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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

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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).

REFERENCES

Page 25 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

26

(1) Jakhmola, A.; Anton, N.; Vandamme, T. F. Inorganic Nanoparticles Based

Contrast Agents for X-ray Computed Tomography. Adv. Healthcare Mater. 2012, 1,

413-431.

(2) Liu, Y.; Ai, K.; Lu, L. Nanoparticulate X-ray Computed Tomography Contrast

Agents: From Design Validation to in Vivo Applications. Acc. Chem. Res. 2012, 45,

1817-1827.

(3) Shilo, M.; Reuveni, T.; Motiei, M.; Popovtzer, R. Nanoparticles as Computed

Tomography Contrast Agents: Current Atatus and Future Perspectives.

Nanomedicine 2012, 7, 257-269.

(4) Lee, N.; Choi, S. H.; Hyeon, T. Nano-Sized CT Contrast Agents. Adv. Mater.

2013, 25, 2641-2660.

(5) Lusic, H.; Grinstaff, M. W. X-ray-Computed Tomography Contrast Agents.

Chem. Rev. 2013, 113, 1641-1666.

(6) Stieger-Vanegas, S. M.; Cebra, C. K. Contrast-Enhanced Computed

Tomography of the Gastrointestinal Tract in Clinically Normal Alpacas and Llamas. J.

Am. Vet. Med. Assoc. 2013, 242, 254-260.

(7) McCollough, C. H.; Leng, S. A.; Yu, L. F.; Fletcher, J. G. Dual- and Multi-Energy

CT: Principles, Technical Approaches, and Clinical Applications. Radiology 2015,

276, 637-653.

(8) Yeh, B. M.; FitzGerald, P. F.; Edic, P. M.; Lambert, J. W.; Colborn, R. E.;

Marino, M. E.; Evans, P. M.; Roberts, J. C.; Wang, Z. J.; Wong, M. J.; Bonitatibus, P.

Page 26 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

27

J., Jr. Opportunities for New CT Contrast Agents to Maximize the Diagnostic

Potential of Emerging Spectral CT Technologies. Adv. Drug Deliver. Rev 2017, 113,

201-222.

(9) FitzGerald, P. F.; Colborn, R. E.; Edic, P. M.; Lambert, J. W.; Torres, A. S.;

Bonitatibus, P. J.; Yeh, B. M. CT Image Contrast of High-Z Elements: Phantom

Imaging Studies and Clinical Implications. Radiology 2016, 278, 723-733.

(10) Pan, D.; Roessl, E.; Schlomka, J.-P.; Caruthers, S. D.; Senpan, A.; Scott, M.

J.; Allen, J. S.; Zhang, H.; Hu, G.; Gaffney, P. J.; Choi, E. T.; Rasche, V.; Wickline,

S. A.; Proksa, R.; Lanza, G. M. Computed Tomography in Color: NanoK-Enhanced

Spectral CT Molecular Imaging. Angew. Chem. Int. Ed. 2010, 49, 9635-9639.

(11) Pan, D.; Schirra, C. O.; Senpan, A.; Schmieder, A. H.; Stacy, A. J.; Roessl, E.;

Thran, A.; Wickline, S. A.; Proska, R.; Lanza, G. M. An Early Investigation of

Ytterbium Nanocolloids for Selective and Quantitative “Multicolor” Spectral CT

Imaging. ACS Nano 2012, 6, 3364-3370.

(12) Wang, Y.; Jiang, C.; He, W.; Ai, K.; Ren, X.; Liu, L.; Zhang, M.; Lu, L. Targeted

Imaging of Damaged Bone in Vivo with Gemstone Spectral Computed Tomography.

ACS Nano 2016, 10, 4164-4172.

(13) Jin, Y.; Ni, D.; Gao, L.; Meng, X.; Lv, Y.; Han, F.; Zhang, H.; Liu, Y.; Yao, Z.;

Feng, X.; Bu, W.; Zhang, J. Harness the Power of Upconversion Nanoparticles for

Spectral Computed Tomography Diagnosis of Osteosarcoma. Adv. Funct. Mater.

