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Poly(L-aspartamide)-based reduction-sensitive micelles as nanocarriers to improve doxorubicin content in cell nuclei and to enhance antitumor activity.

A reduction-sensitive graft polymer PHEA-S-S-C16 with poly{α,β-[N-(2-hydroxyethyl)-L-aspartamide]} (PHEA) as a backbone and a disulfide-containing alkyl as a side chain (HOOC-S-S-C16 ) is synthesized and evaluated for intracellular DOX delivery. PHEA-S-S-C16 can self-assemble into micelles in aqueous media and load DOX at a total content of 7.3%. In vitro release studies reveal that the release rate of DOX from PHEA-S-S-C16 micelles is accelerated in the presence of DTT. The results of cell experiments indicate that DOX-loaded mPEG-S-S-C16 micelles can achieve rapid DOX release in HeLa cells, as compared with their reduction-insensitive counterparts. Endocytosis inhibition analysis indicates that PHEA-S-S-C16 micelles entered cells mainly via clathrin-mediated endocytosis.