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 α-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.

Helmholtz Zentrum Geesthacht Centre for Materials and Coastal Research D 21502 Geesthacht Germany

Institut Galien Paris Sud CNRS UMR 8612 LabEx LERMIT Univ Paris Sud Université Paris Saclay F 92296 Châtenay Malabry France

Institute of Physics ELI Beamlines Academy of Sciences of the Czech Republic Na Slovance 2 CZ 18221 Prague Czech Republic

National Center for Protein Science Shanghai and Shanghai Institute of Biochemistry and Cell Biology Shanghai 200120 P R China

Shanghai Key Laboratory of Functional Materials Chemistry State Key Laboratory of Bioreactor Engineering and Institute of Applied Chemistry School of Chemistry and Molecular Engineering East China University of Science and Technology Shanghai 200237 P R China

State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design School of Pharmacy East China University of Science and Technology Shanghai 200237 P R China

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