Organelle-Targeted Photosensitizers for Enhanced Photodynamic Therapy of Cancer

Photodynamic therapy (PDT) efficacy is limited by the random intracellular distribution of conventional photosensitizers (PSs), as reactive oxygen species (ROS) have an extremely short half-life. Organelle-targeted PSs can enhance PDT efficacy by concentrating ROS at critical subcellular sites, yet systematic evaluation and comparison of different organelle targets using a uniform parent PS remain scarce. Herein, a panel of organelle-targeted PSs using pyropheophorbide a (Ppa) as the parent photosensitizer was synthesized via a facile amide condensation reaction, including mitochondria-targeted PS (Ppa-Mit), lysosome-targeted PS (Ppa-Lys), endoplasmic reticulum-targeted PS (Ppa-ER), and nucleus-targeted PS (Ppa-Nuc). These PSs retained the optical properties of parent Ppa and exhibited precise organelle localization. Ppa-Mit showed the highest cellular uptake and ROS generation, while Ppa-Lys displayed the strongest photocytotoxicity with the lowest IC50 (0.109 μM) against Panc02 cells. Flow cytometry confirmed that all PSs induced tumor cell death primarily via inducing cell apoptosis. Notably, in this study, lysosome-targeted Ppa (Ppa-Lys) exhibited the strongest photocytotoxicity among the four organelle-targeted PSs tested in Panc02 cells. This study demonstrates lysosomal-targeting modification of PSs as a universal and effective strategy to improve the antitumor efficacy of PDT, providing valuable insights for rational PS design.