Exploring the Phototherapeutic Applications of Mitochondria-Targeted COUPY Photocages of Antitumor Drugs

Photocleavable protecting groups hold great promise in photopharmacology to control the release of bioactive molecules from their caged precursors within specific subcellular compartments. Herein, we describe a series of photocages based on a COUPY scaffold, incorporating chlorambucil (CLB) and 4-phenylbutyric acid (4-PBA) as bioactive payloads that can be efficiently activated with visible light. Confocal microscopy confirmed the preferential accumulation of CLB and 4-PBA N-hexyl COUPY photocages in the mitochondria, which exhibited a remarkable phototoxicity against cancer cells upon green-yellow light irradiation, with IC₅₀ values in the nanomolar range. This effect was attributed to a synergistic mechanism involving the photorelease of the bioactive payloads and the intrinsic photogeneration of Type I and Type II ROS by the COUPY scaffold within mitochondria. Thus, COUPY-caged derivatives of CLB and 4-PBA underscore the potential of COUPY-caging groups as a versatile platform to develop innovative light-activated agents operating simultaneously through photodynamic therapy and photoactivated chemotherapy.