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Enhanced nuclear delivery of anti-cancer drugs using micelles containing releasable membrane fusion peptide and nuclear-targeting retinoic acid

Abstract

Biodegradable cross-linked N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer micelles can improve the accumulation of drug cargo in tumors by prolonging their circulation time. However, drug delivery can still be ineffective because of intracellular degradation in lysosomes and poor delivery to the nucleus. In this work, we prepared a novel micelle by grafting the hydrophobic HA2 membrane fusion peptide onto hydrophilic HPMA copolymers via a linker that would be cleaved in lysosomes, allowing the HA2 peptide to be released and disrupt lysosome membranes. In addition, we conjugated the drug cargo (H1 peptide) to nucleus-targeting all-trans retinoic acid, and then encapsulated the conjugates into micelles. The drug-loaded micelles efficiently escaped lysosomes and targeted the nucleus in MCF-7 breast cancer cells in culture. They also strongly inhibited tumor growth in mice bearing MCF-7 tumor xenografts, without causing appreciable systemic toxicity. Removing the retinoic acid or preventing cleavage of HA2 resulted in extremely inefficient lysosomal escape and nuclear delivery, translating into low anti-cancer efficacy in vitro and in vivo. These results suggest that micelle modifications to evade lysosomes and target the nucleus can improve the efficacy of anti-cancer drugs. Our results further suggest that the ability to escape lysosomes improves nuclear distribution of drug cargo more than the addition of the nuclear-targeting retinoic acid.

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Publication details

The article was received on 28 Apr 2017, accepted on 31 Jul 2017 and first published on 03 Aug 2017


Article type: Paper
DOI: 10.1039/C7TB01177F
Citation: J. Mater. Chem. B, 2017, Accepted Manuscript
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    Enhanced nuclear delivery of anti-cancer drugs using micelles containing releasable membrane fusion peptide and nuclear-targeting retinoic acid

    Z. Zhou, Y. Liu, L. Wu, L. Li and Y. Huang, J. Mater. Chem. B, 2017, Accepted Manuscript , DOI: 10.1039/C7TB01177F

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