Synthesis of an amphiphilic graft copolymer bearing a hydrophilic poly(acrylate acid) backbone for drug delivery of methotrexate

Abstract

A well-defined amphiphilic graft copolymer consisting of a hydrophilic poly(acrylic acid) (PAA) backbone and hydrophobic poly(lactic acid) side chains was synthesized by the combination of reversible addition–fragmentation chain transfer (RAFT) polymerization, ring open polymerization (ROP), and the grafting-from strategy. RAFT homopolymerization of an OH-containing tert-butyl 2-((4-hydroxy-butanoyloxy)methyl)acrylate (tBHBMA) monomer was first conducted to give a well-defined PtBHBMA homopolymer bearing pendant hydroxyls in every repeat unit. The pendant hydroxyls of PtBHBMA directly initiated the ROP of lactide without post-polymerization functionality transformation so as to provide a well-defined poly(tert-butyl acrylate)-g-poly(lactic acid) (PtBA-g-PLA) graft copolymer via the grafting-from strategy. The hydrophobic PtBA backbone was transformed into a hydrophilic PAA backbone to afford the target well-defined PAA-g-PLA amphiphilic graft copolymer (M_w/M_n = 1.17) containing equally-distributed carboxyls along the backbone. The PAA-g-PLA amphiphilic graft copolymer shows pH-responsive micellization behavior and it can self-assemble into non-toxic large compound micelles under certain conditions for loading methotrexate (MTX). The in vitro accumulative release characteristics of MTX-loaded micelles were investigated by UV/vis spectroscopy. In comparison with free MTX, the MTX-loaded nanoparticles display higher cytotoxicity against MG-63 in 24, 48 and 72 h.