文献类型：期刊文献

英文题名：Disruption of Tumor Cells Using a pH-Activated and Thermosensitive Antitumor Lipopeptide Containing a Leucine Zipper Structure

作者：Wang, Sijia[1];Wang, Tong[1];Zhang, Junqi[2,3];Xu, Shouhong[1];Liu, Honglai[1]

机构：[1]East China Univ Sci & Technol, Sch Chem & Mol Engn, Key Lab Adv Mat, Shanghai 200237, Peoples R China;[2]Fudan Univ, Sch Basic Med Sci, Key Lab Med Mol Virol, MOE, Shanghai 200032, Peoples R China;[3]Fudan Univ, Sch Basic Med Sci, MOH, Shanghai 200032, Peoples R China

年份：2018

卷号：34

期号：30

起止页码：8818

外文期刊名：LANGMUIR

收录：;EI(收录号：20182605368511);WOS:【SCI-EXPANDED(收录号:WOS:000440768400012)】；

基金：Financial support for this work was provided by the National Natural Science Foundation of China (no. 21776071) and the National Natural Science Foundation of China for Innovative Research Groups (no. 51621002).

语种：英文

外文关键词：Cell death - Fatty acids - Tumors - Infrared reflection - Lanthanum compounds - Diseases - Monolayers - Adsorption - Cancer cells - Peptides - Phospholipids

摘要：Antitumor peptides may potentially alleviate the problem of chemoresistance but do not yet target tumor cells and would be cytotoxic to normal cells. Here, we designed a pH-activated and thermosensitive lipopeptide (C6-Pep) containing a leucine zipper and an alkyl chain and assessed the ability of C6-Pep to kill cancer cells. Pep, the same sequence without the N-terminal hexanoic acid moiety, was generated as a less hydrophobic control. First, lipopeptide adsorption into lipid monolayers was studied using Langmuir-Blodgett and polarization modulation infrared reflection adsorption spectroscopy. Under weakly acid conditions, electrostatic interactions between C6-Pep and negatively charged phospholipids increased the adsorption/insertion of C6-Pep (vs Pep) into lipid monolayers. Cargo leakage from liposomes was assayed to model lipopeptide-induced lipid membrane disruption. The ability of C6-Pep to disrupt liposomes depended on the peptide molecular structure/hydrophobicity, solution pH, and temperature-induced uncoiling of the zipper structure; the greatest cargo leakage from the liposome with negative charge was observed for C6-Pep at pH 5.5 under mildly hyperthermic conditions (45 degrees C). In vitro, C6-Pep was significantly more cytotoxic toward HeLa cells at pH 5.5 under hyperthermic conditions than at pH 7.4 and/or 37 degrees C. Overall, this study demonstrates that amphipathic C6-Pep can insert into cell membranes in the low-pH tumor microenvironment, whereas the application of heat promotes the uncoiling of the zipper structure, leading to the disruption of tumor cell membranes and cell death. pH-activated and thermosensitive C6-Pep represents a promising tool to kill cancer cells via a strategy that does not invoke chemoresistance and may have low side effects.