Journal
ADVANCED MATERIALS
Volume 32, Issue 36, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.202001108
Keywords
anticancer; membrane-lytic strategies; pH-sensitivity; polymer therapeutics; polypeptides
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Funding
- National Key Research and Development Program of China [2016YFC1100701]
- National Natural Science Foundation of China [51773196, 51573184, 51520105004, 51833010]
- Youth Innovation Promotion Association of CAS [2017266]
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An antineoplastic drug-free anticancer strategy enabled by host defense peptides (HDPs)-mimicking synthetic polypeptides is reported. The polypeptide exhibits a broad spectrum of anticancer activity in 12 cancer cell lines, including drug-resistant and highly metastatic tumor cells. Detailed mechanistic studies reveal that the cationic anticancer polypeptide (ACPP) can directly induce rapid necrosis of cancer cells within minutes through a membrane-lytic mechanism. Moreover, a pH-sensitive zwitterionic derivative of ACPP (DA-ACPP) is prepared for in vivo application. DA-ACPP shows negligible hemolysis under neutral physiological conditions, and can be converted back to ACPP in slightly acidic tumor environments, resulting in selective killing of cancer cells. Consequently, DA-ACPP shows an effective inhibition of tumor growth in both 4T1 orthotopic breast tumor models and B16-F10 melanoma pulmonary metastatic models. Overall, these findings demonstrate that synthetic HDPs-mimicking polypeptides represent safe and effective antineoplastic agents, which sheds new light on the development of drug-free synthetic polymers for cancer therapy.
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