Rhenium Sulfide Nanoparticles as a Biosafe Spectral CT

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Biological and Medical Applications of Materials and Interfaces

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 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 27, 2019

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ACS Applied Materials & Interfaces

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 3 ACS Paragon Plus Environment


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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 4 ACS Paragon Plus Environment

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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 5 ACS Paragon Plus Environment


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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 8 ACS Paragon Plus Environment

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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 11 ACS Paragon Plus Environment


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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 15 ACS Paragon Plus Environment


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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 16 ACS Paragon Plus Environment

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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 19 ACS Paragon Plus Environment


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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. 20 ACS Paragon Plus Environment

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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 21 ACS Paragon Plus Environment


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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 25 ACS Paragon Plus Environment


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Rhenium Sulfide Nanoparticles as a Biosafe Spectral CT

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