Tumor-targeted nanosystem with hypoxia inducible factor 1α inhibition for synergistic chemo-photodynamic therapy against hypoxic tumor.

Photodynamic therapy (PDT) holds an essential role in the therapy of tumors. However, PDT consumes tissue oxygen and diminishes its own efficacy by inducing tumor hypoxia through the HIF-1α/VEGF pathway. Therefore, overcoming the photodynamic exacerbation of tumor hypoxia could reverse tumor microenvironment and enhance PDT. In this study, BC-PDA/HA loaded with bufalin (BUF) and chlorin e6 (Ce6) were developed for synergistic cancer chemo-photodynamic therapy. BC-PDA/HA, modified with hyaluronic acid (HA), exhibited CD44-targeting capability and enhanced cellular uptake in vitro. Moreover, in the acidic tumor microenvironment, BC-PDA/HA could on-demand release Ce6 and BUF, inducing PDT upon 660 nm irradiation. Simultaneously, the released BUF not only served as a chemotherapeutic agent, but also inhibited HIF-1α expression, reversing the PDT-induced tumor hypoxia. Furthermore, compared to free Ce6, BC-PDA/HA enhanced tumor accumulation and retention in vivo. BC-PDA/HA could also effectively improve hypoxia and inhibit tumor angiogenesis to enhance PDT efficacy, demonstrating synergistic chemo-PDT activity. In conclusion, this work provided a novel strategy for synergistic chemo-photodynamic therapy against breast cancer.