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.