Chirality-mediated polypeptide micelles for regulated drug delivery

Two kinds of triblock poly(ethylene glycol)–polyleucine (PEG–PLeu) copolymers were synthesized through the ring-opening polymerization of l-Leu N-carboxyanhydride (NCA), or equivalent d-Leu NCA and l-Leu NCA with amino-terminated PEG as a macroinitiator. The amphiphilic copolymers spontaneously self-assembled into spherical micellar aggregations in an aqueous environment. The micelle with a racemic polypeptide core exhibited smaller critical micelle concentration and diameter compared to those with a levorotatory polypeptide core. A model anthracycline antineoplastic agent, i.e., doxorubicin (DOX), was loaded into micelles through nanoprecipitation, and the PEG–P(d,l-Leu) micelle exhibited higher drug-loading efficacy than that with a P(l-Leu) core—this difference was attributed to the flexible and compact P(l-Leu) core. Sustained in vitro DOX release from micelles with both levorotatory and racemic polypeptide cores was observed, and the DOX-loaded PEG–P(d,l-Leu) micelle exhibited a slower release rate. More interestingly, DOX-loaded micelles exhibited chirality-mediated antitumor efficacy in vitro and in vivo, which are all better than that of free DOX. Furthermore, both enhanced tumor inhibition and excellent security in vivo were confirmed by histopathological or in situ cell apoptosis analyses. Therefore, DOX-loaded PEG–PLeu micelles appear to be an interesting nanoscale polymeric formulation for promising malignancy chemotherapy.