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About Catalytic Materials

Catalytic Materials is a company focused on the medical equipment manufacturing and service sector. The company's main offerings include the development, production, and sale of medical diagnostic equipment, specifically devices for in vitro diagnosis and point-of-care testing. The company primarily serves the healthcare industry. It is based in Pittsboro, North Carolina.

Headquarters Location

325 Heartland Drive

Pittsboro, North Carolina, 27312,

United States

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Catalytic Materials Patents

Catalytic Materials has filed 4 patents.

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7/25/2008

6/8/2010

Catalysis, Commodity chemicals, Chemical processes, Phenyl compounds, Monomers

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Application Date

7/25/2008

Grant Date

6/8/2010

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Catalysis, Commodity chemicals, Chemical processes, Phenyl compounds, Monomers

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Latest Catalytic Materials News

Synergetic Photodynamic-Photothermal-Chemotherapy Dual Targeting Nanoplatform Effective Against Breast Cancer in-Mice Model

Nov 6, 2023

Na Li,1 Xiaochun Jiang,2 Wanju Zhang,1 Wenping Xiao,1 Zhaona Wu,1 Huirong Wang,1 Feng He1 1Li Shizhen College of Traditional Chinese Medicine, Huanggang Normal University, Huanggang, 438000, People’s Republic of China; 2Hubei Key Laboratory for Processing and Application of Catalytic Materials, College of Chemistry and Chemical Engineering, Huanggang Normal University, Huanggang, 438000, People’s Republic of China Introduction: Combined multimodal therapy for breast cancer is a promising therapeutic approach to increase treatment efficacy and reduce systemic toxicity. The present study aimed to develop a novel multifunctional drug release nanoplatform based on RGD-conjugated hyaluronic acid (HA)-functionalized copper sulfide (CuS) for activatable dual-targeted synergetic therapy against cancer. Methods: The pH and NIR-responsive dual-targeting nanoplatform CuS:Ce6@HA:DOX@RGD was prepared, characterized, and evaluated for its stability and photodynamic and photothermal properties. The loading and release of the drug were measured at different pH values with or without laser radiation using the dialysis method. The cellular uptake of the platform specifically by the tumor cells treated with different formulations was investigated through fluorescence imaging. The in vitro and in vivo biosafety levels were assessed systematically. Finally, the antitumor efficiencies against breast cancer were assessed via in vitro and in vivo experiments. Results: The spheroid CuS:Ce6@HA:DOX@RGD exhibited remarkable stability and monodispersity in solution. The photosensitive CuS and Ce6 could simultaneously absorb the near-infrared light efficiently to convert NIR light to fatal heat and to generate reactive oxygen species. The CuS:Ce6@HA:DOX@RGD dissociated under an acid environment, causing the release of DOX into the tumor to accelerate upon laser irradiation. The CuS:Ce6@HA:DOX@RGD exhibited target-specific and strong binding ability via a synergic CD44/αvβ3 receptor-mediated bimodal targeting, which led to improved therapeutic efficacy. The tumor growth was effectively inhibited using synergetic photodynamic/photothermal/chemo therapy. No evident systemic toxicity was noted during treatment. Conclusion: The newly prepared CuS:Ce6@HA:DOX@RGD has great potential as an activatable theranostic nanoplatform for efficient dual-targeted synergistic therapy against breast cancer. Keywords: responsive nanoplatform, targeting, drug delivery, synergistic therapy, breast cancer Graphical Abstract: Introduction Multifunctional nanoplatforms for multimodal therapy have advanced greatly in recent years, which has improved the therapeutic efficiency against malignant tumors. Currently, several therapeutic nanoplatforms have been approved for cancer therapy, including liposomes, polymeric micelles, and albumin nanoparticles. 1–4 However, it is important to develop an efficient multifunctional nanoplatform that exhibits high drug-loading efficiency, enhanced targeting and multiple therapeutic modalities. The nanoplatform could realize effective delivery of drugs into the site of interest and specific targeting of tumors or other disease sites with an optimized therapeutic strategy and low side effect. 5–7 In this regard, a variety of stimuli-activatable nanoplatforms capable of overcoming the above-stated issues have been developed. 8–11 An activatable nanoplatform maintains an intact state and, therefore, does not affect the normal and healthy cells until its delivery to its target. However, with specific recognition or stimuli, these nanoplatforms are activated. Moreover, the activatable nanoplatform as drug delivery can induce controlled drug-release while being stimuli-responsive. 