2018, 28, 1802656.

Page 27 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

28

(14) Cui, Y. Y.; Yang, J.; Zhou, Q. F.; Liang, P.; Wang, Y. L.; Gao, X. Y.; Wang, Y.

T. Renal Clearable Ag Nanodots for in Vivo Computer Tomography Imaging and

Photothermal Therapy. ACS Appl. Mater. Interfaces. 2017, 9, 5900-5906.

(15) Liu, Y.; Ai, K.; Liu, J.; Yuan, Q.; He, Y.; Lu, L. A High-Performance

Ytterbium-Based Nanoparticulate Contrast Agent for In Vivo X-Ray Computed

Tomography Imaging. Angew. Chem. Int. Ed. 2012, 51, 1437-1442.

(16) Liu, Z.; Ju, E.; Liu, J.; Du, Y.; Li, Z.; Yuan, Q.; Ren, J.; Qu, X. Direct

Visualization of Gastrointestinal Tract with Lanthanide-Doped BaYbF5 Upconversion

Nanoprobes. Biomaterials 2013, 34, 7444-7452.

(17) Sun, Y.; Peng, J. J.; Feng, W.; Li, F. Y. Upconversion Nanophosphors Naluf(4):

Yb, Tm for Lymphatic Imaging In Vivo by Real-Time Upconversion Luminescence

Imaging under Ambient Light and High-Resolution X-ray CT. Theranostics 2013, 3,

346-353.

(18) Wang, J.; Ni, D.; Bu, W.; Zhou, Q.; Fan, W.; Wu, Y.; Liu, Y.; Yin, L.; Cui, Z.;

Zhang, X.; Zhang, H.; Yao, Z. BaHoF5 Nanoprobes as High-Performance Contrast

Agents for Multi-Modal CT Imaging of Ischemic Stroke. Biomaterials 2015, 71,

110-118.

(19) McGinnity, T. L.; Dominguez, O.; Curtis, T. E.; Nallathamby, P. D.; Hoffman, A.

J.; Roeder, R. K. Hafnia (HfO2) Nanoparticles as an X-Ray Contrast Agent and

Mid-Infrared Biosensor. Nanoscale 2016, 8, 13627-13637.

Page 28 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

29

(20) Oh, M. H.; Lee, N.; Kim, H.; Park, S. P.; Piao, Y.; Lee, J.; Jun, S. W.; Moon, W.

K.; Choi, S. H.; Hyeon, T. Large-Scale Synthesis of Bioinert Tantalum Oxide

Nanoparticles for X-ray Computed Tomography Imaging and Bimodal Image-Guided

Sentinel Lymph Node Mapping. J. Am. Chem. Soc. 2011, 133, 5508-5515.

(21) Liu, Z.; Liu, J.; Wang, R.; Du, Y.; Ren, J.; Qu, X. An Efficient Nano-Based

Theranostic System for Multi-Modal Imaging-Guided Photothermal Sterilization in

Gastrointestinal Tract. Biomaterials 2015, 56, 206-218.

(22) Cheng, L.; Liu, J.; Gu, X.; Gong, H.; Shi, X.; Liu, T.; Wang, C.; Wang, X.; Liu,

G.; Xing, H.; Bu, W.; Sun, B.; Liu, Z. PEGylated WS2 Nanosheets as a

Multifunctional Theranostic Agent for in vivo Dual-Modal CT/Photoacoustic Imaging

Guided Photothermal Therapy. Adv. Mater. 2014, 26, 1886-1893.

(23) Yong, Y.; Cheng, X.; Bao, T.; Zu, M.; Yan, L.; Yin, W.; Ge, C.; Wang, D.; Gu,

Z.; Zhao, Y. Tungsten Sulfide Quantum Dots as Multifunctional Nanotheranostics for

In Vivo Dual-Modal Image-Guided Photothermal/Radiotherapy Synergistic Therapy.

ACS Nano 2015, 9, 12451-12463.

