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Biological and Medical Applications of Materials and Interfaces
Rhenium Sulfide Nanoparticles as a Biosafe Spectral CT Contrast Agentfor Gastrointestinal Tract Imaging and Tumor Theranostics in vivo
Xiaoyi Wang, Jiaojiao Wang, Jinbin Pan, Fangshi Zhao,Di Kan, Ran Cheng, Xuening Zhang, and Shao-Kai Sun
ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b10479 • Publication Date (Web): 26 Aug 2019
Downloaded from pubs.acs.org on August 28, 2019
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Rhenium Sulfide Nanoparticles as a Biosafe Spectral CT Contrast Agent for Gastrointestinal Tract Imaging and Tumor Theranostics in vivo
Xiaoyi Wang,‡,# Jiaojiao Wang,†,# Jinbin Pan,§ Fangshi Zhao,§ Di Kan,† Ran Cheng,†
Xuening Zhang,*,‖ and Shao-Kai Sun*,†
†School of Medical Imaging, Tianjin Medical University, Tianjin 300203, China
‡Department of Radiology and Ultrasound, The Second Hospital of Tianjin Medical
University, Tianjin 300211, China
§Department of Radiology, Tianjin Key Laboratory of Functional Imaging, Tianjin
Medical University General Hospital, Tianjin 300052, China
‖ Department of Radiology, The Second Hospital of Tianjin Medical University,
Tianjin 300211, China
KEYWORDS: Rhenium sulfide, Biosafety, Spectral CT imaging, Gastrointestinal tract,
Tumor theranostics
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ABSTRACT: Spectral CT imaging as a novel imaging technique shows promising
prospects in accurate diagnosis of various diseases. However, clinical iodinated
contrast agents suffer from poor signal-to-noise ratio, and emerging heavy
metal-based CT contrast agents arouses great biosafety concern. Herein, we show
the fabrication of rhenium sulfide (ReS2) nanoparticles, a clinic radiotherapy
sensitizer, as a biosafe spectral CT contrast agent for gastrointestinal tract imaging
and tumor theranostics in vivo by teaching old drugs new tricks. The ReS2
nanoparticles were fabricated in a one-pot facile way at room temperature, and
exhibited sub-10 nm size, favorable monodispersity, admirable aqueous solubility
and strong X-ray attenuation capability. More importantly, the proposed
nanoparticles own outstanding spectral CT imaging ability and undoubted biosafety
as a clinic therapeutic agent. Besides, the ReS2 nanoparticles possess appealing
photothermal performance due to their intense near-infrared absorption. The
proposed nanoagent not only guarantees obvious contrast enhancement in
gastrointestinal tract spectral CT imaging in vivo, but also allows effective CT
imaging-guided tumor photothermal therapy. The proposed “teaching old drugs new
tricks” strategy shortens the time and cuts the cost required for clinical application of
nanoagents based on existing clinical toxicology testing and trial results, and lays
down a low-cost, time-saving and energy-saving way for the development of
multifunctional nanoagents toward clinical applications.