12–15 For instance, the near-infrared (NIR)-responsive nanoplatform induces photothermal heating to directly destroy cancer cells, thereby remarkably improving the chemotherapeutic efficacy by triggering drug release. 16–18 So far, several nanoplatforms with infrared absorption, such as carbon-based, 19 , 20 gold-based 21 , 22 and mesoporous silica-based nanoplatforms, 23 , 24 have been used as photothermal therapy agents. The copper sulfide (CuS) nanoparticles have gained particular interest in recent years owing to their high photothermal conversion efficiency, convenient preparation, low cost, good biodegradability, low cytotoxicity, and excellent photoelectric properties. 25–29 The modification of bovine serum albumin (BSA) on CuS results in ultrasmall biosafe CuS-BSA nanoparticles, which exhibit promoted drug loading capacity. Moreover, CuS-BSA may be loaded with a photosensitive reagent (chlorin e6, Ce6), generating a multifunctional nanoplatform CuS:Ce6 for combined photodynamic and photothermal therapy (PDT/PTT). Importantly, the surface decoration of CuS:Ce6 is highly desirable for the construction of tumor-targeted and stimuli-responsive drug delivery systems. Hyaluronic acid (HA) has been used widely for fabricating drug delivery systems owing to its biodegradable and non-toxic nature. HA-based nanoplatforms serve as activatable delivery system for high drug loading and exhibit a pH-responsive and heat-responsive switch. 30–32 HA shell is able to be degraded by hyaluronidase to trigger drug release in cells. 31 Moreover, HA as a powerful targeting moiety binds specifically to the cluster determinant 44 (CD44) receptor, which is overexpressed on cancer cells. 33 , 34 In addition, HA with multiple functional groups may be modified with target molecules (RGD) and then loaded with chemotherapeutic drug (doxorubicin, DOX). In order to enhance interaction with the surface receptors on cancer cells, the surface of an HA-based delivery systems is decorated with the RGD for constructing dual-targeted drug delivery systems. According to the author’s knowledge, few studies have reported the construction of HA-coated CuS for multimodal therapy against cancer. Therefore, it is of significance to design tumor-targeted and activatable multifunctional nanoplatforms, using simple and mild methods for facilitating photodynamic and photothermal therapy plus chemotherapy (PDT/PTT/Chemo) to provide accurate and optimized therapy against cancer. In this context, a novel multifunctional therapeutic system based on CuS:Ce6@HA:DOX@RGD nanoplatform was constructed to co-encapsulate chemo-drug doxorubicin (DOX) and photosensitizer (Ce6) for multimodality treatment. The physicochemical properties of the established nanoplatform were investigated. The results revealed that the CuS:Ce6@HA:DOX@RGD could specifically target CD44 and bind to the alpha v beta 3 (αvβ3) integrin receptors, 35 which are overexpressed in tumor cells and tumor stroma, thus achieving enhanced tumor-targeted drug delivery. The cellular uptake and targeting ability of CuS:Ce6@HA:DOX@RGD were evaluated in MCF-7 cells. Upon irradiation with NIR laser, the Ce6 and CuS in the CuS:Ce6@HA:DOX@RGD generated substantial ROS and heat, respectively, to fully release DOX for suppressing tumor growth in combination with PDT/PTT/Chemo. The in vitro/vivo biosafety levels and therapeutic effects were then evaluated systematically. Materials and Methods Copper(II) chloride dihydrate (CuCl2·2H2O), sodium sulfide nonahydrate (Na2S·9H2O) and Sodium hyaluronic acid (HA) were obtained from Beijing lark technology co., Ltd. (Beijing, China). Bovine Serum Albumin (BSA) was purchased from Sigma Aldrich (St. Louis, MO, USA). Chlorin e6 (Ce6), Doxorubicin (DOX), 4, 6-diamidino-2-phenylindole (DAPI) and Calcein-AM were obtained from Beijing lark technology co., Ltd. (Beijing, China). RGD was bought from China Peptides Co., Ltd. (Shanghai, China). 1-ethyl-3(3-(dimethylamino)propyl)carbodiimide (EDC), N-Hydroxy-sulfosuccin-imide (Sulfo-NHS), 2,7-dichlorofluorescein diacetate (DCFH-DA), 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and Dulbecco’s Modified Eagle’s Medium (DMEM) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Human breast cancer MCF-7 cells were acquired by Fuzhou University. Female mice (Balb/c, weighing ∼20 g, 4 weeks old) were obtained from the Laboratory Animal Center of Wuhan Servicebio Biology Technology Co., Ltd. Ultrapure water (18.2 MΩ·cm) was used throughout the entire experiments. The Preparation of CuS and CuS:Ce6 According to previous reports, CuS was prepared with slightly modification. 