(24) Boisselier, E.; Astruc, D. Gold Nanoparticles in Nanomedicine: Preparations,

Imaging, Diagnostics, Therapies and Toxicity. Chem. Soc. Rev. 2009, 38,

1759-1782.

(25) Rabin, O.; Perez, J. M.; Grimm, J.; Wojtkiewicz, G.; Weissleder, R. An X-Ray

Computed Tomography Imaging Agent Based on Long-Circulating Bismuth Sulphide

Nanoparticles. Nat. Mater. 2006, 5, 118-122.

Page 29 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

30

(26) Ai, K.; Liu, Y.; Liu, J.; Yuan, Q.; He, Y.; Lu, L. Large-Scale Synthesis of Bi2S3

Nanodots as a Contrast Agent for In Vivo X-ray Computed Tomography Imaging.

Adv. Mater. 2011, 23, 4886-4891.

(27) Kinsella, J. M.; Jimenez, R. E.; Karmali, P. P.; Rush, A. M.; Kotamraju, V. R.;

Gianneschi, N. C.; Ruoslahti, E.; Stupack, D.; Sailor, M. J. X-Ray Computed

Tomography Imaging of Breast Cancer by using Targeted Peptide-Labeled Bismuth

Sulfide Nanoparticles. Angew. Chem. Int. Ed. 2011, 50, 12308-12311.

(28) Liu, J.; Zheng, X.; Yan, L.; Zhou, L.; Tian, G.; Yin, W.; Wang, L.; Liu, Y.; Hu, Z.;

Gu, Z.; Chen, C.; Zhao, Y. Bismuth Sulfide Nanorods as a Precision Nanomedicine

for in Vivo Multimodal Imaging-Guided Photothermal Therapy of Tumor. ACS Nano

2015, 9, 696-707.

(29) Zheng, X.; Shi, J.; Bu, Y.; Tian, G.; Zhang, X.; Yin, W.; Gao, B.; Yang, Z.; Hu,

Z.; Liu, X.; Yan, L.; Gu, Z.; Zhao, Y. Silica-Coated Bismuth Sulfide Nanorods as

Multimodal Contrast Agents for a Non-Invasive Visualization of the Gastrointestinal

Tract. Nanoscale 2015, 7, 12581-12591.

(30) Li, Z. L.; Hu, Y.; Howard, K. A.; Jiang, T. T.; Fan, X. L.; Miao, Z. H.; Sun, Y.;

Besenbacher, F.; Yu, M. Multifunctional Bismuth Selenide Nanocomposites for

Antitumor Thermo-Chemotherapy and Imaging. ACS Nano 2016, 10, 984-997.

(31) Wang, Y.; Wu, Y.; Liu, Y.; Shen, J.; Lv, L.; Li, L.; Yang, L.; Zeng, J.; Wang, Y.;

Zhang, L. W.; Li, Z.; Gao, M.; Chai, Z. BSA-Mediated Synthesis of Bismuth Sulfide

Page 30 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

31

Nanotheranostic Agents for Tumor Multimodal Imaging and Thermoradiotherapy.

Adv. Funct. Mater. 2016, 26, 5335-5344.

(32) Wei, B.; Zhang, X.; Zhang, C.; Jiang, Y.; Fu, Y.-Y.; Yu, C.; Sun, S.-K.; Yan,

X.-P. Facile Synthesis of Uniform-Sized Bismuth Nanoparticles for CT Visualization

of Gastrointestinal Tract in Vivo. ACS Appl. Mater. Interfaces. 2016, 8, 12720-12726.

(33) Lei, P.; An, R.; Zhang, P.; Yao, S.; Song, S.; Dong, L.; Xu, X.; Du, K.; Feng, J.;

Zhang, H. Ultrafast Synthesis of Ultrasmall Poly(Vinylpyrrolidone)-Protected Bismuth

Nanodots as a Multifunctional Theranostic Agent for In Vivo Dual-Modal

CT/Photothermal-Imaging-Guided Photothermal Therapy. Adv. Funct. Mater. 2017,

27, 1702018.

