Fabrication of thermo and pH-dual sensitive hydrogels with optimized physiochemical properties via host-guest interactions and acylhydrazone dynamic bonding

Stimuli-responsive polymeric hydrogels based on host-guest interactions have demonstrated potential as smart drug delivery platforms. However, host-guest interactions alone have been repeatedly highlighted to provide insufficient mechanical strength for the formed hydrogels likely due to the generally low grafting degrees of functional groups and steric hindrance of polymer backbone and grafted functions. Herein, a combination strategy of reversible addition-fragmentation chain-transfer polymerization (RAFT) and dual crosslinking was employed to fabricate thermo- and pH-dual responsive hydrogels with enhanced mechanical properties. Specifically, two kinds of poly (N-isopropyl acrylamide) (PNIPAM)-based well-defined thermo-sensitive polymers, denoted as PH and PG, consisting of β-cyclodextrin (β-CD) and adamantane (Ad) groups were synthesized via RAFT copolymerization. A facile mixing of PH and PG with commercially available adipic dihydrazide led to the construction of hydrogels via host-guest interactions and dynamic acylhydrazone bonding. The resulting hydrogels not only exhibited pH-switchable sol-gel transitions and temperature-dependent swelling behaviors, but also possessed good stretchability (fracture stress up to 39.97 kPa) and self-healing property (self-healing efficiency above 90%). Notably, the resulting hydrogels showed pH-responsive controlled spatiotemporal release administration of rhodamine B due to the presence of dynamic acylhydrazone links. Together with good cytocompatibility, the hydrogels developed herein represent promising candidates for potential transdermal drug delivery.