From cell membrane to lysosome: Arginine modification boosts the phototoxic index of zinc phthalocyanine for efficient bladder cancer treatment

Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) generated by photosensitizers under light to kill cancer cells. The phototoxic index (PI) indicates the safe therapeutic window of photosensitizers, and an ideal photosensitizer should have a high PI. Monosubstituted zinc phthalocyanine (ZnPc-COOH) exhibits excellent phototoxicity in bladder cancer cell (T24, IC 50  = 10.7 nM). However, its localization in mitochondria leads to high dark toxicity (IC 50  = 2.12 μM), resulting in a PI of less than 200. In this study, the binding ability of phthalocyanine to the cell membrane was significantly enhanced by side-chain modification with arginine. By taking advantage of the fluidity of the membrane structure, the drug was transported to the lysosome. After modification with Arg, the dark toxicity of ZnPc-COOH decreased by nearly 100 times, and the PI increased to 8979, which is 12 times that of the clinical photosensitizer Photosens®. In a mouse model of non-muscle-invasive bladder cancer (NMIBC), ZnPc-Arg demonstrated therapeutic effects comparable to those of the clinical drug mitomycin C (MMC). This study provides valuable references for the design of photosensitizers with high PI.