Development of Mitochondria‐Targeting Photosensitizers via Topoisomerase I Inhibition

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. We designed and synthesized mitochondria-targeting photosensitizers via Top1 inhibition activity of IQ. IQ6 effectively suppressed Top1 activity and IQ-Ps enabled the visualization of the covalent adduct with Top1. IQ-S1 showed potent anti-proliferative activity against cancer cells and presented photoinduced redistribution with sequential targeting of the mitochondria and nucleus depending on irradiation time.+image