Synthesis of a GNRs@mSiO2-ICG-DOX@Se-Se-FA Nanocomposite for Controlled Chemo-/Photothermal/Photodynamic Therapy

Article abstract of DOI:10.1002/ejic.201800572

A novel GNRs@mSiO₂ core–shell nanocomposite has been synthesized to integrate sensitive chemotherapy with photodynamic therapy (PDT) and photothermal therapy (PTT) for enhanced antitumor treatment by using gold nanorods (GNRs) as the core and mesoporous silica (mSiO₂) as the shell. After modifying with -NH₂, Indocyanine Green (ICG, negative charge) and doxorubicin hydrochloride (DOX, positive charge) molecules could be stored in the mesopores by the layer-by-layer assembly method through electrostatic interactions. To inhibit leakage from the mesopores, a sensitive Se–Se linker was synthesized and adopted as a nanovalve coated on the outside of the nanoparticles (GNRs@mSiO₂-ICG-DOX@Se-Se). Under NIR (808 nm) irradiation, heat elevation (derived from GNR/ICG) and generation of reactive oxygen species (ROS, derived from ICG) can also be detected in vitro. Owing to the redox sensitivity of Se–Se, GNRs@mSiO₂-ICG-DOX@Se-Se showed reduction (GSH)- as well as oxidation (ROS)-triggered DOX release. To further ensure specific targeting, folic acid (FA) was grafted to the outside of the nanoparticles, because of the high expression of FA receptors on tumor cells. Detailed cell experiments performed with the nanoparticles and HepG2 as typical cancer cells showed enhanced cytotoxicity towards the cancer cells owing to the synergistic effect of chemotherapy, PTT, and PDT. On account of the different GSH concentrations in cancer and normal cells and the switch-on/off application of NIR irradiation, the GNRs@mSiO₂-ICG-DOX@Se-Se-FA nanoparticles show potential for applications in cancer therapy.

Full text of DOI:10.1002/ejic.201800572

A Journal of
Accepted Article
Title: The synthesis of GNRs@mSiO2-ICG-DOX@Se-Se-
FA nanocomposite for controlled chemo-/photothermal/
photodynamic therapy
Authors: Na An, Huiming Lin, and Fengyu Qu
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To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.201800572
Link to VoR: http://dx.doi.org/10.1002/ejic.201800572

10.1002/ejic.201800572
European Journal of Inorganic Chemistry
The synthesis of GNRs@mSiO2-ICG-DOX@Se-Se-FA
nanocomposite for controlled chemo-/photothermal/photodynamic
therapy
Na An, Huiming Lin,* and Fengyu Qu*
Key Laboratory of Photochemical Biomaterials and Energy Storage Materials,
Heilongjiang Province , College of Chemistry and Chemical Engineering, Harbin
Normal University, Harbin, 150025, P. R. China
Tel (Fax): +86 451 88060653
E-mail: qufengyu@hrbnu.edu.cn and linhuiming@hrbnu.edu.cn
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
Abstract
Here, a novel core-shell nanocomposite was synthesized to integrate
sensitive-chemotherapy with photodynamic therapy (PDT) and photothermal therapy
(PTT) for enhanced antitumor efficiency by using gold nanorods core and
mesoporous silica as shell (GNRs@mSiO2) nanoparticle as host. After modified with
–NH2, indocyanine green (ICG, negative charge) and doxorubicin hydrochloride
(DOX, positive charge) molecules could be stored in mesopores by layer-by-layer
assembly method depending on the electrostatic interaction. To further inhibit the
leakage, sensitive Se-Se linker was synthesized and adopted as nanovalve coated
outside the nanoparticles (GNRs@mSiO2-ICG-DOX@Se-Se). Under NIR (808 nm)
irradiation, the heat elevation (derived from GNR/ICG) and ROS generation (derived
from ICG) also can be detected in vitro. Owing to the redox sensitive of Se-Se,
GNRs@mSiO2-ICG-DOX@Se-Se revealed the reduction (GSH) as well as oxidation
(ROS) triggered DOX release. To further make sure the specific targeting, folic acid
(FA) was grafted outside due to the excess expression of FA receptor on tumor cells.
The detailed cell experiments by using HepG2 as typical cancer cells showed the
enhanced cytotoxicity to cancer cells owing to the synergistic effect of chemotherapy,
PTT, and PDT. On account of the distinction of GSH concentration in cancer/normal
cells and the on-demand operation of NIR, GNRs@mSiO2-ICG-DOX@Se-Se-FA
exhibited the potential application on cancer therapy.
Keywords: GNRs@mSiO2; sensitive release; NIR; PDT; PTT
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
1 Introduction
Systematic combination of different anticancer treatments can overcome
drawbacks of individual methods to improve the efficiency1, 2, 3, 4. With the
development of nanotechnology, some nanocomposites have attracted increasing
attention on nanomedicine owing to their advanced physical, chemical and biological
properties5, 6, 7, 8. However, to integrate multicomponent into one nanoplantform to
achieve the most intelligent combination for selective and synergistic therapy remains
a great challenge9, 10
.