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INTRODUCTION
Contrast agents-enhanced computed tomography (CT) imaging is of immense value
in clinic examinations owing to the advantages of great spatial resolution, short
scanning time, deep tissue penetration, and 3D visualization for tissues of interest,
and frequently used in disease diagnosis in clinic.1-6 The conventional CT
distinguishes tissues with different X-ray attenuation by a polychromatic beam, which
makes it challenging in differentiating accumulated contrast agents (CA) from
surrounding tissues in enhanced CT scanning.1-6 The emerging spectral CT based
on dual-energy imaging technique and multidetector imaging technique make it
possible to differentiate different matters.7-9 Spectral CT employs a more precise
detector, images at multiple single-photon energy points, and thus can reflect the
change information of X-ray absorption of the matter at different energies.7
Multidimensional information such as monochromatic images, spectral Hounsfield
unit (HU) curves, material decomposition, and effective atomic number can be
acquired in spectral CT scanning, enabling material differentiation by acquisition of
energy-independent basis material density.8 In addition, monochromatic energy
images in spectral CT can reduce beam hardening artifacts and metal artifacts, and
improve signal-to-noise ratio.7-8 These extraordinary advantages make spectral CT
promising in accurate diagnosis of various diseases.7-13
Iodinate small molecules have been used in contrast-enhanced CT imaging in
clinic for more than 20 years, and substantively new contrast agents have not been
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developed up to now.5 However, the low signal-noise ratio derived from the low
K-edge of iodine (33.2 keV) makes iodinate small molecules and iodine-based
nanomaterials unsatisfactory for spectral CT imaging.8-9 Recently, sensitive CT
nanoagents containing metal elements with high atomic number, such as Ag14,
Yb15-16, Lu17, Ho18, Hf19, Ta20, W21-23, Au24, Bi25-34, and Re35-38-based nanostructures,
have been successfully utilized for enhanced CT imaging. The high atomic number
elements endow these metal-contained nanoparticles with excellent superiority in
spectral CT, and still keep high X-ray attenuation capability at higher peak operation
voltage settings.7-13 Despite the significant progress, these nanomaterials still suffer
from great biosafety concerns for clinical applications.8 Therefore, it is highly desired
to develop novel contrast agents with high X-ray absorption ability and good
biocompatibility for spectral CT imaging.
The high-cost and time-consuming nature of new drug development make new
drug discovery great challenging. The confirmation of efficiency and safety of a new
drug may require several years or decades. Converting the indications of existing
drugs from one theranostic area to another one, in another word, teaching old drugs
with new tricks, is an alternative way for drug discovery, which shortens the time and
cuts the cost required for clinical implementation based on existing drug clinical
toxicology testing and trial results. Recently, several amazing new functions have
been discovered from old drugs.39-40 For instance, lanosterol has been found to
significantly decrease performed protein, reduce cataract severity and increase
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transparency in vivo, providing a charming pharmacological way for cataract
treatment without surgery.41 More encouragingly, Fe3O4 nanoparticles as a magnetic
resonance imaging contrast agent approved by Food and Drug Administration (FDA)
have been demonstrated to possess intrinsic therapeutic effect for early metastases
of breast and lung cancers, beginning an iron age for cancer treatment.42 Inspiringly,
brand new functions are highly expected to be explored from old drugs for spectral
CT imaging.
Transition metal dichalcogenide (TMD) nanomaterials,43-45 such as TiS2,46 FeS2,47
MoS248-49, WS222-23, 50 and Bi2S334 nanostructures, have shown a bright future in
biomedical sensing, imaging and therapy due to their attractive physiochemical
features, especially for medical theranostics. Among various TMD nanomaterials,
rhenium sulfide (ReS2) nanoagent is an effective drug that has been applied in
preclinical study for tumor radiotherapy in mice51-53 and effective radiation
synovectomy54-58 as well as sentinel node detection cooperated with 99mTc in human
body.59-63 ReS2 nanoagent also possesses great potential of spectral CT imaging
based on its expectable strong X-ray absorption ability resulted from the high atomic
number of Re element (Z = 75).8, 35-36 Thus, ReS2 nanoparticles are an excellent
candidate to be endowed with new functions for noninvasive spectral CT imaging
with definite biosafety. Besides, the strong near-infrared (NIR) absorption endows
ReS2 nanoparticles with excellent photothermal therapy ability. Very recently, ReS2
nanostructures have been developed for CT/photoacoustic/SPECT imaging-guided
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photothermal radiotherapy for tumors, but the spectral CT imaging potential of ReS2
nanoparticles has not been explored so far.35-36
Herein, we show a “teaching old drugs new tricks” strategy to employ ReS2
nanoparticles, a model old nanodrug for preclinical radiotherapy sensitizer, for
gastrointestinal (GI) tract spectral CT imaging as well as spectral CT imaging and
photothermal therapy of tumors in vivo. The sub-10 nm ReS2 nanoparticles with
excellent monodispersity and water solubility were fabricated in a one-pot facile
procedure at room temperature. The nanoagent not only exhibits impressive spectral
CT imaging ability and photothermal conversion performance, but also owns
convincingly neglectable cytotoxicity and in vivo toxicity as a preclinical drug. ReS2
nanoparticles were successfully applied in GI tract spectral CT imaging and
CT-guided photothermal therapy of tumors (Scheme 1). To the best of our
knowledge, ReS2 nanoparticles are used as a high-performance and biosafe spectral
CT imaging contrast agent for theranostics in vivo for the first time.