25 Briefly, a CuCl2·2H2O solution (0.1 mmol, 10 mL) was mixed with a BSA solution (50 mg/mL, 10 mL) and stirred at 37 °C for 0.5 h. After the reaction, a NaOH solution was dipped into the above mixture. Subsequently, a Na2S·9H2O solution (242.16 mg/mL, 0.8 mL) was added to the above solution and stirred for 8 h. Then, the solution were dialyzed and dried to obtain the final product. BSA was conjugated with Ce6 by EDC and Sulfo-NHS in DMSO. The CuS:Ce6 was prepared following the same procedure as above. The Synthesis of CuS:Ce6@HA:DOX@RGD First, a mixture of CuS:Ce6 (1.0 mg) and HA (10.0 mg) in Tris-HCl solution buffer was stirred at room temperature for 24 h. The obtained CuS:Ce6@HA was dialyzed in PBS solution (pH 7.4). Then, EDC (20 mg) and Sulfo-NHS (20 mg) dissolved in anhydrous DMF (1 mL) were added to the above solution and reacted at room temperature for 30 min under stirring slowly. Next, 1.0 mL of RGD (1 mg/mL) solution were added and stirred overnight at room temperature. Then, the obtained CuS:Ce6@HA@RGD were dialyzed for 24 h. The CuS:Ce6@HA@RGD loaded with DOX was prepared by mixing equal amounts of DOX (2.5 mg/mL) and CuS:Ce6@HA@RGD, and the mixture was then stirred for 24 h at room temperature in the dark. The resulting mixture was dialyzed for 24 h and centrifuged. The products were designated as CuS:Ce6@HA:DOX@RGD. Characterization The morphology and elemental composition of nanoparticles were characterized by a transmission electron microscopy (TEM, JEM-2010FEF, Japan). The particle sizes were tested by Dynamic Light Scattering (DLS, Mastersizer 3000, England). Zeta potentials were measured on a Malvern Zeta sizer-Nano Z instrument. The UV-vis-NIR absorption spectra were recorded on UV3600i plus spectrophotometer (Shimadzu, Japan). The Fluorescence spectra were recorded with a fluorescence spectrophotometer (Edinburgh FLS920, England). Thermal images of solutions were obtained by a Fluke infrared thermal camera. The FL images were obtained on Nikon inverted DM4000 M fluorescence microscope and Olympus FV3000 confocal laser scanning microscope. The amount of Ce6 and DOX was respectively measured with a Nicolet Evolution 300 ultraviolet-visible (UV-vis) spectrometer at 395 and 480 nm. Stability The CuS:Ce6@HA:DOX@RGD were dispersed into serum, cell culture medium, and PBS (pH 7.4) at 37 °C within a week. At preset time points, the particle sizes of CuS:Ce6@HA:DOX@RGD were monitored by DLS to investigate the stability. Meantime, the suspension was exposed to NIR irradiation (1.5 W/cm2) to investigate its photostability. Detection of Photodynamic and Photothermal Ability DCFH-DA was used as a chemical probe to detect the generation of ROS. 36 The DCFH-DA was respectively added into 2 mL of PBS, Ce6 and CuS:Ce6@HA:DOX@RGD solution in the dark. Then, the mixture was irradiated with 663 nm laser (1.5 W/cm2) for different times (0, 1, 3, 6, 10, and 15 min), respectively. After irradiation, the fluorescence spectra of DCF at 522 nm were tested to evaluate the generation of ROS. The CuS:Ce6@HA:DOX@RGD were incubated cells and then washed with PBS. DCFH-DA was added and then washed after incubation for 30 min. After laser radiation, the fluorescence intensity at 522 nm was determined using a fluorescence spectrophotometer. Control group was not treated, and the CuS:Ce6@HA:DOX@RGD group was not illuminated with a laser. The aqueous solutions of CuS and CuS:Ce6@HA:DOX@RGD were irradiated with a 980 nm laser at 1.5 W/cm2 for 6 min. During the irradiation, the temperature was recorded at 0, 1, 2, 3, 4, 5, and 6 min. The corresponding thermal images at 0, 1, 2, 3, 4, 5, and 6 min were acquired by an infrared thermal camera. The CuS:Ce6@HA:DOX@RGD solution at a series of concentrations (25, 50, 100, 150, and 200 μg/mL) were exposed to 980 nm laser at 1.5W/cm2 for 6 min. The CuS:Ce6@HA:DOX@RGD solution under 980 nm irradiation with various power densities (0.5, 0.75, 1.0, and 1.5 W/cm2) were also monitored. The photothermal stability of CuS:Ce6@HA:DOX@RGD was evaluated by on/off-cycle irradiation experiment. In vitro pH/NIR-Responsive Evaluation To investigate the pH/NIR-responsive DOX release, the CuS:Ce6@HA:DOX@RGD solution were transferred into the dialysis bag, which were dialyzed in different pH conditions (pH 7.4, 6.0, and 5.0) in the presence and absence of hyaluronidase (HY), respectively. Also, we assessed the effect of NIR irradiation on the release behavior of DOX. At selected time points, 1 mL of the release medium was collected and replaced with the same fresh buffered solution. Subsequently, the released DOX was quantified by a UV-vis spectrometer. Moreover, the fluorescence recovery was examined in pH 5.0 without and with 980 nm laser. The fluorescence changes of released DOX were monitored. Cell Uptake and Intracellular DOX Release MCF-7 cells and normal cells were respectively seeded into 6-well plate at a density of 1×104 cells and incubated for 12 h. Then, DOX, CuS:Ce6@HA:DOX and CuS:Ce6@HA:DOX@RGD were respectively cultured with MCF-7 cells for 4 h. Similarly, the CuS:Ce6@HA:DOX@RGD were cultured with normal cells for 4 h. For competitive binding test, the MCF-7 cells were pretreated