Non‐Covalently Stapled H<sup>+</sup>/Cl<sup>−</sup> Ion Channels Activatable by Visible Light for Targeted Anticancer Therapy
Qishuo Zhong, Yin Cao, Xiaopan Xie, Yuhang Wu, Zhiqing Chen, Qiuping Zhang, Chunyan Jia, Zhen Wu, Pengyang Xin, Xiaosheng Yan, Zhiping Zeng, Changliang Ren
Abstract
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 (IC 50 =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.