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Scheme 1. Schematic illustration of ReS2 nanoparticles for GI tract spectral CT
imaging and tumor theranostics based on the strategy of “teaching old drugs new
tricks”.
RESULTS AND DISCUSSION
Synthesis and Characterization of ReS2 Nanoparticles. To demonstrate the
feasibility of “teaching old drugs new tricks” strategy, ReS2 nanoparticles as an old
drug model were synthesized via a one-pot facile method at room temperature.64
Briefly, sodium perrhenate and sodium thiosulfate were dissolved in ethylene glycol.
Upon addition of HCl into the mixture, the colorless solution became almost black
gradually, indicating the formation of ReS2 nanoparticles. After a short reaction time
for 40 min, NaOH aqueous solution was introduced to adjust the pH into neutral in
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order to terminate the reaction. It should be noted that the appropriate amount of
NaOH is essential, and excessive NaOH will lead to the potential decomposition of
ReS2 nanoparticles. The HRTEM image indicated the as-prepared ReS2
nanoparticles exhibited uniform sphere morphology with a small size of 3 ± 0.21 nm
(Figure 1a). The hydrodynamic diameter of the nanoparticles was determined to be
10 ± 0.31 nm by dynamic light scattering (DLS) analysis (Figure S1). The small size
and uniform morphology of as-prepared ReS2 nanoparticles benefitted their
biomedical applications. The XRD pattern of the ReS2 nanoparticles is consistent to
previous reports (Figure S2).35, 37-38 The X-ray photoelectron spectroscopy (XPS)
spectra showed compound state of Re and S. Two distinct peaks at 44.4 and 42.1
eV in the spectrum of Re corresponded to the Re 4f5/2 and Re 4f7/2 states,
respectively (Figure 1b). The core 2p1/2 and 2p3/2 level peaks of sulfur were located
at 164.5 and 163.0 eV (Figure 1c). The XPS characterization confirmed the
formation of ReS2 nanoparticles.35, 37-38 FT-IR spectra of ReS2 nanoparticles gave a
strong absorption band of -OH stretch in the range of 3000-3600 cm-1 (Figure S3)
derived from the presence of ethylene glycol on the surface of the nanoparticles.
During the synthesis process, the solvent, ethylene glycol, not only played a crucial
role in the growth control of ReS2 nanoparticles but also were anchored on the
surface of the nanoparticles to make them monodispersed and water-soluble. Thus
ReS2 nanoparticles could be well dispersed in various media including water, PBS
and 10% culture medium for 3 days (Figures S4, S5). It was found that not only the
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colors of these solutions kept homogeneous without the formation of precipitation,
but also the nanoparticles’ size exhibited a neglectable change, showing excellent
colloidal stability of ReS2 nanoparticles.
The as-prepared ReS2 nanoparticles, a kind of semiconductor with a band-gap of
1.61 eV, exhibited strong near-infrared (NIR) absorption in the range of 600-900 nm
(Figure 1d).65 A good linear correlation was found between the absorption at 808 nm
and the concentrations of ReS2 nanoparticles, revealing their good aqueous
dispersity and favorable optical stability. The strong and stable NIR absorption
ensures a great potential of ReS2 nanoparticles in the application of photothermal
therapy.
