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

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 RGDconjugated 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/alpha v beta 3 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.