Polyaspartamide-based multi-responsive micelle with sheddable shell for antitumor drug delivery

In this paper, a novel multi-responsive hybrid-brush polymer is prepared by facile aminolysis of poly(succinimide) with the amino-disulfide-linked poly(ethylene glycol) monomethyl ether (mPEG-SS-NH2), octadecylamine (C18), phenethylamine (PEA), 1-(3-aminopropyl) imidazole (API) and 5-aminopentanol (AP). In aqueous solution, the polyaspartamide derivatives obtained can respond to changes of pH, temperature or both; they self-assemble into micelles under physiological conditions and thus can be used as a drug delivery platform. Doxorubicin (Dox)-loaded micelles are stable under normal physiological conditions but become susceptible when encountering acidic medium or a reducing environment or both, which embodies the environment of cancer tissue. The in vitro release profile revealed that intensified Dox release kinetics can be realized at lower pH (5.0) and higher reductant concentration (dithiothreitol, 10 mM) by the synergistic effect of imidazole group protonation with disulfide linkage cleavage. Cytotoxicity assays show that the blank micelles have low cytotoxicity and the Dox-loaded micelles possess anticancer activity against HeLa cells similar to that of free Dox. The completely new method used in this work may be a useful strategy to construct multifunctional micelles for diversified applications such as drug delivery vehicles.