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Figure 1. Synthesis and characterization of ReS2 nanoparticles. (a) HRTEM image of
ReS2 nanoparticles. (b) Re 4f XPS spectra and (c) S 2p XPS spectra of ReS2
nanoparticles. (d) UV-vis-NIR absorbance spectra of ReS2 nanoparticles with different
concentrations (0.02, 0.05, 0.08 and 0.10 mg/mL).
Photothermal Performance of ReS2 Nanoparticles. The strong NIR absorption
motivated us to investigate photothermal performance of ReS2 nanoparticles in vitro.
Various concentrations of nanoparticles were irradiated for 10 min by an 808 nm
laser at different power intensities (0.3, 1 and 3 W/cm2), and the temperature
changes of the solution were recorded by a thermocouple thermometer. Figures 2a,
S6 and S7 showed the temperature of ReS2 nanoparticles solutions increased
remarkably over time under laser irradiation in both concentration-dependent and
power intensity-dependent manner. The temperature of 0.5 mg/mL ReS2 solution
could increase by 45 °C with the illumination of 808 nm laser at the power density of
3 W/cm2 (Figure 2a), while the temperature of pure water only increased by 9 °C
under the same condition. The photothermal conversion efficiency (η) of ReS2
nanoparticles was calculated to be 27.63% (Figure S8). To obtain the visualized
temperature changes, infrared images of various solutions were taken during
photothermal heating process, and the results were consistent to those measured by
thermocouple thermometer (Figure 2b).
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Photothermal Stability of ReS2 Nanoparticles. To investigate the photothermal
stability, ReS2 nanoparticles solution (0.5 mg/mL) was irradiated by an 808 nm laser
(3 W/cm2) for 5 min, followed by shutting down the laser and naturally cooling the
solution for 5 min. This cycle was repeated for five times (Figure 2c). In the first
cycle, the temperature of ReS2 solution could elevate about 41 °C and in the
following four cycles they all achieved similar temperature enhancement (41-43 °C).
The solution of ReS2 nanoparticles before and after the illumination exhibited the
same color without the formation of precipitation. In addition, the absorption spectra
of ReS2 nanoparticles before and after five cycles of laser ON/OFF were both
recorded, and there was no obvious difference between them (Figure 2d). The above
results indicated that ReS2 nanoparticles not only owned admirable photothermal
efficacy, but also exhibited favorable photothermal stability.
Figure 2. Photothermal performance and stability of ReS2 nanoparticles. The
photothermal heating curves (a) and infrared images (b) of pure water and ReS2
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nanoparticles with concentrations of 0.05, 0.10, 0.25, 0.50 mg/mL under an 808 nm
laser irradiation (3.0 W/cm2) at room temperature. (c) Temperature changes of ReS2
nanoparticles over five cycles of exposure to an 808 nm laser at the power density of
3.0 W/cm2 (Laser ON: 5 min; Laser OFF: 5 min). (d) UV-vis-NIR absorbance spectra
of ReS2 nanoparticles before and after five photothermal heating cycles. Inserts are
photos of ReS2 solution before and after five photothermal heating cycles. (e)
Cellular viability after incubation with different concentrations of ReS2 nanoparticles
for 24 h. (f) Fluorescent images of 4T1 cells after treatments with ReS2 (0.1 mg/mL)
with or without an 808 nm laser exposure at the power density of 3.0 W/cm2 for 10
min and dual-staining. Cells incubated without ReS2 were regarded as control group.
Cytotoxicity Assessment of ReS2 Nanoparticles. The cytotoxicity of ReS2
nanoparticles was evaluated by a standard MTT assay. The cell viability of 4T1 cells
was recorded after incubated with various concentrations of ReS2 nanoparticles for
24 h. The cell viability kept more than 80% after exposure to ReS2 nanoparticles with
different concentrations even up to 0.12 mg/mL for 24 h, indicating low cytotoxicity of
ReS2 nanoparticles (Figure 2e).
