Single Molecule for Trifecta PDT: Tailor-Made Three-Organelle-Targeting Type I Photosensitizer for Cancer Cell-Selective Photodynamic Therapy under Hypoxia

High Resolution Image Download MS PowerPoint Slide Cancer cell-selective multiorganelle-targeting type I photosensitizers (PSs) may greatly enhance the treatment efficiency of photodynamic therapy (PDT) and revolutionize cancer therapy. However, the related systematic design strategies remain vague. Herein, we developed a series of three-organelle-targeting PSs with varied N-containing substituents, which localized in the plasma membrane, mitochondria, and nucleus of cancer cells. These molecules exhibited diverse photosensitizing capabilities, ranging from non-photosensitivity to pure type I or II photosensitization or a mix of type I/II photosensitization. We investigated and discussed the structure–function relationship among these molecules. Notably, ACR-DME, as a type I PS, can selectively bind to cancer cells over noncancer cells, which demonstrated impressive PDT efficacy to cancer cells under hypoxic conditions and effectively curbed the proliferation of 4T1 tumors in vivo . Our findings contribute valuable insights for the design of effective PSs for trifecta PDT under hypoxic conditions, propelling advancements in cancer treatment strategies.