Chemotherapy is widely used for anticancer by employing cytotoxic drugs11, 12, 13
To improve the specific accumulation and the permeability-retention (EPR) effect,
functional nanoparticles were used as the nanocarriers for targeted drug delivery to
optimize chemotherapy. Besides, photothermal therapy (PTT) and photodynamic
therapy (PDT) also possesses outstanding advantages on cancer treatment, such as
low side effects, and remote controllability, especially avoiding chemo-resistance14, 15,
16. The development of PTT and PDT heavily depends on photothermal and
photosensitive agents17, 18. Near-infrared (NIR) illumination phototherapy is ideal for
real applications because of the superior tissue penetration ability19, 20. Up to now,
many kinds of photothermal sensitizers can absorb NIR light and convert it to heat,
such as gold, carbon, and grapheme oxide nanostructures21. Among these, gold
nanorods (AuNRs) can provide a tunable and strong longitudinal surface plasmon
resonance (LSPR) across the 600−1300 nm spectral range, which are considered to
have great potential for combined PTT and PDT22, 23, 24. Yeh et al. have designed a
rod-in-shell (rattle-like) Au nanostructure, which is responsive to the first (650-950
nm) and second (1000-1350 nm) NIR windows, revealing the potential application in
the hyperthermia-based therapy25. Chen and co-workers have conjugated
low-molecular-weight polyethylenimine onto the surfaces of gold nanorods with high
gene transfection activity, low cytotoxicity, photoacoustic imaging ability, and
photothermal therapeutic properties26. Choi et al. have published a gold nanorod
(GNR)-photosensitizer complex for noninvasive NIR fluorescence imaging and
PTT/PDT in various cancers27.
.
However, the LSPR peak of AuNRs could be shifted to the visible spectral
region because of their easy clustering and aggregation, resulting in a low efficiency
of phototherapy in the NIR window. In order to overcome this weakness, some hard
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
substances were deposited on AuNRs to remain their monodispersity. Yu and
co-workers have reported a AuNRs@C core−shell nanocomposites showing the
favourable photothermal and biocompatibility properties under NIR light irradiation28.
In addition, with well biocompatibility, large surface area/pore volume, tunable
morphologies/functionalization, mesoporous silica is considered as one of the most
potential candidates of biomaterials. The coating of mesoporous silica shell on
AuNRs was also thought to be an efficient way29. Furthermore, the porous structure
also supplies abundant space for the loading of anticancer drugs as well
photosensitive agents (PS).
In this paper, a nanocomposite integrated with chemotherapy, PTT and PDT in
synergistic manner, is illustrated in Scheme 1. First, -NH2 modified AuNRs@mSiO2
core-shell nanopartiles were synthesized as the host. Under layer-by-layer assembly
means, PS agent (Indocyanine green, ICG) and anticancer drug (Doxorubicin
hydrochloride, DOX) were loaded into the mesopore of mSiO2 shell due to the
electrostatic interaction. To make sure few leakages and well defined drug release,
sensitive diselenide derivative was prepared and it was grafted outside the mesopore
as nanovalve via a simple silane coupling reaction (Figure S1). In addition, folic acid
(FA) was introduced to enhance the cancer targeting performance. When the
nanocomposite (GNRs@mSiO2-ICG-DOX@Se-Se-FA) was taken up by cancer cells
via pinocytosis or phagocytosis, the diselenide nanovalve breaking induces DOX
release owing to the high expression of GSH in cancer cell. Upon 808 nm irradiation,
diselenide nanovalve which is also sensitive with ROS-trigger DOX release as well.
Furthermore, the PDT and PTT causing by NIR irradiation are useful secondary
cancer treatment in microenvironment. So, the PDT and PTT combines with
chemotherapy would further improve the cytotoxicity to cancer cell.
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
Scheme.1 Schematic illustration of the synthesis of NIR sensitive nanocomposites and the
chemotherapy, PDT and PTT process.
2. Results and Discussion
2.1 Material Characterization
Transmission electron microscopy (TEM) was used to reveal the structure of the
as-synthesized sample. As shown in Figure 1A, the average length and width of
GNRs was 67 and 18 nm, respectively (ca. 3.7:1 aspect ratio). After the coating of
mSiO2, the synthesized GNRs@mSiO2 possesses uniform core-shell structure with
mSiO2 shell about 23 nm in thickness (Figure 1B). And the worm-like mesoporous
structure of the silica layer also can be found, obviously. That provides plenty of
space for the loading of guest molecules. Comparing with Figure 1B, the blurred
mesoporous structure as displaying in Figure 1C is ascribed to the loading of
DOX/ICG and the grafting of Se-Se linker. Furthermore, the absorption spectra of the
GNRs and GNRs@mSiO2 were investigated (Figure 1D). Both of the two samples
exhibit two absorption bands at 510 and 800 nm, corresponding to the transverse
plasmon resonance and longitudinal plasmon resonance, respectively. After silica
shell coating, the adsorption peak of GNRs@mSiO2 shift to 817 nm, which is in
accord with the related researches, due to a local increase of refractive index and the
scattering from the silica shells30. Importantly, the longitudinal SPR peak of
GNRs@mSiO2 remains in the NIR region that is significant to insure the relative high
transmissivity to biological tissues. Furthermore, the structure of these
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
nanocomposites was further revealed by XRD (Figure 1E and 1F). From Figure 1E,
the diffraction peaks match well with the standard Au phase (JCPDS card no.
65-2870). Furthermore, an additional diffraction peak at about 22.2° of
GNRs@mSiO2 is owing to the amorphous SiO2 framework. As displayed in Figure 1F,
only one diffraction peak at 2.28° in LAXRD suggests the worm-like mesoporous
structure of GNRs@mSiO2 that also is consistent with TEM data shown in Figure 1B.