Cellular Photothermal Therapy. The excellent photothermal performance in vitro
and low cytotoxicity motivated us to investigate the photothermal therapy of ReS2
nanoparticles in cellular level. 4T1 cells were incubated with ReS2 nanoparticles
(0.02, 0.04, 0.08, 0.1 mg/mL), followed by the irradiation of an 808 nm laser (3
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W/cm2) for 10 min. Then cell viabilities were evaluated by a standard MTT assay.
The combination of ReS2 nanoparticles treatment and laser illumination gave rise to
remarkable cell destruction in a concentration-dependent manner. Less than 15% of
cells survived when 4T1 cells were treated with 0.1 mg/mL ReS2 nanoparticles in
combination with laser irradiation. In contrast, the cells treated with ReS2
nanoparticles or laser illumination alone did not lead to an obvious cell death (Figure
S9). The fluorescent staining using Calcein-AM and PI was also performed to
differentiate the live and dead cells. The fluorescent images indicated only the
combination of ReS2 nanoparticles treatment and laser illumination could cause
destructive cell ablation (Figure 2f, S10). The above results demonstrated excellent
photothermal therapy capability of ReS2 nanoparticles against tumor cells.
CT and Spectral CT Imaging in Vitro. We further assessed the in vitro X-ray
attenuation ability of ReS2 nanoparticles via CT imaging in vitro compared with clinic
iohexol. The CT images revealed a significantly improved brightness with increasing
concentrations of ReS2 nanoparticles and iohexol. The Hounsfield units (HU) values
of both ReS2 nanoparticles and iohexol increased linearly with concentrations of Re
and I elements under the voltage of 120 kV (clinically used), respectively. Obviously,
ReS2 nanoparticles produced a higher CT imaging brightness and HU value than
iohexol with the same radiodense element concentrations. The above results
indicated ReS2 could produce equivalent contrast effect at a lower concentration
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compared with iohexol, while the reduced dosage requirement is of great
significance for patients due to the lower risk of side effects.
To investigate the feasibility of spectral CT imaging using ReS2 nanoparticles,
monochromatic images and spectral CT value curves of ReS2 nanoparticles and
clinic iohexol were acquired. There is a linear relationship between CT values and
contrast agent concentrations at different X-ray energies. When the energy
increased from 40 keV to 150 keV, the slope disparities between ReS2 nanoparticles
and clinic iohexol became more and more obvious at the equivalent concentrations
(Figure 3a-c). It is difficult to make a discrimination between ReS2 nanoparticles and
clinic iohexol under lower energy level (such as 60 keV) even at a high
concentration. However, compared with the sharp decline of CT values of iohexol
with the increase of energy, the CT values of ReS2 showed a slight decrease with
the increase of energy owing to the powerful X-ray attenuation capability of Re
element at high energy level (Figure 3d). These results demonstrated the superior
spectral CT imaging ability of ReS2 nanoparticles compared with iohexol.
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Figure 3. HU curves and monochromatic spectral CT images of different
concentrations (5-35 mM Re or I) of ReS2 and iohexol at (a) 60 keV, (b) 100 keV, (c)
140 keV; (d) The HU values and monochromatic spectral CT images of ReS2 (35
mM Re) and iohexol (35 mM I) at different monochromatic energies.
CT Imaging of GI Tract. The favorable CT imaging ability of as-prepared ReS2
nanoparticles revealed their feasibility for GI tract CT imaging as a biocompatible
contrast agent. For noninvasive and real-time GI tract imaging, Kunming mice were
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orally administered with ReS2 nanoparticles, followed by scanning on a CT imaging
system at different time points. The 3D-rendering CT images showed the stomach
and proximal small intestine were brightened at 5 min after oral administrations of
ReS2 nanoparticles, and then got clearer and clearer as time went on (Figure 4a).
After 3 h, a part of nanoparticles began to migrate to the distal small intestine. 72 h
later, all the nanoparticles were cleared from body, ensuring the minimal potential
reverse effects on organism. The above results demonstrated ReS2 nanoparticles
could serve as a reliable contrast agent in GI tract CT imaging for the examination of
various diseases of digestive systems.
