Preparation of photo-cross-linked pH-responsive polypeptide nanogels as potential carriers for controlled drug delivery

Diblock and triblock copolymers, including poly(ethylene glycol monomethyl ether)-b-poly(L-glutamic acid-co-gamma-cinnamyl-L-glutamate) (mPEG-b-P(LGA/CLG)) and poly(L-glutamic acid-co-gamma-cinnamyl-L-glutamate)-b-poly(ethylene glycol)-b-poly(L-glutamic acid-co-gamma-cinnamyl-L-glutamate) (P(LGA/CLG)-b-PEG-b-P(LGA/CLG)), were synthesized by ring-opening polymerization (ROP) of gamma-benzyl-L-glutamate-N-carboxyanhydride (BLG-NCA) monomer with PEG-based macroinitiator, deprotection of the benzyl groups and subsequent chemical modification with cinnamyl alcohol. The structures of copolymers were confirmed by (1)H NMR and GPC analyses. Pyrene-probe-based fluorescence technique revealed that these diblock and triblock copolymers could self-assemble into micelles in aqueous solution at pH 7.4 spontaneously, with PEG shells and P(LGA/CLG) cores. Under UV-irradiation at lambda = 254 nm, the P(LGA/CLG) blocks in the cores of the micelles were cross-linked through the photodimerization of the cinnamyloxy groups, yielding nanogels. The nanogels were characterized by (1)H NMR, FT-IR, SEM, AFM and DLS. The nanogels were pH-responsive and their properties could be tuned by varying the compositions of block copolymers. In vitro MTT assay demonstrated that the nanogels were biocompatible to HeLa cells, rendering their potential for drug delivery applications. Rifampin as a model drug was loaded into the nanogels. The in vitro rifampin release behaviors of nanogels could be affected by both the compositions of block copolymers and solution pH. These properties indicated that the pH-responsive nanogels fabricated by photo-cross-linking polypeptide micelles can be used as drug carriers for intelligent drug delivery.