B
C
A
50 nm
50 nm
50 nm
Figure 1. TEM images of (A) GNRs, (B) GNRs@mSiO2, (C) GNRs@mSiO2-ICG-DOX@Se-Se,
(D) The UV/Vis spectrum of GNRs and GNR@mSiO2, (E) Wide-angle XRD and (F) low-angle
XRD patterns of GNRs@mSiO2.
The mesopore silica shell supplies the plenty of room for the loading of guest
molecules. To improve the loading amount, first GNRs@mSiO2 was modified with
–NH2 groups. The successful organic modification and drug loading was also verified
by FT-IR spectroscopy (Figure 2A). The wide absorption peak at 3432 cm-1 is
ascribed to the stretching vibration of -OH from Si-OH and the absorption peak at
1
1089 cm- is ascribed to the Si-O-Si framework of mSiO2. Figure 2(A)b, the two
1
absorption peaks at 2919 and 2850 cm- were the symmetric and anti-symmetric
vibration absorption peak caused by C-H. And the absorption peaks at 1579 (N–H
in-plane deformation) and 796 cm−1 (N–H out-of-plane deformation) can prove the
successful modification of amine group. As exhibited in Figure 2(A)c, the emerging
peak at 1220 cm-1 ascribing to the S=O asymmetric stretching testifies the joint of
ICG. From Figure 2(A)d, the absorption peaks at 1750 cm-1 due to the C=O functional
groups of DOX. In addition, the Se-Se vibration (722 cm−1) in Figure 2(A)e further
confirms that Se-Se linker has been successfully introduced. Moreover, the Zeta
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
potentials of these composites were also detected to further reveal the modification
process (Figure 2B). GNRs@mSiO2 displays the negative Zeta potential (-10.99±1.62
mV) on account of the surface Si-OH with negative charge. While that increases to
8.15±1.09 mV of GNRs@mSiO2-NH2 due to the positive charge of -NH2. With
sulfonate group, ICG (negative charge) can be connected onto GNRs@mSiO2-NH2
owing to the electrostatic interaction, inducing the negative charge of
GNRs@mSiO2-ICG (-1.45±1.08 mV). And the negative surface of
GNRs@mSiO2-ICG also provides the site for the further loading of DOX molecules
with positive charge. The increasing Zeta potential of GNRs@mSiO2-ICG-DOX
(3.76±1.61 mV) and GNRs@mSiO2-ICG-DOX@Se-Se (5.70±0.81 mV) further
testifies the DOX loading and Se-Se linker modification. So, the amount of –NH2
graft also can influence the ICG as well as DOX loading amount (Table S1). In
addition, the UV/Vis absorption spectra of these materials were investigated (Figure
2C). Comparing with GNRs@mSiO2, the emerging absorption peak at 483 and 737
nm of GNRs@mSiO2-ICG-DOX@Se-Se is derived from the typical adsorption of
DOX and ICG, respectively.
Figure 2.(A) FTIR spectra of (a) GNRs@mSiO2, (b) GNRs@mSiO2-NH2, (c) GNRs@mSiO2-ICG,
(d) GNRs@mSiO2-ICG-DOX and (e)GNRs@mSiO2-ICG-DOX@Se-Se, (B) Zeta potentials and
(C) the UV/Vis spectrum of these samples.
To investigate the porous structure of the nanocomposite, N2 adsorption-desorption
isotherms of GNRs@mSiO2 and GNRs@mSiO2-ICG-DOX@Se-Se2 were carried out
(Figure 3). The typical IV isotherm curves reveal the mesoporous structure of mSiO2
shell. And the hysteresis loop at high P/P0 region is ascribed to the void derived from
the accumulation of these small nanoparticles. Moreover, after the organic
modification and drug loading, the corresponding surface area and pore volume
reduces from 531.87 m2 g-1, and 0.51 cm3 g-1 to 402.15 m2 g-1 and 0.23 cm3 g-1 (Table
S2).
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
Figure 3. (A) Nitrogen adsorption–desorption isotherms and (B) pore size distribution curves of
these samples.
2.2 Photothermal and photodynamic properties
The temperature of GNRs@mSiO2 and GNRs@mSiO2-ICG2 suspension solution
under laser irradiation (808 nm, 2 W cm-2) was monitored to evaluate the
photothermal efficiency. As shown in Figure 4A, when 808 nm NIR is introduced, the
temperature increases obviously, and all the samples show the time-dependent
temperature increase. Under illuminating for 14 min, GNRs@mSiO2 reaches 47.3 ℃.
After loading of ICG, the temperature of GNRs@mSiO2-ICG2 further rises to
49.5 ℃. Meanwhile, pure water just shows 31.2 ℃ under the same condition. Based
on Figure 4A, it is believed that the rapid temperature rise of GNRs@mSiO2 and
GNRs@mSiO2-ICG2 is ascribed to GNRs and ICG, which are typical photothermal
agents. Then temperature increasing test under different laser irradiation intensity (1,
2 and 3 W cm-2) of GNRs@mSiO2-ICG2 was carried out (Figure 4B). The maximal
temperature of GNRs@mSiO2-ICG2 increases to 45.0, 47.3 and 49.5℃ under 1, 2
and 3 W cm-2 irradiation, respectively. The photothermal conversion efficiency (η) is
calculated according to formula (1) .
(
)
ℎ퐴 푇max − 푇 − 푄0
s
(1)
 =
퐼(1 − 10−퐴
)
Calculated from the Figure 4C and D, photothermal conversion coefficient (η) of
GNRs@mSiO2-ICG2 is about 23.8 %. From the above result, the as-synthesized
GNRs@mSiO2-ICG2 exhibits the remarkable time/intensity-dependent temperature
elevation that is significant for the controlled photothermal therapy in practical
application.
