Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 45, Pages 13307-13311Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201507157
Keywords
cisplatin; combination therapy; drug-resistance; enzymes; self-assembly
Categories
Funding
- NIH [R01A142746]
- DOD OCRP [W81XWH-10-1-0263, W81XWH-14-1-0092, W81XWH-14-1-0205]
- International S&T Cooperation Program of China (ISTCP) [2015DFA50310]
- NSFC [81471727]
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Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug-resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme-instructed self-assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug-resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre-installed on the precursors to form the peptides that self-assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug-resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non-cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects.
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