Synergistic effects of photodynamic therapy and chemotherapy: Activating the intrinsic/extrinsic apoptotic pathway of anoikis for triple-negative breast cancer treatment

Triple-negative breast cancer (TNBC) is a highly invasive and metastatic subtype of breast cancer that often recurs after surgery. Herein, we developed a cyclodextrin-based tumor-targeted nano delivery system that incorporated the photosensitizer chlorin e6 (Ce6) and the chemotherapeutic agent lonidamine (LND) to form the R6RGD-CMβCD-se-se-Ce6/LND nanoparticles (RCC/LND NPS). This nanosystem could target cancer cells, avoid lysosomal degradation and further localize within the mitochondria. The RCC/LND NPS had pH and redox-responsive to control the release of Ce6 and LND. Consequently, the nanosystem had a synergistic effect by effectively alleviating hypoxia, enhancing the production of cytotoxic reactive oxygen species (ROS) and amplifying the efficacy of photodynamic therapy (PDT). Furthermore, the RCC/LND NPS + light weakened anoikis resistance, disrupted extracellular matrix (ECM), activated both the intrinsic apoptotic pathway (mitochondrial pathway) and extrinsic apoptotic pathway (receptor death pathway) of anoikis. In addition, the nanosystem showed significant anti-TNBC efficacy in vivo. These findings collectively demonstrated that RCC/LND NPS + light enhanced the anticancer effects, induced anoikis and inhibited tumor cell migration and invasion through a synergistic effect of chemotherapy and PDT. Overall, this study highlighted the promising potential of the RCC/LND NPS + light for the treatment of TNBC.