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
C
D
Figure 4. (A) Temperature elevation of water and aqueous dispersion of GNRs@mSiO2 and
GNRs@mSiO2-ICG under 2 W cm-2 808 nm irradiation, (B) Temperature elevation of aqueous
dispersion of GNRs@mSiO2-ICG2 with different power density (1, 2 and 3 W cm-2) as a function
of irradiation time. (C) Temperature evolution of the dispersion of GNRs@mSiO2-ICG2 during
heating (laser on) and cooling (laser off). (D) Thermal equilibrium time constant of the four
systems determined by fitting the time data versus negative natural logarithm of the driving force
temperature from the cooling period. Sample concentration is 0.5 mg mL-1.
As we all known, ICG molecules can absorb NIR to reach the high vibration energy
level of excited state. Then it does not only generate thermal energy but also ROS
during the deactivation process. The 1O2 generation of GNRs@mSiO2-ICG NPs upon
808 nm irradiation was assessed by monitoring the photo degradation of
diphenylisobenzofuran (DPBF), which is a widely used singlet oxygen detector.
Figure 5A shows the UV/Vis spectra of DPBF cultured with GNRs@mSiO2-ICG2
after 808 nm NIR irradiation (2 W cm-2) for 0-80 min. From Figure 5A, the typical
absorption of DPBF significantly decreases with 808 nm irradiation, implying the
efficient generation of 1O2 from GNRs@mSiO2-ICG. In addition, the decay curves of
DPBF absorbance at 407 nm incubated with different samples as a function of
irradiation time was summarized in Figure 5B. GNRs@mSiO2 does not give notable
degradation of DPBF even on exposure to 808 nm NIR for 80 min, whereas
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
GNRs@mSiO2-ICG shows a clear degradation of DPBF. Increasing the loading
amount of ICG, the sample reveals enhanced degradation activation as well as
1
increased O2 generation. With most amount of ICG, GNRs@mSiO2-ICG2 possess
1
the most generation of O2. The above results indicated that GNRs@mSiO2-ICG NPs
could be used as a photothermal and photodynamic agent for simultaneous PDT/PTT
therapy triggered by single 808 nm laser.
Figure 5. (A) UV/Vis spectra of DPBF after irradiation of GNRs@mSiO2-ICG2 with 808 nm NIR
(2 W cm–2) for 0 to 80 min and (B) the decay curves of DPBF absorbance at 407 nm in different
solutions as a function of irradiation time.
2.3. Drug release profiles
To further insure the triggered release behaviors of these nanocomposites, sensitive
Se-Se linker was synthesized to encapsulate drug molecules in the mesopore and the
corresponding controlled release was investigated as shown in Figure 6. From Figure
6A, all the samples display the GSH triggered DOX release, distinctly. In the absence
of GSH, GNRs@mSiO2-ICG-DOX@Se-Se1, GNRs@mSiO2-ICG-DOX@Se-Se2 and
GNRs@mSiO2-ICG-DOX@Se-Se3 all show the low release rate with few release
amounts below 14.15 % within 48 h. With GSH in the media, the release rates were
enhanced remarkably and the release amount of DOX can reach as high as 85.13 %,
80.03
%
and
73.77
%
for
GNRs@mSiO2-ICG-DOX@Se-Se1,
GNRs@mSiO2-ICG-DOX@Se-Se3,
GNRs@mSiO2-ICG-DOX@Se-Se2
and
respectively. In addition, the amount of Se-Se linker also influences the release
performance. As exhibited in Figure 6A, with the least amount of Se-Se linker,
GNRs@mSiO2-ICG-DOX@Se-Se1 possesses the highest DOX release up to 85.13 %
(with GSH), while the most DOX leak about 14.15 % (without GSH) also can be
found from GNRs@mSiO2-ICG-DOX@Se-Se1 due to the insufficient Se-Se linker.
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European Journal of Inorganic Chemistry
However, too much Se-Se linker also is not insufficiency owing to its low drug
release (73.77 % of GNRs@mSiO2-ICG-DOX@Se-Se3) even with GSH. Here,
GNRs@mSiO2-ICG-DOX@Se-Se2 was thought to be the appropriate one to reveal
the low leak without GSH and the high release amount with GSH. Moreover, the
effect of GSH concentration on the DOX release was also investigated by varying 5,
10, and 20 mM of GSH in media. From Figure 6B, 5 mM of GSH induces 62.99 %
DOX release at 24 h, and that aggrandizes to 83.03 % and 91.00 % with the increase
of GSH to 10 and 20 mM, respectively. The GSH concentration-dependent drug
release as shown in Figure 6B further confirms the GSH-sensitive DOX release
behavior of GNRs@mSiO2-ICG-DOX@Se-Se. From Figure 2B, the Zeta potential of
GNRs@mSiO2-ICG-DOX@Se-Se treated with GSH drops to -1.52 mV, due to the
fact that the sensitive Se-Se bond can be broken by some reducing agents, including
GSH, to form –Se-H group with negative charge. In view of the above investigation,
it is believed that the sensitive release behavior is owing to the Se-Se linkers. They
were used as nanovalves and modified outside mesopore to inhibit drug leak. With
GSH, the Se-Se linker was cleaved to induce nanovalves open and drug release. That
is significant for the specific drug release to tumor fractions with high concentration
of GSH and low leak in normal tissue (low concentration of GSH).
