Photoinduced Carbene for Effective Photodynamic Therapy Against Hypoxic Cancer Cells

Photodynamic therapy (PDT) has attracted much attention because of its advantages over chemotherapy, such as broad spectrum, high selectivity, and low drug resistance. However, most photosensitizers (PSs) used in PDT are O2-dependent and show limited therapeutic efficacy toward hypoxic solid tumors. Therefore, developing PSs that produce reactive oxygen species (ROS) in an O2 -independent manner is highly demanded. Herein, we constructed a novel O2-independent PS (TPA-N) based on & alpha;-diazo-aryl acetate, which could generate reactive carbene under visible light irradiation. Photoinduced carbene could react with biosubstrates and cause significant carbene stress and ROS, effectively killing tumor cells even under hypoxic conditions. TPA-N showed much less O2 dependence compared with traditional PDT reagent protoporphyrin IX. A mechanistic study suggested that TPA N could induce mitochondrial membrane potential collapse and upregulate apoptosis-related proteins upon light irradiation. This work provided a reliable strategy for developing O2-independent PSs against hypoxic tumor cells through photoinduced carbene.