Polypeptide-based star-block quadripolymers as unimolecular nanocarriers for the simultaneous encapsulation of hydrophobic and hydrophilic guests

Star-block quadripolymers PEI-g-(PLF-b-PLL-b-PEG) and PEI-g-(PLF-b-PLG-b-PEG) [i.e., a polyethylenimine (PEI) core, an amphiphilic copolypeptide poly(l-phenylalanine)-b-poly(l-lysine) (PLF-b-PLL) or poly(l-phenylalanine)-b-poly(l-glutamic acid) (PLF-b-PLG) inner shell, and a poly(ethylene glycol) (PEG) outer shell] were synthesized, characterized, and evaluated as drug nanocarriers. The star-block quadripolymers were obtained by sequential ring-opening polymerizations of l-phenylalanine N-carboxyanhydride and ε-benzyloxycarbonyl-l-lysine N-carboxyanhydride or γ-benzyl-l-glutamate N-carboxyanhydride initiated by the terminal primary amines of PEI. Subsequently, the periphery was PEGylated, and the poly(l-lysine) or poly(l-glutamic acid) side chains were deprotected. The synthesized star-block quadripolymers were characterized with 1H NMR, gel permeation chromatography (GPC), and laser light dynamic scattering (DLS). These polymers were well dispersed in aqueous solutions and resembled amphiphilic unimolecular micelles. The encapsulation study demonstrated that these polymers can solubilize nonpolar model compounds through hydrophobic interactions. Dialysis and spectrophotometric titration experiments indicated that these polymers could efficiently encapsulate hydrophilic model compounds via electrostatic interactions. Furthermore, the synthesized quadripolymers could entrap hydrophobic and hydrophilic model compounds in the site-isolated state simultaneously. The entrapped hydrophilic model compounds demonstrated sustained release at physiological pH and accelerated release when the pH was either increased or decreased. The simultaneous encapsulation of versatile guest molecules as well as the pH-responsive releasing properties of these star-block quadripolymers could be potentially useful in the controlled drug co-delivery applications.