A Design Strategy of Pure Type-I Thiadiazolo[3,4-g]quinoxaline-based Photosensitizers for Photodynamic Therapy

Most photosensitizers (PSs) for photodynamic therapy (PDT) can generate singlet oxygen through transferring energy with oxygen, called Type-II PSs. However, the microenvironment of solid tumor is usually anoxic. Type-I PSs can generate reactive oxygen species (ROS) through transferring electron to substrate, showing more efficient in PDT. But pure Type-I PSs are very rare. The relationship between PSs' chemical structure and Type-I mechanism has not been explicitly stated. In this study, two thiadiazolo [3,4-g]quinoxaline (TQ) PSs (PsCBz-1 and PsCBz-2) are synthesized through introducing carbazole groups to the 4,9-position of TQ backbone. Comparing with their prototype PS, 4,9-dibrominated TQ (TQs-4), the introduction of carbazole groups reverses the reaction mechanism of PSs from pure Type-II to pure Type-I. Excitingly, the water-dispersible nanoparticles (NPs) of PsCBz-1 can achieve strong phototoxicity in vitro under both normoxia and hypoxia through Type-I mechanism. In addition, PsCBz-1 NPs also exhibits remarkable PDT antitumor effect in vivo. This study provides a feasible design strategy for pure Type-I PSs.