(34) Cheng, Y.; Zhang, H. Novel Bismuth-Based Nanomaterials Used for Cancer

Diagnosis and Therapy. Chem. Eur. J. 2018, 24, 17405-17418.

(35) Shen, S.; Chao, Y.; Dong, Z.; Wang, G.; Yi, X.; Song, G.; Yang, K.; Liu, Z.;

Cheng, L. Bottom-Up Preparation of Uniform Ultrathin Rhenium Disulfide

Nanosheets for Image-Guided Photothermal Radiotherapy. Adv. Funct. Mater. 2017,

27, 1700250.

(36) Miao, Z. H.; Lv, L. X.; Li, K.; Liu, P. Y.; Li, Z.; Yang, H.; Zhao, Q.; Chang, M.;

Zhen, L.; Xu, C. Y. Liquid Exfoliation of Colloidal Rhenium Disulfide Nanosheets as a

Multifunctional Theranostic Agent for In Vivo Photoacoustic/CT Imaging and

Photothermal Therapy. Small 2018, 14, e1703789.

Page 31 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

32

(37) Shim, J.; Oh, A.; Kang, D. H.; Oh, S.; Jang, S. K.; Jeon, J.; Jeon, M. H.; Kim,

M.; Choi, C.; Lee, J.; Lee, S.; Yeom, G. Y.; Song, Y. J.; Park, J. H.

High-Performance 2D Rhenium Disulfide (ReS2) Transistors and Photodetectors by

Oxygen Plasma Treatment. Adv. Mater. 2016, 28, 6985-6992.

(38) Aliaga, J. A.; Alonso-Nunez, G.; Zepeda, T.; Araya, J. F.; Rubio, P. F.;

Bedolla-Valdez, Z.; Paraguay-Delgado, F.; Farias, M.; Fuentes, S.; Gonzalez, G.

Synthesis of Highly Destacked ReS2 Layers Embedded in Amorphous Carbon from

a Metal-Organic Precursor. J. Non-cryst. Solids. 2016, 447, 29-34.

(39) Gupta, S. C.; Sung, B.; Prasad, S.; Webb, L. J.; Aggarwal, B. B. Cancer Drug

Discovery by Repurposing: Teaching New Tricks to Old Dogs. Trends Pharmacol.

Sci 2013, 34, 508-517.

(40) Chen, H. J.; Wu, J. L.; Gao, Y.; Chen, H. Y.; Zhou, J. Scaffold Repurposing of

Old Drugs Towards New Cancer Drug Discovery. Curr. Top. Med. Chem. 2016, 16,

2107-2114.

(41) Zhao, L.; Chen, X.-J.; Zhu, J.; Xi, Y.-B.; Yang, X.; Hu, L.-D.; Ouyang, H.; Patel,

S. H.; Jin, X.; Lin, D.; Wu, F.; Flagg, K.; Cai, H.; Li, G.; Cao, G.; Lin, Y.; Chen, D.;

Wen, C.; Chung, C.; WangYandong; Qiu, A.; Yeh, E.; Wang, W.; Hu, X.; Grob, S.;

Abagyan, R.; Su, Z.; Tjondro, H. C.; Zhao, X.-J.; Luo, H.; Hou, R.; Jefferson, J.;

Perry, P.; Gao, W.; Kozak, I.; Granet, D.; Li, Y.; Sun, X.; Wang, J.; Zhang, L.; Liu, Y.;

Yan, Y.-B.; Zhang, K. Lanosterol Reverses Protein Aggregation in Cataracts. Nature

2015, 523, 607-611.

Page 32 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

33

(42) Zanganeh, S.; Hutter, G.; Spitler, R.; Lenkov, O.; Mahmoudi, M.; Shaw, A.;

Pajarinen, J. S.; Nejadnik, H.; Goodman, S.; Moseley, M.; Coussens, L. M.;

Daldrup-Link, H. E. Iron Oxide Nanoparticles Inhibit Tumour Growth by Inducing

Pro-Inflammatory Macrophage Polarization in Tumour Tissues. Nat. Nanotechnol.

2016, 11, 986-994.

