Tuning Excited-State TICT Dynamics in Hemicyanine Type I Photosensitizers for Hypoxia-Tolerant Photodynamic Therapy of Cholangiocarcinoma

This is the authors' abstract. We don't add key points for this paper.

Although photodynamic therapy (PDT) has emerged as a promising treatment for unresectable cholangiocarcinoma, the hypoxic tumor microenvironment severely limits oxygen-dependent Type II photochemical processes, resulting in insufficient reactive oxygen species (ROS) generation and compromised therapeutic outcomes. Therefore, developing Type I photosensitizers (PSs) with optimized excited-state dynamics and efficient hypoxia-tolerant ROS generation is critical for improving PDT efficacy under hypoxic conditions. Herein, we developed three hemicyanine-based Type I PSs (HCy1–3) and systematically investigated the relationship between molecular structure, TICT-mediated excited-state relaxation, and ROS generation behavior. By modulating the electron-donating capability of donor moieties, the TICT characteristics of the hemicyanine scaffold were precisely tuned, thereby regulating the competition between nonradiative decay and ROS-generating pathways. Among them, HCy3 exhibited enhanced excited-state utilization and the highest Type I ROS generation efficiency under both normoxic and hypoxic conditions. Furthermore, HCy3 efficiently accumulated in mitochondria and induced mitochondrial dysfunction, leading to superior photodynamic cytotoxicity against cholangiocarcinoma cells under hypoxia compared with the clinically used PS HiPorfin. The therapeutic potential of HCy3 was further validated in cholangiocarcinoma organoids. This study establishes a structure–photophysics-photochemistry correlation between TICT regulation and Type I ROS generation, providing a mechanistic strategy for designing high-performance hypoxia-tolerant PSs for PDT.