Journal
NANO LETTERS
Volume 21, Issue 13, Pages 5730-5737Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.1c01469
Keywords
Self-Assembly; Peptides; Drug Delivery; Mitochondrion-Targeting; Antagonists
Categories
Funding
- Fundamental Research Funds for the Central Universities (Nankai University) [63213070]
- National Natural Science Foundation of China [21774065, 51933006, 81972903]
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Mitochondrion-targeting therapy has great potential in cancer treatment, but limited therapeutic efficiency is a challenge. A mitochondrion-targeting supramolecular antagonist was developed, inducing tumor cell death by promoting apoptosis and preventing survival simultaneously. The combined therapeutic effect of the BH3 domain and CPT drug in the supramolecular antagonist efficiently inhibits tumor growth.
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.
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