(43) Liu, T.; Cheng, L.; Liu, Z. Two Dimensional Transitional Metal Dichalcogenides

for Biomedical Applications. Acta Chim. Sinica. 2015, 73, 902-912.

(44) Li, X.; Shan, J.; Zhang, W.; Su, S.; Yuwen, L.; Wang, L. Recent Advances in

Synthesis and Biomedical Applications of Two-Dimensional Transition Metal

Dichalcogenide Nanosheets. Small 2017, 13, 1602660.

(45) Manzeli, S.; Ovchinnikov, D.; Pasquier, D.; Yazyev, O. V.; Kis, A. 2D Transition

Metal Dichalcogenides. Nat. Rev. Mater. 2017, 2, 17033.

(46) Qian, X.; Shen, S.; Liu, T.; Cheng, L.; Liu, Z. Two-Dimensional TiS2

Nanosheets for in Vivo Photoacoustic Imaging and Photothermal Cancer Therapy.

Nanoscale 2015, 7, 6380-6387.

(47) Meng, Z.; Wei, F.; Ma, W.; Yu, N.; Wei, P.; Wang, Z.; Tang, Y.; Chen, Z.;

Wang, H.; Zhu, M. Design and Synthesis of "All-in-One" Multifunctional FeS2

Nanoparticles for Magnetic Resonance and Near-Infrared Imaging Guided

Photothermal Therapy of Tumors. Adv. Funct. Mater. 2016, 26, 8231-8242.

Page 33 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

34

(48) Chou, S. S.; Kaehr, B.; Kim, J.; Foley, B. M.; De, M.; Hopkins, P. E.; Huang, J.;

Brinker, C. J.; Dravid, V. P. Chemically Exfoliated MoS2 as Near-Infrared

Photothermal Agents. Angew. Chem. Int. Ed. 2013, 52, 4160-4164.

(49) Liu, T.; Wang, C.; Gu, X.; Gong, H.; Cheng, L.; Shi, X.; Feng, L.; Sun, B.; Liu,

Z. Drug Delivery with PEGylated MoS2 Nano-sheets for Combined Photothermal and

Chemotherapy of Cancer. Adv. Mater. 2014, 26, 3433-3440.

(50) Wang, S. G.; Zhao, J. L.; Yang, H. L.; Wu, C. Y.; Hu, F.; Chang, H. Z.; Li, G.

X.; Ma, D.; Zou, D. W.; Huang, M. X. Bottom-up Synthesis of WS2 Nanosheets with

Synchronous Surface Modification for Imaging Guided Tumor Regression. Acta

Biomater. 2017, 58, 442-454.

(51) Yu, J. F.; Yin, D. Z.; Min, X. F.; Guo, Z. L.; Zhang, J.; Wang, Y. X.; Knapp, F. F.

Re-188 Rhenium Sulfide Suspension: A Potential Radiopharmaceutical for Tumor

Treatment Following Intra-Tumor Injection. Nucl. Med. Biol. 1999, 26, 573-579.

(52) Yu, J. F.; Yin, D. Z.; Min, X. F.; Guo, Z. L.; Zhang, J.; Wang, Y. X.; Knapp, F. F.

Preparation of Re-188 Rhenium Sulfide Suspension and Its Biodistribution Following

Intra-Tumor Injection in Mice. J. Labelled. Compd. Rad 1999, 42, 233-243.

(53) Yu, J. F.; Zhang, R. P.; Dai, X. L.; Min, X. F.; Xu, J. Y.; Hu, W. Q.; Yin, D. Z.;

Zhou, W.; Xie, H.; Wang, Y. X.; Knapp, F. F. Intratumoral Injection with Re-188

Rhenium Sulfide Suspension for Treatment of Transplanted Human Liver Carcinoma

in Nude Mice. Nucl. Med. Biol. 2000, 27, 347-352.

Page 34 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

35

(54) Li, P.; Chen, G.; Zhang, H.; Shen, Z. Radiation Synovectomy by

Re-188-Sulfide in Haemophilic Synovitis. Haemophilia 2004, 10, 422-427.