with a large excess of HA, RGD and HA plus RGD for 2 h, respectively. Subsequently, the CuS:Ce6@HA:DOX and CuS:Ce6@HA:DOX@RGD were added and incubated for 2 h, respectively. To evaluate the cellular pH/NIR-responsive DOX release, MCF-7 cells were respectively incubated for 1, 2 and 4 h with and without laser radiation. Afterward, all cells were observed and fluorescent images were recorded by a fluorescence microscope. To quantitatively measure the cellular uptake and DOX release, MCF-7 cells were washed and lysed after different treatments. Next, the supernatant was collected by centrifugation. The fluorescence intensity of DOX was determined using a fluorescence spectrophotometer. In vitro Therapeutic Effect with Laser The synergistic effect of PDT/PTT/Chemo in MCF-7 cells was assessed by MTT assay and calcein AM/PI staining. MCF-7 cells were incubated 4 h with PBS (pH=7.4) and CuS:Ce6@HA:DOX@RGD, respectively. The cells were divided into seven groups: (a) control (treated with PBS) without laser; (b) control (PBS) + NIR; (c) CuS:Ce6@HA:DOX@RGD; (d) CuS:Ce6@HA:DOX@RGD+663 nm; (e) CuS:Ce6@HA:DOX@RGD+980 nm; (f) CuS:Ce6@HA@RGD+663 nm+980 nm; (g) CuS:Ce6@HA:DOX@RGD+663 nm+980 nm. After 12 h, the cells were rinsed with PBS. The cell viability was tested by MTT assay. The dead/live cells were also stained with calcein-AM/PI and imaged by fluorescence microscope. MCF-7 cells were incubated with different concentrations of CuS:Ce6@HA:DOX@RGD for 4 h and then divided into four groups: (a) without laser; (b) with 663 nm; (c) with 980 nm; (d) with 663 and 980 nm. The cells were incubated for another 12 h. The MTT assay was performed to test cell viability. In vivo Antitumor Evaluation The tumor-bearing mice were randomly divided into six groups as follow (n = 5 in each group): (a) control (treated with PBS) without laser; (b) control (PBS) + NIR; (c) CuS:Ce6@HA:DOX@RGD (1.5 mg/kg); (d) CuS:Ce6@HA:DOX@RGD (1.5 mg/kg)+663 nm; (e) CuS:Ce6@HA:DOX@RGD (1.5 mg/kg)+980 nm; (f) CuS:Ce6@HA:DOX@RGD (1.5 mg/kg)+663 nm+980 nm. All groups of mice were intravenously injected with the same volume (200 μL). The tumors sites in irradiation groups were irradiated with 1.5 W/cm2. The tumor size and body weight of each mice were measured every two days. All mice were sacrificed after 14 days. The tumors were harvested for weighting, photo imaging, hematoxylin and eosin (H&E) staining. The tumor growth inhibition rate was estimated using the following formula: Inhibition %= (1-Mtreated group/ Mcontrol group) × 100%, where Mtreated group and Mcontrol group were the average tumor weights. Ultimately, major organs (liver, kidney, spleen, heart, and lung) of mice from the six groups were harvested for histological examination. Biosafety Assessment For in vitro toxicity assessment, various concentrations of CuS:Ce6@HA:DOX@RGD (0, 12.5, 25, 50, 100 and 200 μg/mL) were incubated with normal cells for 12 or 24 h, respectively. MTT assay was executed to measure cell viability. Meanwhile, the cell viability was also determined by a standard calcein-AM/PI live/dead assay. The fluorescence images of the cells were captured by fluorescence microscope. A standard hemolysis test was performed to evaluate blood compatibility of CuS:Ce6@HA:DOX@RGD. Briefly, the collected blood was washed with saline and centrifuged. The diluted red cell suspension was respectively mixed with CuS:Ce6@HA:DOX@RGD with various concentration. Deionized H2O and PBS were used as a positive or negative control, respectively. The absorbance of each group was then measured at 540 nm. The hemolysis percentage was calculated as the following formula: Hemolysis% = (Sample absorbance-negative control absorbance) / (positive control absorbance-negative control absorbance) × 100%. To assess in vivo toxicity, the healthy Balb/c mice were respectively intravenously injected with PBS or Ce6@HA:DOX@RGD (1.5 mg/kg). The body weights of mice were monitored for 14 days after treatment. At the desired time point, blood was drawn for serum biochemistry assay and routine blood analysis. Results and Discussion The morphologies of CuS:Ce6 and CuS:Ce6@HA:DOX@RGD were characterized through TEM, and the results are presented in Figure 1A and B , respectively. The TEM images revealed that the nanoparticles displayed excellent dispersity and The mean size of CuS:Ce6@HA:DOX@RGD (~ 20 nm) was much larger than that of CuS:Ce6 (~ 8 nm) due to the coating of HA. The average hydrodynamic diameters were measured using DLS. As depicted in Figure 1C , there was a slight increase in the hydrodynamic diameter was observed compared to the diameter in the TEM image, which was attributed to the adequate number of carboxyl groups in CuS:Ce6 and the adorned RGD molecule in CuS:Ce6@HA:DOX@RGD. The zeta potential change ( Figure 1D ) of the nanoparticles was within the range from −15 mV to −29 mV, which might be attributed to a dynamic self-assembly process of the