De novo design of type-l photosensitizer agents based on structure-inherent low triplet energy for hypoxia photodynamic therapy

Photodynamic therapy (PDT), owing to its low invasiveness, high efficiency, fewer side effects, spatiotemporal controllability and good selectivity, has attracted increasing attention for its tremendous potential in revolutionizing conventional strategies of tumor treatment. However, hypoxia is a common feature of most malignancies and has become the Achilles' heel of PDT. Currently, Type II photosensitizers (PSs) have inadequate efficacy for PDT due to the inherent oxygen consumption of the anoxic tumor microenvironment. Moreover, due to the absence of a general molecular design strategy and the limitations imposed by the energy gap law, Type-I PSs are less reported. Therefore, the development of Type-I PSs with hypoxia resistant capabilities is urgently required. Herein, in this study, we have obtained pure Type-I materials for the first time by employing a strategy that decreases the triplet energy levels of the π-conjunction bridge. A sufficient donor-acceptor interaction reduces the lowest triplet energy level and aids in the transfer of excitons from singlet to triplet levels. With this strategy, dibenzofulvene derivatives (FEs) displayed purely Type-I ROS generation. Among them, FE-TMI exhibits superior Type-I reactive oxygen species-generation performance, showcasing the great potential of PDT in treating tumor cells under hypoxic conditions and several types of solid tumors in mouse in vivo experiments. This work provides a practical solution for the future design of Type-I PDT materials and is aimed at enhancing PDT efficiency.