文献类型：期刊文献

英文题名：Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1-hexokinase-II complex

作者：Liu, Dan[1,2];Angelova, Angelina[3];Liu, Jianwen[4,5];Garamus, Vasil M.[6];Angelov, Borislav[7];Zhang, Xinlei[1,2];Li, Yawen[1,2];Feger, Guillaume[3];Li, Na[8,9];Zou, Aihua[1,2]

机构：[1]East China Univ Sci & Technol, Sch Chem & Mol Engn, State Key Lab Bioreactor Engn, Shanghai Key Lab Funct Mat Chem, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Sch Chem & Mol Engn, Inst Appl Chem, Shanghai 200237, Peoples R China;[3]Univ Paris Saclay, Univ Paris Sud, Inst Galien Paris Sud, LabEx LERMIT,CNRS,UMR 8612, F-92296 Chatenay Malabry, France;[4]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[5]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[6]Helmholtz Zentrum Geesthacht, Ctr Mat & Coastal Res, D-21502 Geesthacht, Germany;[7]Acad Sci Czech Republ, ELI Beamlines, Inst Phys, Slovance 2, CZ-18221 Prague, Czech Republic;[8]Natl Ctr Prot Sci Shanghai, Shanghai 200120, Peoples R China;[9]Shanghai Inst Biochem & Cell Biol, Shanghai 200120, Peoples R China

年份：2019

卷号：7

期号：30

起止页码：4706

外文期刊名：JOURNAL OF MATERIALS CHEMISTRY B

收录：;EI(收录号：20193207273718);WOS:【SCI-EXPANDED(收录号:WOS:000477985400010)】；

基金：We gratefully acknowledge the support of this work from the National Natural Science Foundation of China (no. 21573070, 21872051, and U1832144), the Youth Innovation Promotion Association of Chinese Academy of Science (no. 2017319), and the Czech Science Foundation (GACR project no. 17-00973S). SAXS analysis benefited from the use of the SasView application, originally developed under NSF Award DMR-0520547. SasView also contains code developed with funding from the EU Horizon 2020 programme under the SINE2020 project (no. 654000).

语种：英文

外文关键词：Circular dichroism spectroscopy - Self assembly - Diseases - X ray scattering - Dichroism - Cell death - Peptides - Biological organs

摘要：Mitochondria-targeting peptides represent an emergent tool for cancer inhibition. Here supramolecular assemblies of novel amphiphilic cell-penetrating peptides for targeting cancer cell mitochondria are reported. The employed strategy aims at amplifying the apoptotic stimuli by weakening the mitochondrial VDAC1 (voltage-dependent anion channel-1)-hexokinase-II (HK-II) interaction. Peptide engineering is performed with the N-terminus of the HK-II protein, which binds to VDAC1. First, a designed positively charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV). Second, a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV in order to enhance the intracellular delivery of the HK-II scaffold. The self-assembly properties of these two synthetic peptides are investigated by synchrotron small-angle X-ray scattering (BioSAXS) and cryogenic transmission electron (cryo-TEM) imaging, which evidence the formation of nanoassemblies of ellipsoid-like shapes. Circular dichroism (CD) spectroscopy demonstrates the induction of partial alpha-helical structures in the amphiphilic peptides. Confocal microscopy reveals the specific mitochondrial location of Pal-pHK-pKV assemblies in human non-small cell lung cancer (NSCLC) A549 cells. The cytotoxicity and apoptotic studies indicate the enhanced bioactivity of Pal-pHK-pKV self-assembled reservoirs, which cause massive A549 cell death with regard to pHK-pKV. Of significance, Pal-pHK-pKV treatment of non-cancerous NCM460 cells resulted in substantially lower cytotoxicity. The results demonstrate the potential of self-assembled lipo-peptide (HK-II-derived) conjugates as a promising strategy in cancer therapy.