(55) van der Zant, F. M.; Jahangier, Z. N. Z.; Moolenburgh, J. D.; van der Zee, W.;

Boer, R. O.; Jacobs, J. W. G. Radiation Synovectomy of the Ankle with 75 MBq

Colloidal (186)Rhenium-Sulfide: Effect, Leakage, and Radiation Considerations. J.

Rheumatol. 2004, 31, 896-901.

(56) Li, P.; Yu, J.; Chen, G.; Jiang, X.; Tang, Z.; Chen, S.; Jiang, L.; Tang, L.; Yin,

D. Applied Radioactivity in Radiation Synovectomy with Re-188 Rhenium Sulfide

Suspension. Nucl. Med. Commun. 2006, 27, 603-609.

(57) Klett, R.; Lange, U.; Haas, H.; Voth, M.; Pinkert, J. Radiosynoviorthesis of

Medium-sized Joints with Rhenium-186-Sulphide Colloid: A Review of the Literature.

Rheumatology 2007, 46, 1531-1537.

(58) Chojnowski, M. M.; Felis-Giemza, A.; Kobylecka, M. Radionuclide

Synovectomy - Essentials for Rheumatologists. Reumatologia 2016, 54, 108-116.

(59) Watanabe, T.; Kimijima, I.; Ohtake, T.; Tsuchiya, A.; Shishido, F.; Takenoshita,

S. Sentinel Node Biopsy with Technetium-99m Colloidal Rhenium Sulphide in

Patients with Breast Cancer. Brit. J. Surg. 2001, 88, 704-707.

(60) Kato, H.; Miyazaki, T.; Nakajima, M.; Takita, J.; Sohda, M.; Fukai, Y.; Masuda,

N.; Fukuchi, M.; Manda, R.; Ojima, H.; Tsukada, K.; Asao, T.; Kuwano, H.; Oriuchi,

N.; Endo, K. Sentinel Lymph Nodes with Technetium-99m Colloidal Rhenium Sulfide

in Patients with Esophageal Carcinoma. Cancer 2003, 98, 932-939.

Page 35 of 37



123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

36

(61) Koizumi, M.; Nomura, E.; Yamada, Y.; Takiguchi, T.; Tanaka, K.; Yoshimoto,

M.; Makita, M.; Sakamoto, G.; Kasumi, F.; Ogata, E. Sentinel Node Detection Using

Tc-99m-Rhenium Sulphide Colloid in Breast Cancer Patients: Evaluation of 1 Day

and 2 Day Protocols, and a Dose-Finding Study. Nucl. Med. Commun. 2003, 24,

663-670.

(62) Weiss, M.; Kunte, C.; Schmid, R. A.; Konz, B.; Dresel, S.; Hahn, K. Sentinel

Node Mapping in Patients with Malignant Melanoma Using Melanoma Tc-99m

Colloidal Rhenium Sulfide. Clin. Nucl. Med. 2003, 28, 379-384.

(63) Mochiki, E.; Kuwano, H.; Kamiyama, Y.; Aihara, R.; Nakabayashi, T.; Katoh,

H.; Asao, T.; Oriuchi, N.; Endo, K. Sentinel Lymph Node Mapping with

Technetium-99m Colloidal Rhenium Sulfide in Patients with Gastric Carcinoma. Am.

J. Surg. 2006, 191, 465-469.

(64) Tu, W.; Denizot, B. Synthesis of Small-Sized Rhenium Sulfide Colloidal

Nanoparticles. J. Colloid Interf. Sci. 2007, 310, 167-170.

(65) Al-Dulaimi, N.; Lewis, E. A.; Lewis, D. J.; Howell, S. K.; Haigh, S. J.; O'Brien, P.

Sequential Bottom-up and Top-down Processing for the Synthesis of Transition

Metal Dichalcogenide Nanosheets: The Case of Rhenium Disulfide (ReS2). Chem.

Commun. 2016, 52, 7878-7881.

(66) American National Standard Institute, ANSI Z136. 1-2000, American National

Standard for Safe Use of Lasers, Orlando, Fl, 2000.

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