nanoparticles. The results of the EDS analysis depicted in Figure 1E revealed that CuS:Ce6@HA:DOX@RGD was composed of Cu, S, C, N, and O elements. Moreover, the elemental mapping images ( Figure 1F ) showed that the signals of Cu, S, C, N, and O were dispersed homogeneously across the selected area of the CuS:Ce6@HA:DOX@RGD sample. The optical properties were then studied using UV-vis-NIR spectroscopy. As illustrated in Figure 1G , the CuS:Ce6@HA:DOX@RGD exhibited a significant characteristic absorption peak of CuS at 980 nm. Subsequently, the drug-loading efficiency of the nanoparticles was determined using ultraviolet spectroscopy. The CuS:Ce6@HA:DOX@RGD exhibited a high drug-loading efficiency (13.6 wt % for Ce6 and 14.5 wt % for DOX), which enabled adequate co-delivery of the photosensitizer and the chemotherapeutic agent. In addition, the negligible changes were observed in HD, which indicated that CuS:Ce6@HA:DOX@RGD had excellent colloidal stability after one week of storage even under laser irradiation ( Figure 1H and I ). Collectively, these results demonstrated that CuS:Ce6@HA:DOX@RGD nanoparticles with excellent stability had been prepared successfully and could be used in subsequent experiments. Figure 1 TEM images of CuS:Ce6@BSA (A) and CuS:Ce6@HA:DOX@RGD (B). (C) Size distribution of CuS:Ce6@BSA and CuS:Ce6@HA:DOX@RGD. (D) Zeta potentials of CuS:Ce6@BSA, CuS:Ce6@HA, CuS:Ce6@HA@RGD, and CuS:Ce6@HA:DOX@RGD. (E) EDS of the CuS:Ce6@HA:DOX@RGD. (F) Elemental mapping images of the CuS:Ce6@HA:DOX@RGD. (G) UV-vis-NIR absorbance spectra of CuS and CuS:Ce6@HA:DOX@RGD. (H) Hydrodynamic diameters (HD) measurement of the CuS:Ce6@HA:DOX@RGD in PBS and DMEM. (I) Hydrodynamic diameters (HD) measurement of the CuS:Ce6@HA:DOX@RGD in PBS and DMEM with laser irradiation. To assess photodynamic performance of CuS:Ce6@HA:DOX@RGD, the ROS levels were investigated with a probe (DCFH-DA), an indicator that ROS can rapidly oxidize it to emit fluorescence at 522 nm. The generated ROS levels were assessed based on the changes of the fluorescence at 522 nm. The fluorescence signal was observed, as depicted in Figure 2A and B , upon laser irradiation. Moreover, the fluorescence intensity changes were recorded at 522 nm, and the results are presented in Figure 2C . No significant change was detected in PBS (control group) with 15 min of laser irradiation. However, the intensity of the fluorescence emitted from the Ce6 and CuS:Ce6@HA:DOX@RGD solutions apparently increased with the increase in the duration of irradiation. As shown in Figure 2D , a high amount of ROS was generated according to the strong fluorescent intensity at 522 nm in CuS:Ce6@HA:DOX@RGD-treated cells after laser irradiation. These results illuminated that CuS:Ce6@HA:DOX@RGD could produce enough ROS to result in cellular toxicity. In view of the broad absorbance in the near-infrared region of CuS, the photothermal conversion of CuS:Ce6@HA:DOX@RGD in aqueous solution was evaluated under continuous laser irradiation at 980 nm and 1.5 W/cm2 for 6 min. As depicted in Figure 2E , the temperature of both CuS and CuS:Ce6@HA:DOX@RGD respectively increased by approximately 30°C within 6 min, while no evident temperature change was observed for the PBS solution (control group). These results demonstrated that when using laser irradiation at 1.5 W/cm2 for 6 min, the temperature was sufficiently high to kill cancer cells. The temperature elevation curve after four cycles of heating and natural cooling is depicted in Figure 2F , which illustrates that the excellent photothermal stability of the CuS:Ce6@HA:DOX@RGD. The real-time thermal images captured during the NIR laser irradiation are presented in Figure 2G . Furthermore, CuS:Ce6@HA:DOX@RGD exhibited remarkable photothermal performance that was dependent on concentration and laser irradiation power density-dependent photothermal performance ( Figure 2H and I ). These results indicated that the potential of the CuS:Ce6@HA:DOX@RGD has the potential as an activatable PDT/PTT agent for killing cancer cells. Figure 2 DFC fluorescence spectra of Ce6 (A), and CuS:Ce6@HA:DOX@RGD (B) upon 663 nm laser irradiation. (C) The DFC fluorescence intensity at 522 nm in PBS, Ce6 and CuS:Ce6@HA:DOX@RGD as a function of irradiation time. (D) The intracellular DFC fluorescence intensity at 522 nm after different treatments. (E) Temperature change curve of CuS:Ce6@HA:DOX@RGD, CuS, and PBS with 980 nm laser irradiation. (F) Photothermal stability of CuS:Ce6@HA:DOX@RGD. (G) Real-time thermal imaging of CuS (a), and CuS:Ce6@HA:DOX@RGD (b) solution upon laser irradiation. (H) Temperature increase curves of CuS:Ce6@HA:DOX@RGD at various concentrations during NIR irradiation. (I) Temperature increase curves of CuS:Ce6@HA:DOX@RGD under various power densities. Responsiveness of CuS:Ce6@HA:DOX@RGD to pH change and NIR irradiation was monitored in a release medium. As shown in Figure 3A , in the presence of hyaluronidase, the cumulative release of DOX reached 51.8% at pH 5.0 without laser irradiation, obviously higher than that without hyaluronidase (26.2% at pH 5.0). In contrast, a negligible release was detected at pH 7.4. The main reason is that hyaluronidase had higher enzymatic activity to degrade HA shell under acidic conditions than in neutral environment, which allowed some of the DOX to be released from the carrier, in agreement with a previous report. 