Development of Mitochondria‐Targeting Photosensitizers via Topoisomerase I Inhibition

Abstract Photodynamic therapy (PDT) is an important oncologic intervention option for combating drug resistance of current chemotherapy in cancer. To improve spatiotemporal control, the development of subcellular organelle‐targeting photosensitizers is critical due to the diffusion limits of short‐lived ROS. Mitochondrial topoisomerase 1 (TOP1MT), exclusively localized in mitochondria, is emerging as a promising target for anticancer treatment. In this work, we designed and synthesized mitochondria‐targeting photosensitizers via Top1 inhibition activity of IQ6 and visualized the covalent adducts between the engaged proteins and the synthesized photoaffinity labeling probes ( IQ‐Ps ). Positively charged derivatives ( IQ‐Ss ) were also synthesized and their photo‐induced cytotoxicity was assessed to select IQ‐S1 . Based on the cellular accumulation of IQ‐S1 in mitochondria and the enhanced PDT activity, we demonstrated that IQ‐S1 functions as a photosensitizer with sequential targeting of mitochondria and nucleus depending on irradiation times. Our findings suggest that the translocation of IQ‐S1 is related to the damage to mitochondrial Top1. The synthesized IQ‐S1 may contribute to the identification and tracking of cellular target proteins along with the PDT progression.