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Enzyme-instructed self-assembly of a novel histone deacetylase inhibitor with enhanced selectivity and anticancer efficiency

Abstract

Nowdays, how to improve the selectivity of chemotherapy drugs and reduce their side effects is still a significant challenge for cancer research. Although enzyme-instructed self-assembly (EISA) has provided a promising approach for selective cancer therapy, the application of EISA is still suffer from requiring much higher concentrations for inhibiting cancer cells. Therefore, new strategies are needed to maximize the anticancer efficacy as well as preserve the selectivity of EISA. In this study, we rationally designed and synthesised a novel peptide-based prodrug molecule, NapGDFDFpYSV, combining enzyme-instructed self-assembly (EISA) with the YSV anticancer peptide. The activity of the prodrug molecule was remarkably reduced by masking “Y” with a phosphoryl (-PO3) group and was recovered through dephosphorylation in situ by ALP catalysis. The resulting monomer, NapGDFDFYSV, as a hydrogelator further self-assembled into the nanodrug on the cell surface, resulting in enhanced cellular uptake and selective high cytotoxicity to cells overexpressing ALP via action on histone deacetylase. Moreover, the required cell inhibition concentration of NapGDFDFpYSV was much lower than its critical micelle concentration (CMC), exhibiting outstanding advantages compared with separately used EISA without the anticancer peptide. Our study provides a new strategy to improve the cytotoxicity selectivity and bioactivity of chemotherapy drugs as well as the anticancer efficiency of EISA.

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Publication details

The article was received on 06 Nov 2018, accepted on 11 Jan 2019 and first published on 11 Jan 2019


Article type: Paper
DOI: 10.1039/C8BM01422A
Citation: Biomater. Sci., 2019, Accepted Manuscript
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    Enzyme-instructed self-assembly of a novel histone deacetylase inhibitor with enhanced selectivity and anticancer efficiency

    Y. Gao, C. Zhang, J. Chang, C. Yang, J. Liu, S. Fan and C. Ren, Biomater. Sci., 2019, Accepted Manuscript , DOI: 10.1039/C8BM01422A

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