Injectable Acylhydrazone-Linked RAFT Polymer Hydrogels for Sustained Protein Release and Cell Encapsulation

Abstract

A new class of temperature responsive polymer, termed PADO, is synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Synthesized from copolymerization of diacetone acrylamide (DAAM), di(ethylene glycol) ethyl ether acrylate (DEGA), and oligo(ethylene glycol) methyl ether acrylate (OEGA), PADO polymer phase separates at temperature above its LCST (36°C to 42°C) due to enhanced hydrophobic interactions between the short ethylene glycol side chains. Solution of PADO polymers exhibited injectable shear-thinning properties and reached sol-gel transition rapidly (< 5 min) at 37°C. When the ketone moieties on DAAM were linked by adipic acid dihydrazdie (ADH), PADO polymers formed crosslinked and injectable acylhydrazone hydrogels, which were hydrolytically degradable at a mild acidic environment owing to the pH sensitive acylhydrazone bonds. The pH-responsive degradation kinetics could be controlled by tuning polymer contents and ketone/hydrazide ratio. Importantly, the injectable PADO hydrogels were highly cytocompatible and could be easily formulated for pH-responsive sustained protein delivery.