Figure 6C shows the release profiles of GNRs@mSiO2-ICG-DOX@Se-Se2 under
different light irradiation intensities. To avoid the photothermal effect, the irradiation
was introduced 2 min every half an hour and without any insulation measure. In
compared with the dark condition, 808 nm NIR light accelerates the release rate. By
increasing the irradiation times, the release amount increases as well. It takes 2 h
(with irradiation for 8 min) for GNRs@mSiO2-ICG-DOX@Se-Se2 to reach 6.02 %
release, and after 8 h (with irradiation for 32 min) the release raise to 25.31 % (1 W
cm-2). Further elevating the irradiation intensity, the release can be enhanced to
33.31 % (2 W cm-2) and 37.75 % (3 W cm-2). It is known that Se-Se bond is cleavable
not only by reducing agents, but also by oxidizing agent. Based on the above
investigation in Figure 5, NIR simulates GNRs@mSiO2-ICG to induce ROS
generation, which could disrupt Se-Se linker and cause drug release. In addition, the
broken of Se-Se bond under NIR was also monitored by Zeta potential. From Figure
2B, Zeta potential of GNRs@mSiO2-ICG-DOX@Se-Se2 treated by NIR decreases
from 5.70±0.81 to -0.52±0.20 mV, because the oxidization of Se-Se bond leaves
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
–Se-OOH at the surface. In addition, the release performance with continuous NIR
irradiation was carried out. From Figure 6D, when 808 nm NIR was introduced for 10
min, 22.19 % DOX release can be detected. Prolonging the illumination to 20 and 30
min, the release aggrandizes to 30.54 % and 47.92 %, respectively. Further extending
the irradiation to 40 min, the release increases slowly to 50.36 %, tending to its
equilibrium.
To further study the release performance of GNRs@mSiO2-ICG-DOX@Se-Se2 under
different conditions, Higuchi model was used to treat these release data. As we known,
drug release kinetics from an insoluble porous carrier matrix are frequently described
by the Higuchi model, and the release rate could be described by the equation (2):
Q = 푘t1
(2)
⁄
2
in which Q denotes the amount of drug released from the materials, t is time, and k is
the Higuchi dissolution constant. According to the model, for a purely
diffusion-controlled process, the linear relationship is valid for the release of
relatively small molecules distributed uniformly throughout the carrier. As shown in
Figure 6E, without GSH and irradiation, dissolution constant k equals to 1.69. That
increases remarkably to 14.31, 23.39 and 35.26 with addition of GSH to 5, 10 and 20
mM, owing to GSH-triggered Se-Se linker broken and drug release. And the higher
concentration of GSH can induce the faster linker disruption as well as the higher
dissolution constant. The pulsing irradiation also induces the dissolution constant rise
to 10.78-16.32. Increasing the irradiation intensity to 3W cm-2, k grows to 16.32, due
to more ROS generation. By comparing the release performances, GSH makes the
higher k and release amount than that of illumination. From Figure 2B,
GNRs@mSiO2-ICG-DOX@Se-Se treated by GSH (-1.52 mV) possesses the lower
Zeta potential than that of the treated by 808 nm NIR (-0.52 mV). This means that
under these conditions, GSH is more effective to induce the bond broken than
illumination (ROS generation). In addition, the continuous 808 nm illumination leads
to the highest dissolution constant of all (k=63.60). The continuous 808 nm
illumination causes not only ROS generation but also photothermal effect, which can
accelerate the diffusion of DOX out. Even so, the release amount (50.36 %) is also
less than that of GSH (62.90-91.00 %).
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European Journal of Inorganic Chemistry
Figure 6. (A) Release profiles of GNRs@mSiO2-ICG-DOX@Se-Se1(a, d),
GNRs@mSiO2-ICG-DOX@Se-Se2(b, e) and GNRs@mSiO2-ICG-DOX@Se-Se3(c, f) with (a-c)
and without (d-f) 10 mM of GSH, (B) Release profiles of GNRs@mSiO2-ICG-DOX@Se-Se2
with different concentration of GSH, (C) Release profiles ofGNRs@mSiO2-ICG-DOX@Se-Se2
under vary irradiation intensities (every 30 min with irradiation for 2min), (D) Release profiles of
GNRs@mSiO2-ICG-DOX@Se-Se2 with continues illumination, (E) Release Higuchi plot of
DOX released with different release conditions.
2.4 Cell experiments
In order to observe the uptake and subsequent localization of
GNRs@mSiO2-ICG-DOX@Se-Se2-FA, the nanocomposites (500 μg mL-1) were
pre-incubated with the HepG2 cells for 1, 3 and 6 h in the dark and then 808 nm
irradiation for 20 min. As can be seen from Figure 7, the red (DOX, 480 nm) emission
can be found in cytoplasm, implying these nanocomposites have been internalized by
HepG2 cells through endocytosis or macropinocytosis owing to nano-size particles
and -FA targeting. Furthermore, with extending the incubated time, the red
fluorescence emission is enhanced, ascribing to the time-dependent uptake of
GNRs@mSiO2-ICG-DOX@Se-Se2-FA into HepG2. Under 808 nm illuminating,
more red-fluorescence emission emerges in cell nucleus, indicating a continuous
released DOX molecules gathering into nucleus to improve the chemotherapy.
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
Bright Fields
DAPI
DOX
Overlap
1 h
3 h
6 h
6 h
+
NIR
Figure 7.Colocalization fluorescent images recorded for HepG2 cells after incubation with
GNRs@mSiO2-ICG-DOX@Se-Se2-FA (500 μg mL-1) for 1, 3, 6 h and 6 h with 808 nm NIR.