Spectral CT Imaging of GI Tract. Then spectral CT imaging of GI tract was
investigated using the proposed ReS2 nanoparticles and iohexol. At 5 min after the
treatment of ReS2 nanoparticles or iohexol orally, the spectral CT images of kunming
mice were acquired under different energies. 3D-rendering images under different
energies (40-140 keV with a 20-keV increasement) were reconstructed by the
workstation. For conventional CT imaging, the contrast enhancement of GI tract was
detected at 5 min after oral administration of ReS2 nanoparticles, and the
surrounding tissues, such as bone, also showed a high background signal. For
spectral imaging, the CT contrast effect of ReS2 nanoparticles only showed a slight
decrease with the increasing X-ray energy due to the high K-edge value of Re
element (71.7 keV), while the CT signals of the surrounding tissue declined sharply,
making ReS2 an excellent spectral CT contrast for GI tract imaging with high
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signal-to-noise. In contrast, the brightness of iohexol-enhanced GI tract became
weaker drastically with the increasement of the X-ray energy derived from the low
K-edge energy of I (33 keV), which made it difficult to distinguish the contrast agent
from surrounding tissues (Figure 4b). These results clearly proved that ReS2 can be
employed as an excellent spectral CT imaging contrast agent for highly sensitive
imaging in vivo.
Figure 4. CT and Spectral CT imaging of GI tract using ReS2 nanoparticles and
iohexol in vivo. (a) CT images of upper GI tract at various time points after oral
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administration of ReS2 nanoparticles (400 µL, 10 mg/mL). (b) Spectral CT images of
upper GI tract at 5 min after oral administration of ReS2 nanoparticles (400 µL, 10
mg/mL ReS2: 35 mM Re) and iohexol (400 µL, 35 mM I).
CT Imaging of Tumors in vivo. To investigate in vivo CT imaging of tumors, 4T1
tumor-bearing mice were intratumorally injected with 100 μL of ReS2 aqueous
solution (5 mg/mL). The CT imaging was performed on a clinic GE HDCT system
before and after the injection of ReS2 nanparticles. The original HU value of tumor
region was increased from 30~50 to 110~150 immediately upon the injection of ReS2
nanoparticles (Figure S11). The precise CT direction of ReS2 nanoparticles in tumors
greatly benefits the spatially accurate irradiation with laser in subsequent
photothermal therapy.
Spectral CT Imaging of Tumors in vivo. To investigate spectral CT imaging of
tumors in vivo besides GI tract, 4T1 tumor-bearing mice were injected with 100 μL of
ReS2 aqueous solution (5 mg/mL) intratumorally. The spectral CT imaging was
carried out on a Siemens dual-source CT imaging system before and after the
treatment of the contrast agent. The obvious contrast enhancement of tumors was
observed after the administration of ReS2 nanoparticles at various energies, and the
contrast effect of ReS2 nanoparticles was remarkably improved with the
increasement of X-ray energy. In contrast, iodine with the low K-edge (33.2 keV)
makes iohexol only gave a poor contrast enhancement of tumors in spectral CT
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imaging due to the similar declining tendency for CT values of iohexol and
surrounding tissues with the increase of X-ray energy (Figure S12). These results
further demonstrated the relatively constant X-ray attenuation ability of ReS2
nanoparticles across low and high energy setting, showing promising prospect in
high-performance spectral CT imaging for accurate disease diagnosis and
imaging-guided therapy (Figure 5).
Figure 5. Spectral CT images of tumor-bearing mice before and after the injection of
ReS2 nanoparticles (100 µL, 5 mg/mL: 17.5 mM Re) and iohexol (100 µL, 17.5 mM I)
intratumorally. The tumor site was pointed out with green cycle in the first photo in
each group.