31 Therefore, the pH-induced DOX release could prevent DOX release in blood circulation as the tumor tissue had an acidic pH lower than the normal tissue and biological fluids. 37 , 38 On the other hand, the DOX release profile from the CuS:Ce6@HA:DOX@RGD was about 58.2% at pH 5.0 with hyaluronidase and NIR laser, which was more than that of 51.8% with hyaluronidase and without NIR laser. The produced photothermal effect loosened the structure of the HA layer and decreased the viscosity of local HA, 39 , 40 thereby accelerating the release of DOX into the external environment. As expected, irradiation with NIR laser and a mildly acidic environment could induced the degradation of CuS:Ce6@HA:DOX@RGD and the release of DOX. It is noteworthy that the fluorescent signals of DOX were almost entirely quenched after DOX was loaded onto CuS:Ce6@HA@RGD, resulting in a fluorescence switch-off, due to the quenching ability of CuS based on Förster resonance energy transfer (FRET). 41 , 42 As illustrated in Figure 3B , at pH 5.0 and laser irradiation, the fluorescence intensity increased. The pH/NIR-induced DOX release led to DOX fluorescence switch-on. Collectively, these results demonstrated that the CuS:Ce6@HA:DOX@RGD exhibited pH-induced and NIR laser-responsive DOX release propensity, which would facilitate improving the efficiency of antitumor therapy. Figure 3 (A) In vitro cumulative release profile of DOX from CuS:Ce6@HA:DOX@RGD without NIR laser irradiation in different pH (a: pH 5.0, b: pH 6.0, c: pH 7.4) and with hyaluronidase in different pH (d: pH 5.0, e: pH 6.0, f: pH 7.4) and in different pH (g: pH 5.0, h: pH 6.0, i: pH 7.4) with NIR laser irradiation and hyaluronidase. (B) Fluorescence signal recovery of CuS:Ce6@HA:DOX@RGD at pH 5.0 without or with irradiation at indicated time points. We then studied the tumor selectivity of CuS:Ce6@HA:DOX@RGD in MCF-7 cells. The ability of CuS:Ce6@HA:DOX@RGD to target tumor cell was evaluated using fluorescence imaging. As illustrated in Figure 4A , the MCF-7 cells exhibited an extremely weak fluorescence signal in the DOX group, due to nonspecific uptake. The MCF-7 cells treated with CuS:Ce6@HA:DOX exhibited higher fluorescence signals compared to that of the cells treated with DOX, which was attributed due to the ability to bind specifically with the CD44 receptors overexpressed on the surface of cancer cells. However, the fluorescence signals were evidently higher in the CuS:Ce6@HA:DOX@RGD group compared to the CuS:Ce6@HA:DOX group. The fluorescence signals of CuS:Ce6@HA:DOX@RGD in normal cells presented low cellular uptake. These findings indicated that the specific and strong target-binding ability was due to synergic CD44/αvβ3 receptor-mediated bimodal targeting. In addition, the competitive binding of HA/RGD was studied to investigate the binding specificity of CuS:Ce6@HA:DOX@RGD ( Figure 4A ). Free HA/RGD was incubated with MCF-7 cells followed by the addition of CuS:Ce6@HA:DOX@RGD, allowing the receptors on the cells to be blocked by free HA/RGD. Indeed, the cellular uptake of CuS:Ce6@HA:DOX@RGD decreased evidently, confirming that the HA and RGD components in CuS:Ce6@HA:DOX@RGD conferred it with the dual-targeting. Meanwhile, the mean fluorescence intensity of the cells incubated with CuS:Ce6@HA:DOX@RGD was the highest among the different treatment groups ( Figure 4B ), which further confirmed the dual-mode tumor-targeting ability. In order to determine whether the local hyperthermia produced upon laser irradiation would accelerate the release of the loaded DOX specifically into the tumor tissue, the MCF-7 cells were respectively incubated with CuS:Ce6@HA:DOX@RGD with or without laser irradiation. As depicted in Figure 4C , the fluorescence signals of DOX were enhanced upon laser treatment as compared to the signals from non-irradiated cells. The accelerated DOX release after internalization was also confirmed based on the quantified fluorescence intensity ( Figure 4D ). These findings highlighted that the CuS:Ce6@HA:DOX@RGD was efficiently internalized by cancer cells and enhanced the intracellular release of DOX. Figure 4 (A) Cellular uptake of DOX, CuS:Ce6@HA:DOX, CuS:Ce6@HA:DOX@RGD, CuS:Ce6@HA:DOX+HA, CuS:Ce6@HA:DOX@RGD+RGD, and CuS:Ce6@HA:DOX@RGD+ HA+ RGD. C refers to cancer cell. N refers to normal cell. (B) Corresponding intracellular mean fluorescence intensity. (C) Cellular uptake of CuS:Ce6@HA:DOX@RGD after culture for 1, 2 and 4 h with