ROS are generally short-lived molecules and can oxidize plenty of
macromolecules, such as DNA and proteins, which stimulates inflammation and
initiates pro-apoptotic cellular signaling, resulting in the irreversible cell damage. So
the level of intracellular ROS has a great effect on PDT. Here, the intracellular ROS
generation of HepG2 cells incubated with GNRs@mSiO2-ICG-FA was surveyed by
using DCFH-DA as an indicator, which is oxidized to form, 2’7’-dichlofluorescein, a
green fluorescent substance inside cells. As shown in Figure 8, strong green
fluorescence is observed in HepG2 co-cultured with GNRs@mSiO2-ICG-FAunder
808 nm irradiation. However, without NIR irradiation or GNRs@mSiO2-ICG-FA,
there is not remarked green fluorescence in cells. From Figure 8, the intracellular
ROS generation induces GNRs@mSiO2-ICG-FA can be adopted as PDT agent. And
the visualized change of cell survival incubated GNRs@mSiO2-ICG-FAwith 808 nm
irradiation was also recorded by using Calcein AM as living cells dye (Figure S4).
The decrease green fluorescence is ascribed to NIR light-triggered cytotoxicity,
derived from intracellular heat and ROS generation.
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
Bright Fields
DCFH
Control
Control
+
NIR
Materials
Materials
+
NIR
Figure 8.Bright-field and fluorescence images of HepG2 cells after the co-incubation with
GNRs@mSiO2-ICG-FA for 12 h. First row: no GNRs@mSiO2-ICG-FA no NIR light, Second row:
no GNRs@mSiO2-ICG-FA, with NIR light, Third row: GNRs@mSiO2-ICG-FA, no NIR light,
Fourth row: GNRs@mSiO2-ICG-FA and NIR light irradiation (500 μg mL-1, 808 nm, 2 W cm-2,
20 min).
Besides, MTT assay was carried out to further quantificationally analyze the
cytotoxicity of these nanocomposites. The viabilities of HepG2 cells incubated with
different
concentrations
of
GNRs@mSiO2-FA,
GNRs@mSiO2-ICG-FA,
GNRs@mSiO2-ICG-DOX@Se-Se-FA and GNRs@mSiO2-ICG-DOX@Se-Se-FA
with NIR irradiation (2 W cm-2) were summarized in Figure 9. From Figure 9,
GNRs@mSiO2-FA and GNRs@mSiO2-ICG-FA do not show obvious toxicity
towards to HepG2 cells. Even when the concentration rises to 125 μg mL-1, the cell
survival rate remains at 82.67±1.44% and 81.44±1.32%, respectively.
GNRs@mSiO2-ICG-DOX@Se-Se-FA
displays
the
significant
concentration-dependent cell viability. With the increase concentration to 125 μg mL-1,
the cell viability drops to 53.44±2.44%, owing to the intracellular GSH-triggered
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
DOX release. When 808 nm NIR is introduced, the cell viability further decreases to
34.21±1.90 % (125 μg mL-1). The decreased cell viability is mainly attributing to the
combination effect of chemotherapy and PDT/PTT as above investigation. It is known
that the HeLa cell (cervical cancer cell line) possesses high expression of FA-receptor
and cell experiment of HeLa cell treated by GNRs@mSiO2-ICG-DOX@Se-Se-FA
was also carried out as contrast. And the lower cell viability toward HeLa cell
(32.17±2.30 %) than that in HepG2 (34.21±1.90 %) is ascribed to the FA targeting.
Figure 9. Viability of HepG2 and HeLa cells incubated with different concentration of
nanocomposites with and without NIR irradiation (808 nm, 2 Wcm-2 for 20 min).
3 Conclusions
In this chapter, the NIR sensitive GNRs@mSiO2 core-shell nanopartiles were
prepared as host. mSiO2 shell not only remained the monodispersity of GNRs but also
supplied plenty of space for drug storage. By adjusting the surface charge,
photosensitizer ICG and anti-cancer drug DOX can be loaded in the mesopore in
succession depending on the electrostatic interaction. Here, redox response Se-Se
linkers were synthesized to block the orifice and to inhibit drug leakage. The
nanocomposite displayed the GSH-dependent DOX release. Moreover, under NIR
irradiation, the ROS generation also can degrade Se-Se nanovalves to induce DOX
release. Under the investigation of the release kinetics, reduction is more efficient to
induce Se-Se linker broken than oxidation. In addition, the detailed cell experiments
by using HepG2 as typical cancer cells further showed the improved cytotoxicity
owing to the fast uptake, specific chemotherapy and PTT/PDT. These novel
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
advantages also make GNRs@mSiO2-ICG-DOX@Se-Se-FA as a potential candidate
agent for targeted anticancer.
4 Experimental sections
4.1 Materials
All of the chemicals were analytical grade and were used without further purification.
.
chloroauric acid (HAuCl4 3H2O), silver nitrate (AgNO3), hexadecyltrimethyl
ammonium bromide (CTAB), tetraethyl orthosilicate (TEOS), selenium powder,
sodium borohydride (NaBH4), 3-bromo-1-propanol, 3-(triethoxysilyl) propyl
isocyanate,
doxorubicin
hydrochloride
(DOX),
glutathione
(reduced),
N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC), ascorbic
acid, (3-aminopropyl)triethoxysilane(APTES), N-Hydroxysuccinimide (NHS), and
folic
acid
(FA),
were
obtained
from
Aladdin,
(MTT)
China.
and
3-[4,5-dimethylthialzol-2-yl]-2,5-diphenyltetrazolium
bromide
1-octadecene were purchased from Sigma-Aldrich. Dimethyl sulfoxide (DMSO),
hexahydrate, ethanol, n-hexane, dichloromethane, ethyl acetate and tetrahydrofuran
(THF) were purchased from Tianjin Chemical Corp. of China.
