Multifunctional CuBiS-BP@PEI Radiosensitizer with Enhanced Reactive Oxygen Species Activity for Multimodal Synergistic Therapy.

Development of radiosensitizers with high-energy deposition efficiency, electron transfer, and oxidative stress amplification will help to improve the efficiency of radiotherapy. To overcome the drawbacks of radiotherapy alone, it is also crucial to design a multifunctional radiosensitizer that simultaneously realizes multimodal treatment and tumor microenvironment modulation. Herein, a multifunctional radiosensitizer based on the CuBiS-BP@PEI nanoheterostructure (NHS) for multimodal cancer treatment is designed. CuBiS-BP@PEI NHS is able to deposit a high radiation dose into cancer cells, enhancing the radiotherapy effect. Due to the heterostructure and the synergistic effect of CuBiS and black phosphorus (BP), significantly boosted O and •OH generation is obtained under X-ray irradiation, which is promising for extremely efficient radiodynamic therapy. More importantly, the acidic tumor microenvironment (TME) can induce the cycle conversion of Cu to Cu, oxidizing glutathione (GSH) and catalyzing intracellular overproduction of HO into highly toxic •OH, which thus further enhances reactive oxygen species (ROS) production and reduces GSH-associated radioresistance. Furthermore, CuBiS-BP@PEI NHS has an excellent photothermal effect and can effectively transform light into heat. The outcomes of the in vitro and in vivo research confirm that the as-prepared CuBiS-BP@PEI NHS has a high synergistic therapeutic efficacy at a low radiation dose. This work provides a viable approach to constructing a multifunctional radiosensitizer for deep tumor treatment with TME-triggered multiple synergistic therapies.