Photothermal Therapy in vivo. For the evaluation of in vivo photothermal therapy
capacity of ReS2 nanoparticles, twenty Balb/c mice bearing 4T1 tumors were divided
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into 4 groups randomly. These mice were treated with ReS2 nanoparticles (100 µL, 5
mg/mL) in combination with 808 nm laser irradiation (0.3 W/cm2), PBS (10 mM, pH
7.4) in combination with 808 nm laser irradiation (0.3 W/cm2), and ReS2
nanoparticles alone and PBS alone respectively. It should be noted that 0.3 W/cm2 is
FDA-approved laser power for in vivo application.66 During the irradiation process,
temperature change of tumors was recorded by a thermal imaging camera (Figure
6a). After exposure of laser illumination for 10 min, the temperature of tumor site of
mice treated with ReS2 nanoparticles increased sharply by 31 °C, while that of mice
with the injection of PBS only increased less than 10 °C (Figure S13). It suggested
that ReS2 nanoparticles could induce remarkable hyperthermia under the laser
illumination at a safe power intensity.
The volumes of tumors were determined at various time points (Figure 6b) and the
mice were also recorded by taking photos (Figure 6c). Remarkably, the tumors of
mice treated with ReS2 nanoparticles and irradiated by an 808-nm laser began to
scab 1 day later and disappeared finally. (Figure S14). On the contrary, the tumors in
the other three groups kept growing dramatically all the time. The tumors of mice
treated with ReS2 solution alone were 7 times larger than the original ones, and the
sizes of tumors with the injection of PBS in combination with laser irradiation were
nine times those of the original ones. These results clearly demonstrated ReS2
nanoparticles could serve as an excellent phototherapy agent for tumor ablation in
vivo under a safe laser irradiation.
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Figure 6. Photothermal therapy of tumors using ReS2 nanoparticles. (a) Thermal
images of 4T1 tumors bearing mice after intratumoral adminstration of PBS (10 mM,
pH 7.4) and ReS2 nanoparticles (100 µL, 5 mg/mL, dispersed in PBS) under 808 nm
laser irradiation (0.3 W/cm2); The relative volume curves of tumors (b) and photos (c)
of mice with various treatments: PBS, PBS + laser irradiation (808 nm, 0.3 W/cm2,
10 min), ReS2, ReS2 + laser irradiation (808 nm, 0.3 W/cm2, 10 min). *p < 0.05.
In vivo Toxicity. To evaluate in vivo biotoxicity of ReS2 nanoparticles, body weight
change, survival state and histological change of major organs of Kunming mice
were monitored after the subcutaneous or oral administration of ReS2 nanoparticles
or PBS (pH = 7.4, 10 mM). There was no remarkable body weight loss, abnormal
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behaviors or death in experimental group compared with the control group (Figure
S15). In addition, hematoxylin and eosin (H&E) staining was performed to assess
potential histological damage caused by ReS2 nanoparticles (Figure S16, S17), and
the results suggested there was no histopathological damage in main organs (heart,
liver, spleen, lung and kidney for subcutaneous administration, and liver, stomach
and intestine for oral administration) of experimental mice compared to the control
group. In vivo toxicity evaluation revealed that the as-prepared ReS2 nanoparticle as
a classic drug exhibited favorable biosafety.
CONCLUSIONS
In conclusion, to demonstrate the feasibility of “teaching old drugs new tricks”
strategy, a clinic radiotherapy sensitizer, ReS2 nanoparticles, as an old model drug
was employed to explore its potential of GI tract spectral CT imaging and CT-guided
photothermal therapy for tumors. The ReS2 nanoparticles synthesized in a one-pot
facile manner under mild conditions exhibited tiny size, admirable monodispersity,
good water solubility, favorable colloidal stability, high-performance CT and spectral
CT contrast capacity and good photothermal heating ability. The cellular experiments
demonstrated the low cytotoxicity of ReS2 and high efficient photothermal therapy in
vitro, and in vivo toxicity assessments further confirmed the good biocompatibility of
ReS2 nanoparticles. The ReS2 nanoparticles with fascinating features enabled not
only visualizing the GI tract in details by CT and spectral CT imaging, but also CT
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and spectral CT imaging-guided photothermal therapy for tumors in vivo. Especially,
the strong and constant X-ray absorption ability of ReS2 nanoparticles at any energy
ensured superior enhanced spectral CT imaging by them, and enabling effective
distinguishing the region of interest and surrounding tissues with ultrahigh signal to
noise ratio. We believe our proposed “teaching old drugs new Tricks” strategy will
open a new way to develop novel imageable and therapeutic agents for clinic
applications without safety concerns.
