Porphyrin Derivative with Binary Properties of Photodynamic Therapy and Water‐Dependent Reversible Photoacidity Therapy for Treating Hypoxic Tumor

Abstract Porphyrin photosensitizers are the classic drugs in clinical photodynamic therapy (PDT), but the hypoxia of tumor environment and the rapid oxygen consumption of PDT severely weaken their therapeutic effect. A recently reported water‐dependent reversible photoacidity therapy (W‐RPAT) is O 2 ‐independence, providing a solution for the treatment of hypoxic tumors. In this work, TPP‐O‐PEG5, a porphyrin derivative with binary properties of PDT and W‐RPAT, is designed and synthesized for the first time. The nanoparticles (NPs) of TPP‐O‐PEG5 encapsulated with DSPE‐mPEG2000, an amphiphilic polymer approved by Food and Drug Administration, can simultaneously produce reactive oxygen species and H + under irradiation of a 660 nm laser, and revert the H + back under darkness, presenting strong phototoxicity to multiple tumor cell lines with no obvious difference between the IC50 values tested under normoxic (≈20% O 2 ) and hypoxic (<0.5% O 2 ) conditions. Excitingly, in vivo experiments show that the therapeutic effect of TPP‐O‐PEG5 NPs on large hypoxic tumors is better than that of NPe6, a clinical porphin PDT drug. This work provides a novel strategy for porphyrin photosensitizers to break through the limitation of hypoxic environment, and significantly improve the phototherapeutic effect on hypoxic tumors.