Concentration‐Driven Evolution of Adaptive Artificial Ion Channels or Nanopores with Specific Anticancer Activities

Author:

Chen Zhiqing12,Xie Xiaopan12,Jia Chunyan12,Zhong Qishuo12,Zhang Qiuping12,Luo Daoxin12,Cao Yin1,Mu Yuguang3,Ren Changliang12ORCID

Affiliation:

1. State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences Xiamen University Xiamen, Fujian 361102 China

2. Shenzhen Research Institute of Xiamen University Shenzhen, Guangdong 518057 China

3. School of Biological Sciences Nanyang Technological University 60 Nanyang Drive Singapore 637551 Singapore

Abstract

AbstractIn nature, ceramides are a class of sphingolipids possessing a unique ability to self‐assemble into protein‐permeable channels with intriguing concentration‐dependent adaptive channel cavities. However, within the realm of artificial ion channels, this interesting phenomenon is scarcely represented. Herein, we report on a novel class of adaptive artificial channels, Pn‐TPPs, based on PEGylated cholic acids bearing triphenylphosphonium (TPP) groups as anion binding motifs. Interestingly, the molecules self‐assemble into chloride ion channels at low concentrations while transforming into small molecule‐permeable nanopores at high concentrations. Moreover, the TPP groups endow the molecules with mitochondria‐targeting properties, enabling them to selectively drill holes on the mitochondrial membrane of cancer cells and subsequently trigger the caspase 9 apoptotic pathway. The anticancer efficacies of Pn‐TPPs correlate with their abilities to form nanopores. Significantly, the most active ensembles formed by P5‐TPP exhibits impressive anticancer activity against human liver cancer cells, with an IC50 value of 3.8 μM. While demonstrating similar anticancer performance to doxorubicin, P5‐TPP exhibits a selectivity index surpassing that of doxorubicin by a factor of 16.8.

Funder

National Natural Science Foundation of China

Science, Technology and Innovation Commission of Shenzhen Municipality

Publisher

Wiley

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