期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 27, 期 59, 页码 14721-14729出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202102523
关键词
cancer therapy; cell-penetrating peptides; mitochondrion; selectivity; targeted delivery
资金
- National Natural Science Foundation of China [21877130, U1801681]
- Synthetic Biology Research & Development Programme (SBP) of National Research Foundation of Singapore [SBP-P4, SBP-P8]
- Natural Science Foundation of Guangdong Province [2018A030313510, 2021A1515010357]
- Key Field Research and Development Program of Guangdong Province [2019B020235001, 2018B030337001]
- Science Technology & Innovation Commission of Shenzhen Municipality [JCYJ20170818164838252, JCYJ20180307154611145]
Mitochondrion is a promising target for cancer therapy, and cell-penetrating peptides with mitochondrion-targeting ability are efficient tools for delivering therapeutics. New mitochondrion-targeting peptides (MTPs) have been synthesized, with MTP3 showing excellent mitochondrion-targeting ability and potential for drug delivery. The study validated the feasibility of MTP3 by preparing a mitochondrion-targeting prodrug that showed good cytotoxicity against tumor cells while having minimal toxicity towards normal cells.
Mitochondrion is a promising target in cancer therapy. However, gaining access to this organelle is difficult due to the obstacles to cross the complicated mitochondrial membrane. Cell-penetrating peptides (CPPs) with mitochondrion-targeting ability, named mitochondrion-targeting peptides (MTPs), are efficient tools to deliver exogenous therapeutics into mitochondria. Herein, we report several new MTPs, which can be readily synthesized via resin-based solid-phase peptide synthesis. In particular, MTP3 (compound 5), consisting of three positively charged arginines and two D- and L- alternating naphthylalanines, demonstrated excellent mitochondrion-targeting ability with high Pearson's correlation coefficient, suggesting that MTP3 has good potential for mitochondrion-targeted drug delivery. As proof-of-concept, the feasibility of MTP3 was validated by the preparation of a mitochondrion-targeting prodrug (compound 17, doxorubicin-based prodrug). This prodrug was subsequently confirmed to be specifically transported to the mitochondria of tumor cells, where it was able to release the native doxorubicin upon intracellular GSH activation, leading to mitochondrial depolarization and eventually cell death. Importantly, compound 17 showed good cytotoxicity against human tumor cells while negligible toxicity towards normal cells, indicating its potential as a potent mitochondrial medicine for targeted cancer therapy. Our study thus opens a way for engineered CPPs to be used to deliver bioactive cargos in mitochondrion-targeted cancer therapy.
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