A switchable phototherapeutic strategy based on a hypoxia-responsive photosensitizer for heterogeneous tumor ablation

To address poor photodynamic efficacy against hypoxic tumor cells, we have developed a smart photosensitizing agent Ion-BDP whose phototherapeutic mode can be regulated by nitroreductase (NTR) that is rich in hypoxic tumor cells. This photosensitizer (PS) can eliminate outer aerobic tumor cells mainly by generating reactive oxygen species (ROS) upon illumination. Moreover, Ion-BDP is highly sensitive to NTR and capable of converting to BDP by removing the 4-nitrobenzyl group via reduction and subsequent self-immolation under hypoxic condition. The formed BDP behaving as a highly efficient photothermal agent can further kill the hypoxic tumor cells by photothermal therapy (PTT). The synergistic antitumor effects of this PS have been verified by in vitro and in vivo experiments. This study may provide a potential tactic to precisely overcome the inherent therapeutic difficulty arising from O2-distributional heterogeneity in solid tumors. In brief, we have designed, synthesized and evaluated a novel NTR-regulated PS and found that it can remarkably inhibit tumor growth in both hypoxic and normoxic conditions, which is proven to be a distinctive strategy for maximizing phototherapeutic efficacy.