The development of multifunctional polysuccinimide with programmable thermoresponsiveness by modulating the hydrophobic graft architecture for advanced drug delivery applications.

Thermoresponsive polymers that undergo a hydrophobic phase transition above a critical temperature have long been a popular class of materials for biomedical applications, mainly taking advantage of the physiological temperature to expedite drug delivery. However, most thermoresponsive polymers do not offer much avenue for modification to improve and control their properties. Herein, we present a multifunctional polymer platform that allows precise control of thermoresponsiveness via functional grafting. Polysuccinimide (PSI), consisting of succinimidyl ring moieties known for undergoing ring-opening addition with amine-based nucleophiles, is rendered thermoresponsive by conjugating hydrophobic pendant groups along with hydroxyl side chains for aqueous solubility. The resulting thermoresponsive PSI (TPSI) displays variable lower critical solution temperatures dependent on the graft type and density. Furthermore, TPSI-crosslinked hydrogels demonstrate a wide range of physicomechanical properties at different temperatures in response to various graft architectures, which ultimately influences the drug release kinetics. The therapeutic potential of the TPSI hydrogel as a thermoresponsive drug delivery system is assessed using in vitro and in vivo tumor models.