggered
cancer therapy. Nano Today 2018, 19, 146−187.
Yongqian Xu: 0000-0002-3778-7332
Shiguo Sun: 0000-0003-3135-8542
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ACKNOWLEDGMENTS
This work was financially supported by the National Natural
Science Foundation of China (Nos. U1803283, 21878249,
1472016, 21576042). The authors thank Life Science
Research Core Services (LSRCS), Northwest A&F University,
for help with characterizations including SEM, TEM, CLSM,
and flow cytometry.
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DOI: 10.1021/acs.inorgchem.8b02821
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