Oxygen-Independent Two-Photon Photodynamic Therapy Through Novel Photoinduced Triarylamine-Radical Cations

Photodynamic therapy (PDT) generally employs cytotoxic reactive oxygen species (ROS) for eliminating tumors. However, most photosensitizers rely on oxygen to sensitize ROS production, which conflicts with the pathological hypoxia environment in solid tumors. Thus, developing oxygen-independent therapeutic strategies for the combat of tumors is in urgent need. In this work, we report the usage of novel photoinduced reactive nitrogen radical cations for oxygen-independent PDT. Three triarylamine derivatives (PNA-1/2/9) are facilely constructed through a highly efficient one-step reaction from common commercially available reagents, and demonstrate outstanding photoinduced oxidative capabilities, which are confirmed as triarylamine radical cations (PNA^•+). The generation of PNA^•+ does not require oxygen, and its stability surpasses that of ROS, leading to a more effective PDT outcome. Detailed studies reveal the excellent lipid-droplet targeting of PNA and high in vitro PDT efficacy even in hypoxic environments. Remarkably, these triarylamines demonstrate excellent two-photon absorbance with high cross-sections of up to 700 GM. Furthermore, effectively inhibition of tumor growth is observed in mouse model under two-photon excitation (808 nm). To the best of the knowledge, this work is the first case to use triarylamine radical cations for oxygen-independent PDT, opening a new avenue for the effective treatment of hypoxic tumors.