Supramolecular Antagonists Promote Mitochondrial Dysfunction
Li, MM (Li, Mingming) 1Song, YQ (Song, Yanqiu) 1Song, N (Song, Na) 1Wu, GY (Wu, Guangyao) 1Zhou, H (Zhou, Hao) 2Long, JF (Long, Jiafu) 2Zhang, PC (Zhang, Pengcheng) 3, 4Shi, LQ (Shi, Linqi) 1Yu, ZL (Yu, Zhilin) 1
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NANO LETTERS, 2021, 21(13): 5730-5737
DOI 10.1021/acs.nanolett.1c01469
Abstract
Mitochondrion-targeting therapy exhibits great potential in cancer therapy but significantly suffers from limited therapeutic efficiency. Here we report on mitochondrion-targeting supramolecular antagonist-inducing tumor cell death via simultaneously promoting cellular apoptosis and preventing survival. The supramolecular antagonist was created via coassembly of a mitochondrion-targeting pentapeptide with its two derivatives functionalized with a BH3 domain or the drug camptothecin (CPT). While drug CPT released from the antagonist induced cellular apoptosis via decreasing the mitochondrial membrane potential, the BH3 domain prevented cellular survival through facilitating the association between the supramolecular antagonists and antiapoptotic proteins, thereby initiating mitochondrial permeabilization. Both in vitro and in vivo studies confirmed the combinatorial therapeutic effect arising from the BH3 domain and CPT drug within the supramolecular antagonist on cell death and thereby inhibiting tumor growth. Our findings demonstrate an efficient combinatorial mechanism for mitochondrial dysfunction, thus potentially serving as novel organelle-targeting medicines.