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

## TL;DR

This paper explores using COUPY photocages to target antitumor drugs to mitochondria, enabling light-activated cancer cell destruction.

## Contribution

Introduces COUPY photocages as a novel platform combining photodynamic and photoactivated chemotherapy.

## Key findings

- COUPY photocages with CLB and 4-PBA accumulate in mitochondria and show nanomolar phototoxicity against cancer cells.
- The phototoxic effect results from both drug release and ROS generation by the COUPY scaffold.
- This dual mechanism highlights COUPY's potential for developing light-activated therapeutic agents.

## Abstract

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.