Integrating perfluorocarbon and type-I photosensitizer into a single molecule: a phenothiazine-based platform for hypoxia-tolerant PDT

Abstract

Hypoxia-induced resistance remains a major obstacle in photodynamic therapy (PDT) due to the oxygen dependency of conventional type-II photosensitizers. To tackle this issue, we developed a phenothiazine-based small molecule (PFI) that integrates intrinsic oxygen-carrying perfluoroalkyl chains with type-I photodynamic functionality. The perfluorinated segments enable localized oxygen enrichment to counteract tumor hypoxia, while the phenothiazine core generates reactive oxygen species (ROS) via an oxygen-independent type-I pathway, sustaining phototoxicity even under low-oxygen environments. Both in vitro and in vivo studies confirm that PFI effectively accumulates in tumors, relieves hypoxia, and achieves potent antitumor efficacy with negligible side effects. This single-component design offers a facile and robust platform for hypoxia-tolerant photodynamic cancer therapy.