Biodegradable injectable polymer systems exhibiting temperature-responsive covalent hydrogel formation for medical use

摘要

Biodegradable polymers exhibiting temperature-responsive sol-gel transition between room temperature and body temperature are expected to be applied as injectable polymer (IP) systems in biomedical applications. IP solution containing drugs or living cells can be injected by simple syringe injection at the target site in the body to form a hydrogel acting as sustained drug releasing depots or scaffolds for tissue regeneration. For example, Lee et al. reported ABA-type triblock copolymer of poly(lactide-co-glycolide) and poly(ethylene glycol) (PEG) as biodegradable injectable polymer. We also reported several biodegradable IP systems using block copolymers of aliphatic polyesters and branched PEG. However, such IP systems forming physically cross-linked hydrogel are likely to dissociate to sol state under highly wet condition such as intra-peritoneal space. To overcome the problems, we developed an injectable polymer formulation forming chemically cross-linked hydrogel in response to temperature change. We synthesized poly(caprolactone-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(caprolactone-co-glycolic acid) (PCGA-b-PEG-b-PCGA) triblock copolymer bearing succinimidyl groups on its termini. The copolymer was mixed with water-soluble polymer bearing amine groups, sucha as poly-L-Lysine, which can form covalent bonds with the functional groups on the triblock copolymer termini. The mixture solution showed irreversible sol-to-gel transition and covalent bond formation in response to temperature change (Figure 1). The obtained hydrogel showed longer duration time of the gel state in aqueous solution.