Photoactivated hydroxyl radical generators with highly efficient charge separation for oxygen-independent photodynamic therapy

The design of photosensitizers that can generate ·OH from water as well as efficient charge separation (CS) is integral to the hypoxic tumor photodynamic therapy (PDT). However, such ·OH photo-generators are scarcely reported, let alone those based on a simple D-π-A scaffold. Herein, we highlight the ·OH photo-generators TPESPyCx@BSA based on a co-assembly strategy to initiate the photocatalysis of water oxidation into ·OH as well as the efficient charge-separation for oxygen-independent PDT. The TPESPyCx@BSA were constructed by the co-assembly of a series of simple D-π-A scaffold tetraphenylpyridine salt TPESPyCx with BSA. The high-efficiency generation of ·OH was confirmed by the EPR trapping technique, and the isotope tracing experiments revealed that the oxygen source of ·OH generation originated exclusively from the H₂O. The calculated VB potential of TPESPyCx@BSA met the thermodynamic conditions of ·OH produced by the oxidation of water. Deciphered by the transient absorbance spectra, the charge separation state was realized after the co-assembly, which guaranteed the electron transfer to generate ·OH following the oxygen-independent pathway. TPESPyCx@BSA exhibited superb photocytotoxicity even under severe anoxic conditions and excellent antitumor efficacy on in vivo mouse models. This work provides a strategy for constructing oxygen-independent photodynamic agents, which opens up an avenue for effective PDT against hypoxic tumors.