New Janus Organic Type-I Photosensitizer Capable of Transforming Glutathione from Opponent to Ally for Assisting Photodynamic Therapy

The overexpressed glutathione (GSH) in tumor cells was a crucial obstacle to improving the performance of photodynamic therapy (PDT). Complex approaches combined with different substances for PDT and GSH depletion brought potential toxic/side effects of metal ions or used unsustainable disulfide bonds. Therefore, a photosensitizer (PS) capable of continuously depleting GSH and keeping reactive oxygen species (ROS) generation from falling simultaneously is still a challenge. Here, the newly designed Janus-PSs of TBBr and TBT addressed this challenge. They exhibited effective ROS generation of hydroxyl radical ((OH)-O-center dot) and superoxide anion (O-2(center dot-)) in normoxia or hypoxia upon light irradiation. More importantly, these Janus-PSs could continuously deplete GSH by directly utilizing it as an "electron reservoir" in the photoredox process of PDT to promote the O-2(center dot-) generation, resulting in transforming GSH from an opponent to an ally for improving PDT performance. The Janus-PS of TBBr achieved a significant tumor growth inhibition (TGI) rate of 96.3% and a survival rate of 50% for mice even after a 60-day observation from in vivo experiments. Besides offering a novel approach to improve PDT performance, this work also provides new experimental insights into the photoredox mechanism of type-I PSs and potential contributions for PDT from substances in the cellular microenvironment.