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Intracellular Fenton Reaction based on Mitochondria-Targeted Copper(Ⅱ)-Peptide Complex for Induced Apoptosis

Abstract

Cancer cells hydrogen peroxide (H2O2) that induces apoptosis has achieved great process, but the conversion of H2O2 into a highly toxic hydroxyl radical (•OH) directly by Fenton reaction in mitochondria to induce cancer cell apoptosis has been rarely used in biomedical systems. Herein, a metal-peptide complex, comprised of copper-binding GGH (Gly-Gly-His) domain and mitochondria penetrating peptide (MPP), FrFKFrFK-CONH2 (Phe-r-Phe-Lys-Phe-r-Phe-Lys-CONH2, where r = D-arginine) is designed. The GGH is a motif can form coordination complexes with copper(Ⅱ) such that the MPP with alternating cationic and hydrophobic residues could transport copper(Ⅱ) into mitochondria. The copper(Ⅱ)-MPP complex in presence of ascorbate (Asc) exhibites strong cytotoxicity to cell lines, especially HeLa cells, due to the selective intracellular uptake ability of copper(Ⅱ). In mitochondria, the copper(Ⅱ)-MPP complex induces Fenton reaction with endogenous H2O2 to produce high reactive radical •OH. Meanwhile, continuous production of •OH are toxic to cells through depolarizing mitochondrial membrane potential (∆ψm), blocking cell cycle and inducing apoptosis of cancer cells. These results establishes a new system of Cu-mediated •OH generation via intra-mitochondrial Fenton reaction among copper(Ⅱ)-MPP complex, Asc and H2O2 in response to cancer cells microenvironment, which opens a promising treatment in cancer therapies.

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Publication details

The article was received on 23 Mar 2019, accepted on 13 May 2019 and first published on 14 May 2019


Article type: Paper
DOI: 10.1039/C9TB00569B
J. Mater. Chem. B, 2019, Accepted Manuscript

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    Intracellular Fenton Reaction based on Mitochondria-Targeted Copper(Ⅱ)-Peptide Complex for Induced Apoptosis

    X. Li, S. Hao, A. Han, Y. Yang, G. Fang, J. Liu and S. Wang, J. Mater. Chem. B, 2019, Accepted Manuscript , DOI: 10.1039/C9TB00569B

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