在大自然中,神经酰胺是一类鞘脂,具有独特的自组装成蛋白质可渗透通道的能力,具有有趣的浓度依赖性适应性通道腔。然而,在人工离子通道领域,这种有趣的现象几乎没有表现出来。在这里,我们报告了一类新型的自适应人工通道,pn-TPP,基于带有三苯基鳞(TPP)基团作为阴离子结合基序的聚乙二醇化胆酸。有趣的是,分子在低浓度时自组装成氯离子通道,而在高浓度时转化为小分子可渗透的纳米孔。此外,TPP基团赋予分子线粒体靶向特性,使它们能够选择性地在癌细胞的线粒体膜上钻孔,并随后触发caspase9凋亡途径。Pn-TPP的抗癌功效与其形成纳米孔的能力相关。重要的是,由P5-TPP形成的最活跃的群体对人类肝癌细胞表现出令人印象深刻的抗癌活性,IC50值为3.8μM。虽然表现出与阿霉素相似的抗癌性能,P5-TPP的选择性指数超过阿霉素16.8倍。
In 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.