4.2 Instruments
Samples were characterized by transmission electron microscopy (TEM Hitachi
H-8100) at an accelerating voltage of 20 kV. X-ray diffraction (XRD) date is
characterized using a Siemens D5005diffractometer with Cu Ka radiation at 40 kV
and 30 mA. A Fourier transform infrared (FT-IR) spectroscopy spectrometer
(JASCOFT/IR-420) was used to record the infrared spectra of all samples. Zeta
potential was carried out on the Brookhaven. Ultraviolet-visible (UV-Vis) spectra
were taken on a SHIMADZU UV-2550 spectrophotometer. The isotherms of N2
adsorption/desorption were measured at the temperature of liquid nitrogen using a
Micromeritics ASAP 2010M system. The pore size distributions were calculated from
the N2 adsorption isotherms using the Barrett-Joyner-Halenda model. The
fluorescence imaging experiments were carried out on the Leica DFC450C
Microsystems Ltd. using a 10 × objective.
4.3 Synthetic procedures
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
Synthesis of GNRs：GNRs was synthesized by seed-mediated growth by following
procedures described by Jana and Nikoobakht31. CTAB solution (0.20 M, 5 mL) was
mixed with HAuCl4 solution (0.5 mM, 5 mL), then ice-cold NaBH4 solution (0.01 M,
0.60 mL) was added and the mixture was stirred vigorously for 2 min at 25℃
(formation of a brownish yellow seed solution). The growth solution was made by
adding AgNO3 (4 mM, 0.25 mL) and then HAuCl4 (1 mM, 5 mL) to CTAB solution
(0.20 M, 5 mL), under gentle mixing, followed by the addition of ascorbic acid
solution (0.0788 M, 70 μL). To grow nanorods, the seed solution (12 μL) was added
to the growth solution at 27–30℃. The color of the solution changed to burgundy
within 10–20 min. The solution was then centrifuged at 12000 rpm for 15 min, and
the collected CTAB gold nanorods were redispersed in deionized water.
Synthesis of GNRs@mSiO2 The as-synthesized gold nanorods were dispersed in
：
deionized water (10 mL), then 0.1 M NaOH solution was added (pH adjusted to 10)
with vigorous stirring. Three 30 μL injections of 20% TEOS in ethanol were added
under gentle stirring at 30 min intervals. The mixture was stirred for 48 h at 32 ℃,
and the obtained mesoporous silica coated gold nanorods were collected and washed
several times with ethanol to remove the unreacted species. At last, the collected
products were refluxing in methanol (1wt% NaCl) for 3 h at room temperature to
remove the template CTAB.
Synthesis of Diselenide linker (Se-Se linker)：Selenium powder (6.3 mM) was
added to 25 mL of water containing dissolved NaBH4 (13.2 mM) with magnetic
stirring in the ice bath. After the initial vigorous reaction had subsided (10 min), an
additional selenium powder (6.3 mM) was added. The mixture was stirred for 15 min
and then warmed in a steam bath to complete the dissolution of the selenium. A
brownish red aqueous solution of Na2Se2 was obtained32, 33, 34
.
The Na2Se2 solution was removed to a 100 mL flask, which was sealed with a rubber
plug, and then a solution of 1.7513g (12.6 mM) 3-bromo-1-propanol in 20 mL of
anhydrous THF was injected into it under N2 flow. The reaction was performed at
50 ℃ for 6 h and the obtained solution was extracted three times with 20 mL of
CH2Cl2 and dried with anhydrous Na2SO4. The product was then purified by column
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
chromatography with a 1:1 mixture of CH2Cl2 and ethyl acetate as the eluent. A
yellow transparent liquid was obtained with a yield of 45% (HO-Se-Se-OH). 1HNMR
(200 MHz) δ3.78 (t, J=6.2 Hz, 4 H), 3.04 (t, J= 7.2 Hz, 4 H), 2.02 (quintet, J= 6.6 Hz,
4 H), 1.68 (br s, 2 H).
(1.35 mM) HO-Se-Se-OH was dissolved in 5 mL of anhydrous THF in a 20 mL flask
and sealed with a rubber plug. The flask was then degassed by Ar for 20 min.
3-(triethoxysilyl) propyl isocyanate (1.49 mM) in 2 mL anhydrous THF was injected
into the flask under Ar flow. The system was transferred into an oil bath at 50 ℃ to
react for 12 h with stirring.
