Changliang Ren | Angewandte Chemie-International Edition: Non-Covalently Stapled H+/Cl− Ion Channels Activatable by Visible Light for Targeted Anticancer Therapy

Abstract

The development of stimuli-responsive artificial H+/Cl− ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non-covalently stapled self-assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co-transport of H+/Cl− across the membrane with H+/Cl− transport selectivity of 6.0. Upon photoirradiation of the caged C4F-L for 10 min, 90 % of ion transport efficiency can be restored, giving rise to a 10.5-fold enhancement in cytotoxicity against human colorectal cancer cells (IC50=8.5 μM). The mechanism underlying cancer cell death mediated by the H+/Cl− channels involves the activation of the caspase 9 apoptosis pathway as well as the scarcely reported disruption of the autophagic processes. In the absence of photoirradiation, C4F-L exhibits minimal toxicity towards normal intestine cells, even at a concentration of 200 μM.

Link: https://onlinelibrary.wiley.com/doi/10.1002/anie.202314666