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) and superoxide anion (O2•–) 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 O2•– 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.