Synthesis of GNRs@mSiO2-ICG-DOX@Se-Se：First, 30 mg of GNRs@SiO2 was
added to 8 mL of anhydrous methanol and stirred for 10 min before adding of APTES
(10, 20 and 30 μL), then stirring at room temperature for 12 h. The nanoparticles were
collected by centrifugation, washed three times with methanol to obtain
GNRs@mSiO2-NH2. And then, the above sample and 3 mg of ICG were added to 8
mL of anhydrous methanol and stirred for 12 h (The obtained samples are named as
GNRs@SiO2-ICG1, GNRs@SiO2-ICG2 and GNRs@SiO2-ICG3, respectively). Later,
DOX (8 mg) was added and stirring for another 12 h. Finally, Se-Se linker (5, 10 and
15 μL) was dropwised to the mixed solution. The obtained solids (named as
GNRs@SiO2-ICG-DOX@Se-Se1,
GNRs@SiO2-ICG-DOX@Se-Se2,
GNRs@SiO2-ICG-DOX@Se-Se3, respectively) were centrifuged, washed several
times with methanol solution and dried for backup. The amount of DOX and ICG
loading was estimated by UV-Vis spectroscopy at 480 and 783 nm. The loading ratio
(LR wt %) was ascertained by using the formula (3) and (4). The experiments were
repeated three times.
m(initial DOX) − m(
residual DOX
LR wt% =
LR wt% =
) × 100%
(3)
(4)
m(total sample)
m(
) − m(
)
residual ICG
initial ICG
× 100%
m(
)
total sample
Synthesis of FA-Modified GNRs@mSiO2-ICG-DOX@Se-Se：In a typical reaction,
folic acid (441.4 mg), EDC (191.7 mg), NHS (115.1 mg) and APTES (442.7 mg)
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10.1002/ejic.201800572
European Journal of Inorganic Chemistry
were added to DMSO (2 mL). The reaction mixture was reacted for 24 h with stirring
at room temperature. The as-synthesized FA-APTES (100 μL) and
GNRs@SiO2-ICG-DOX@Se-Se (60 mg) were added to methanol (5 mL), and the
reaction mixture was stirred for 24 h. The product was washed twice with methanol to
remove any unreacted species.
In vitro drug release ： To evaluate the drug release properties, the dried
GNRs@SiO2-ICG-DOX@Se-Se nanoparticles were exposed to PBS of pH 6.5 with
10 mM GSH or not. Then the in vitro drug release was performed at 37 ℃. The
solution was taken out to determine the release amount by UV-Vis at different time
intervals. The cumulative drug release was calculated according to the following
formula (5):
mt
⁄
( )
Cumulative drug release % =
× 100% (5)
m
Where mt is the amount of DOX released at time t and m is the total DOX amount
loaded in the nanoparticles.
Photothermal：A volume of 2 mL of sample solution (0.5 mg mL-1) was added to
cuvette and irradiated with 808 nm laser (1, 2 and 3 W cm-2) and the temperature was
recorded every 2 min with Fluke 59 infrared thermometer.
Extracellular singlet oxygen detection：The generation of singlet oxygen was
measured by using DPBF as probe. In a typical process, 1 mg of GNRs@SiO2-ICG
was dispersed well in 2 mL of DPBF solution (0.5 mg mL-1) with stirring in the dark.
Then the mixture was irradiated with 808 nm NIR laser for various time periods. The
generation of singlet oxygen was demonstrated by the characteristic absorbance of the
DPBF using a UV-Vis absorption spectrum.
Cell culture:HepG2 cells (human hepatoma cells) were incubated in monolayer in
Dulbecco's Modified Eagle's Medium (DMEM, Hyclone) supplemented with 10%
(v/v) fetal bovine serum (FBS, Gibco) with 100 U mL-1of penicillin and 100 mg mL-1
of streptomycin under a humidified atmosphere at 37 ℃ with 5 % CO2.
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European Journal of Inorganic Chemistry
Fluorescence imaging: To analyze the ability of cellular internalization, HepG2 cells
were cultured in a 6-well plates with the incubation medium (DMEM) for 24 h.
GNRs@SiO2-ICG-DOX@Se-Se2 was added into the incubation medium at the
concentration of 500 μg mL-1 with the same cell culture condition. After incubation
for 6 h, the medium was removed and the cell was washed twice with PBS (pH = 7.4),
then the fluorescence imaging experiments were carried out on the Leica DFC450 C
Microsystems Ltd. using a 10× objective.
Vitro cell assay: HepG2 cells were used to carry out for MTT test. The cell viability
after treated with the nanoparticles was investigated using MTT assay. The assay was
carried out in five times with the same manner. For the MTT assay, 1×104/well
HepG2 cells were seeded into 96-well plates in 100 μL of media and grown for 24 h
to allow cell attachment. Then the cells were incubated with samples under different
concentrations for 24 h. Afterwards, 20 μL of MTT (5 mg mL-1) solution were added
to the incubation media for 4 h in dark. Upon the removal of MTT solution, the
precipitated formazan violet crystals generated by live cells were dissolved in 150 μL
of dimethyl sulfoxide (DMSO). The absorbance was quantified by a microplate reader
(Bio-TekELx800) with the wavelength of 492 nm. The cytotoxicity was expressed as
the percentage of cell viability compared to untreated cells. The cell viability was
calculated as follows:
Isample
⁄
( )
Cell viability % =
( )
6
× 100%
Iuntreated
Acknowledgements
This work was supported by the National Natural Science Foundation of China
(21471041, 21571045), and College Youth Innovation Talents Training Program of
Heilongjiang Province of China UNPYSCT-2015053.
Supporting information (see footnote on the first page of this article): The synthetic
approach of the as-synthesized Se-Se linker; drug loading; additional results and
analyses of TEM images, UV-Vis spectra, release curves and fluorescence images.
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European Journal of Inorganic Chemistry
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TOC
GNRs@mSiO2 core-shell nanoparticles were synthesized as host to load ICG
and DOX molecules by layer-by-layer assembly method depending on the
electrostatic interaction. Sensitive Se-Se linker was synthesized and grafted outside to
insure the controlled release. Under NIR irradiation, the enhanced cytotoxicity to
cancer cells is derived from the synergistic effect of chemotherapy, PTT, and PDT.
26
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