or without laser irradiation. (D) Corresponding intracellular mean fluorescence intensity after incubation for 1, 2 and 4 h with or without laser irradiation. Cytotoxicity assay was employed to reveal the synergistic antitumour effects of CuS:Ce6@HA:DOX@RGD in MCF-7 cells by the detection of MTT test and live/dead cells staining assays. As depicted in Figure 5A , the CuS:Ce6@HA:DOX@RGD group with two rounds of irradiation exhibited a further powerful cancer cell-killing efficacy compared to the CuS:Ce6@HA:DOX@RGD group with one just round of irradiation and the CuS:Ce6@HA@RGD group with two rounds of irradiation, suggesting a good synergistic therapeutic effect. The cell viability decreased slightly in the CuS:Ce6@HA:DOX@RGD group, while the control and only laser treatment groups exhibited negligible toxicity in MCF-7 cells. The results of the subsequent live/dead cell-staining experiments ( Figure 5B ) revealed the MCF-7 cells stained with PI (dead cells) and calcein-AM (live cells) in different groups. The MCF-7 cells in the CuS:Ce6@HA:DOX@RGD group with two rounds of irradiation exhibited evidently higher killing rates compared to the other five groups. The overall variation trend of the fluorescence pattern was consistent with the MTT results. In addition, the viability of MCF-7 cells decreased greatly as the concentration of CuS:Ce6@HA:DOX@RGD increased ( Figure 5C ), demonstrating dose-dependent apoptosis upon laser irradiation. Collectively, these results demonstrated that the CuS:Ce6@HA:DOX@RGD group with two rounds of irradiation exhibited a synergistic PDT/PTT/Chemo effect that enhanced the efficiency of killing cancer cells. Figure 5 (A) Viabilities of MCF-7 cells after different treatments: control(a), 663 nm+980 nm laser(b), CuS:Ce6@HA:DOX@RGD(c), CuS:Ce6@HA:DOX@RGD+663 nm(d), CuS:Ce6@HA:DOX@RGD+980 nm(e), CuS:Ce6@HA@RGD+663 nm+980 nm(f), and CuS:Ce6@HA:DOX@RGD+663 nm+980 nm(g). (B) Live/dead images of MCF-7 cells stained with calcein AM/PI under different conditions. (C) Viabilities of MCF-7 cells incubated with different concentrations of CuS:Ce6@HA:DOX@RGD without laser irradiation(a), with 663 nm(b), with 980 nm(c), and with 663 nm+980 nm(d) laser irradiation. Encouraged by the high cytotoxicity of CuS:Ce6@HA:DOX@RGD in vitro, we further evaluated the PDT/PTT/Chemo therapeutic efficiency in tumor-bearing mice model. The tumor-bearing mice were divided into six groups and then treated followed by an assessment of the variation trend of tumor volume in the next 14 days. In addition, the relative tumor growth curve was obtained for each group and is depicted in Figure 6A . Notably, the tumor growth in the CuS:Ce6@HA:DOX@RGD group with rounds of irradiation presented the greatest inhibition, owing to the synergetic PDT/PTT/Chemo effect. The CuS:Ce6@HA:DOX@RGD groups with just one round of irradiation presented moderate tumor inhibition due to PDT/Chemo and PTT/Chemo effects. The CuS:Ce6@HA:DOX@RGD group without irradiation presented limited tumor inhibition due to the single Chemo effect. In contrast, the tumor volume in groups a and b increased significantly over the course of treatment. Meanwhile, the body weight of the mice in each group was recorded ( Figure 6B ) during the therapeutic process, and insignificant body weight changes were observed. After treatments for 14 days, the mice were sacrificed (following standard and allowed practices), and the tumors were excised, imaged, weighed, and subjected to further analysis using H&E staining. As depicted in Figure 6C-E , the smallest tumors and the lowest tumor mass were observed in the CuS:Ce6@HA:DOX@RGD group with two rounds of irradiation. The tumor growth inhibition rate reached 90.3% in this group, which was much higher than that noted in the other five groups. Furthermore, the H&E staining results revealed that the CuS:Ce6@HA:DOX@RGD group with two rounds of irradiation presented the most severe morphological changes and necrosis ( Figure 6F ). Collectively, these results indicated that the tumor growth could be effectively inhibited through the synergetic PDT/PTT/Chemo effect. Figure 6 (A) Relative tumor growth curves and (B) the variations of body weight in different groups: (a) control (treated with PBS), (b)control (PBS) + NIR, (c)CuS:Ce6@HA:DOX@RGD, (d)CuS:Ce6@HA:DOX@RGD+663nm, (e)CuS:Ce6@HA:DOX@RGD+980nm; (f) CuS:Ce6@HA:DOX@RGD+663nm+980nm. (C) Photographs of tumors collected from various mice groups after 14 day treatment. (D) Average tumor weight of each group. (E) Tumor inhibition rate of each group. (F) H&E-stained images of tumor tissues section from different groups. **P < 0.01; ***P < 0.001; ****P < 0.0001. It is well recognized that good biocompatibility/biosafety is essential for the application of the prepared CuS:Ce6@HA:DOX@RGD in the field of biomedicine. Therefore, the in vitro/in vivo biocompatibilities of CuS:Ce6@HA:DOX@RGD were evaluated systematically using normal