Carrier-free nanodrug based on small molecule drug and sonosensitizer for enhanced the ferroptosis-driven multimodal synergistic therapy of prostate cancer

Ferroptosis plays a significant role in overcoming the therapeutic resistance of cancer cells. Herein, a carrier-free nanoparticle based on small molecule drug sorafenib (SRF) and sonosensitizer rose bengal (RB) was constructed (named SR NPs) for ferroptosis-driven chemotherapy and sonodynamic synergistic therapy (SDT) of prostate cancer (PCa). SR NPs could be enriched in tumor cells and efficiently inhibit tumor cell proliferation. These nanodrugs could significantly reduce glutathione (GSH) synthesis, and inhibit glutathione peroxidase 4 (GPX4) expression by inhibiting the glutamate/cysteine antiporter system (System Xc^-) pathway of ferroptosis. Moreover, SR NPs-mediated ferroptosis significantly improved the amount of reactive oxygen species (ROS) generated by SDT, inhibited cell migration and adhesion, enhanced the accumulation of lipid peroxides (LPO) and augmented chemo-sonodynamic therapy. Notably, in vivo studies demonstrated that SR NPs enhanced tumor accumulation, exhibited good biocompatibility, and showed high anti-tumor efficacy in PC-3 tumor-bearing mice. This work offered a new strategy to enhance the treatment efficacy of prostate cancer (PCa) through ferroptosis-chemotherapy-sonodynamic synergistic therapy.