Bioactive vesicles from saccharide- and hexanoyl-modified poly(l-lysine) copolypeptides and evaluation of the cross-linked vesicles as carriers of doxorubicin for controlled drug release

We report the synthesis and self-assembly of an amphiphilic glycopolypeptide through the conjugation of both lactobionolactone, a model targeted ligand to HepG2 liver cells, and hexanoyl groups onto poly(l-lysine) (PLL). The self-assembled glycopolypeptide vesicles were stabilized via genipin-cross-link and evaluated as cell-targeted carriers. The experimental data revealed that the saccharide and hexanoyl substitution can regulate the amphiphilic nature and chain conformation of the glycopolypeptide, and subsequently the size of the assembled vesicles. Taking the advantages of the glycopolypeptide vesicles including stable structure, pH-responsiveness, and cell-targeting ability, the glycopolypeptide was employed for drug encapsulation, i.e. doxorubicin (Dox). A high Dox loading level (45 wt.%) can be achieved with the aid of sonication as a pH gradient was applied between the outside and inside of the vesicles. The cross-linked, vesicles loaded with Dox exhibited noticeable pH-sensitive behavior with accelerated Dox release at acidic condition due to the protonation of amino groups and the release rate can be controlled by the genipin to amine feed ratio. The cytocompatibility of the polypeptide was improved upon grafting the saccharide group and cross-link. The Dox-loaded vesicles exhibited a comparable cytotoxicity with respect to free Dox against HepG2 liver cells. These results point to a potential of novel glycopolypeptide vesicles with cross-linkable membrane to be carriers for the delivery of bioactive agents.