cell culture, the hemolysis assay, and whole animal experiments. As depicted in Figure 7A and B , after co-incubation with normal cells at increasing concentrations for 12 h or 24 h followed by the MTT assay indicated that both the cell viabilities remained above 85% at the different concentrations of CuS:Ce6@HA:DOX@RGD (up to 200 μg/mL). Meanwhile, the in vitro cytotoxicity of CuS:Ce6@HA:DOX@RGD was also evaluated using the calcein-AM/PI (live/dead) staining assay. After incubation for 12 h or 24 h, numerous living cells with green fluorescence and only a few dead cells with red fluorescence were observed ( Figure 7C ). The results of the live/dead cell-staining assay were, therefore, consistent with the MTT results, demonstrating negligible cell toxicity. The biocompatibility was further confirmed using the hemolysis assay. The results revealed no apparent hemolysis in the treated group within the experimental concentration range ( Figure 7D ). The hemolysis ratio, in the range of experimental concentrations, was less than 5%. Figure 7 Cell viability after incubation with CuS:Ce6@HA:DOX@RGD at different concentrations for 12 h (A) and 24 h (B). (C) Fluorescence images of cells stained with calcium-AM and PI under different conditions. (D) Hemolysis analysis of CuS:Ce6@HA:DOX@RGD at various concentrations, using PBS and deionized water as a negative and positive control, respectively. (E) The body weights curves of mice after different treatments. After injecting the CuS:Ce6@HA:DOX@RGD solution intravenously into healthy mice, no evident body weight decrease ( Figure 7E ) was observed compared to the mice in PBS group. Subsequently, a blood routine analysis was conducted (including RBC, HGB, WBC, and PLT) to investigate the potential toxicity of CuS:Ce6@HA:DOX@RGD in blood cells and the hematopoietic system. As depicted in Figure 8 , no significant abnormalities were observed between the treatment and control groups after administration for 1 days,7 days, and 14 days. In addition, the blood biochemistry evaluations, including ALB, AST, and ALT, CR and UREA, revealed no evident abnormal changes were observed after administration for 1 days, 7 days, and 14 days ( Figure 8 ). Furthermore, the H&E staining images of the major organs (liver, kidney, spleen, heart, and lung) of the mice in the treated groups were obtained and are presented in Figure 9 . No evident tissue abnormalities were observed after administration for 14 days. These results collectively demonstrated the safety of CuS:Ce6@HA:DOX@RGD for application in anticancer. Figure 8 In vivo toxicology assessment by the routine blood analysis: white blood cell (WBC), red blood cell (RBC), hematocrit (HCT), hemoglobin (HGB), platelet (PLT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC); the blood biochemistry test: alanine transaminase (ALT), Aspartate transaminase (AST), albumin (ALB), lactic dehydrogenase (LDH), total protein (TP), total bilirubin (TBIL), urea (UA), and creatinine (CREA). Figure 9 H&E-stained images of tissues (liver, kidney, spleen, heart, and lung) of the mice harvested from various mice groups (a: control, b: 663nm+980nm, c: CuS:Ce6@HA:DOX@RGD, d: CuS:Ce6@HA:DOX@RGD+663nm, e: CuS:Ce6@HA:DOX@RGD+980nm; f: CuS:Ce6@HA:DOX@RGD+663nm+980nm) after 14 day treatment. Conclusion In the present study, a novel biodegradable nanoplatform named CuS:Ce6@HA:DOX@RGD was fabricated successfully using a facile and green approach. We have demonstrated that the cellular uptake of the CuS:Ce6@HA:DOX@RGD can be improved by CD44/αvβ3-mediated endocytosis. The dual-targeting CuS:Ce6@HA:DOX@RGD possessed excellent biocompatibility and exhibited dual-responsive pH and NIR irradiation DOX release and high photodynamic and photothermal effects. As the result of high cellular internalization and pH/NIR response capability, the CuS:Ce6@HA:DOX@RGD exhibited high cytotoxicity against MCF-7 cancer cells and significant antitumor effect in vivo. Our results demonstrate that CuS:Ce6@HA:DOX@RGD possess great potential for dual-targeting and dual-responsive synergistic therapy and the nanoplatform is expected to serve as a good platform for carrying other therapeutic agents to the micro-environment of tumour. The findings of the present study provided a novel strategy to design an effective and multifunctional nanoplatform exhibiting enhanced therapeutic efficacy against cancer. Ethics Approval All animal and MCF-7 cell procedures were performed in strict accordance with the Guidelines for the Care and Use of Laboratory Animals and approved by the Animal Ethics Committee of Huanggang Normal University. Funding This work was financially supported by the National Natural Science Foundation of China (21765022), the Research Fund of Huanggang Normal University (2042023016), and the Key Research and Development Program of Hubei Province (2022BCE013). Disclosure

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