Hypoxia-responsive paclitaxel prodrugs: linker evaluation and NIR-triggered self-amplifying photodynamic-chemotherapy nanoplatform.

Hypoxia-responsive prodrugs have emerged as a promising strategy for tumor-selective therapy, however, the optimization of responsive linker to maximize drug release efficiency remains critical. In this work, we systematically designed and successfully synthesized five structurally distinct hypoxia-responsive paclitaxel (PTX) prodrugs, identifying the 5-nitrofuryl alcohol (NFA)-modified PTX-NFA as the most efficient prodrug, with nearly complete prodrug reduction (>99%) and PTX release under hypoxic conditions. A hypoxia-responsive nanotherapeutic platform (PC-Ir@PTX-NFA NPs) combining photodynamic therapy and hypoxia-activated chemotherapy was further constructed. The PC-Ir component generates cytotoxic reactive oxygen species under 660 nm irradiation, directly killing tumor cells and exacerbating hypoxia, thereby triggering PTX release in a self-amplifying cycle. This study establishes a comprehensive structure-activity relationship of hypoxia-responsive linkers, offering valuable insights for future prodrug development in hypoxia-related diseases.