MATERIALS AND METHODS
Materials. All reagents used were of at least analytical grade. Sodium perrhenate
(NaReO4) was purchased from Alfa Aesar (Tianjin, China). Sodium thiosulfate
(Na2S2O3·5H2O), NaOH, ethylene glycol (EG), Na2HPO4 and NaH2PO4, 3-(4,
5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) were obtained from
Aladdin Reagent Co. Ltd (Shanghai, China). Calcein acetoxymethyl ester (Calcein
AM) and propidium iodide (PI) were bought from Dojindo (Shanghai, China). DMSO
was provided by Concord Technology (Tianjin, China). Ultrapure water was provided
by Wahaha Group Co. Ltd (Hangzhou, China).
Synthesis of ReS2 Nanoparticles. ReS2 nanoparticles were prepared according to
an established method with a minor modification.64 Typically, 22 mg of NaReO4 and
64 mg of Na2S2O3·5H2O were mixed in 8 mL of EG under vigorously magnetic
stirring, and then 250 µL of hydrochloric acid (6 M) was introduced to initiate the
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reaction. The original colorless solution gradually became yellow, brown and finally
almost black, indicating the formation of ReS2 nanoparticles. After stirring for 40 min,
1 M NaOH was used to adjust pH to neutral to terminate the reaction. The obtained
ReS2 nanoparticles solution was dialyzed to remove unreacted reagents. The
purified ReS2 nanoparticles were kept at 4 °C for further study.
Colloidal Stability Assessment. ReS2 nanoparticles (1 mg/mL) were dispersed in
different media including water, phosphate buffer (PBS, 10 mM, pH 7.4) and 10%
culture medium. The photos of ReS2 nanoparticles solutions were recorded at
different time points and hydrodynamic diameters of the nanoparticles were
determined at the same time points.
ASSOCIATED CONTENT
Supporting Information. Experimental Section, Hydrodynamic size of ReS2
nanoparticles, XRD pattern of ReS2 nanoparticles, FT-IR spectra of ReS2
nanoparticles and ethylene glycol, photos and change of hydrodynamic size of ReS2
nanoparticles dispersed in various media for different time, the temperature change
curves of water and ReS2 nanoparticles, the photothermal conversion efficiency of
ReS2 nanoparticles, cell viability after incubation with ReS2, fluorescent dual-staining
images of 4T1 cells after treatments with ReS2, CT images of mice before and after
intratumoral injection with ReS2 nanoparticles, HU value change of tumors after
intratumoral injection with ReS2 nanoparticles, temperature curves of tumor site at
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the back of balb/c mice after intratumoral injection of PBS and ReS2 under 808 nm
laser exposure, photo of tumor masses exfoliated from tumor-bearing mice after
different treatments, body weight change of Kunming mice after subcutaneous or
oral administration of ReS2 nanoparticles, and H&E staining of vital organs and
digestive organs after administration of ReS2 nanoparticles were included in the
Supporting Information.
AUTHOR INFORMATION
Corresponding Authors
*Email: [email protected] (S.-K. Sun);
*Email: [email protected] (X. Zhang)
ORCID
Shao-Kai Sun: 0000-0001-6136-9969
Notes
The authors declare no competing financial interest.
Author Contributions
#These authors contributed equally to this work.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China
(Grants 81671676, 21435001), and Natural Science Foundation of Tianjin City (No.
18JCYBJC20800).
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Graphical Table of Contents (TOC)
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