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

Abstract

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.