Biomaterials Science 2018-01-19

A pH- and temperature-responsive bioresorbable injectable hydrogel based on polypeptide block copolymer for the sustained delivery of proteins in vivo

Md. Hasan Turabee, Thavasyappan Thambi, Huu Thuy Trang Duong, Ji Hoon Jeong, Doo Sung Lee

文献索引：10.1039/C7BM00980A

摘要

Sustained delivery of protein therapeutics is limited owing to the fragile nature of protein. Despite great potential, delivery of proteins without loss of bioactivity remains challenging for use of protein therapeutics in clinics. To surmount this shortcoming, we report pH- and temperature-responsive in situ-forming injectable hydrogel based on comb-type polypeptide block copolymers for controlled delivery of proteins. Polypeptide block copolymers, composed of hydrophilic polyethylene glycol (PEG), temperature-responsive poly(γ-benzyl-L-glutamate) (PBLG), and pH-responsive oligo(sulfamethazine) (OSM), exhibits pH- and temperature-induced sol-to-gel transition behavior in aqueous solutions. Polypeptide block copolymers were synthesized by combining N-carboxyanhydride-based ring-opening polymerization and post-functionalization of the chain-end using N-hydroxy succinimide ester activated OSM. Physical properties of polypeptide-based hydrogels were tuned by varying composition of temperature- and pH-responsive PBLG and OSM in block copolymers. Polypeptide block copolymers were non-toxic to human embryonic kidney cells at high concentrations (2000 µg/mL). Subcutaneous administration of polypeptide block copolymer sols formed viscoelastic gel instantly at the back of Sprague-Dawley (SD) rats. The in vivo gels exhibited sustained degradation and found to be bioresorbable in 6 weeks without noticeable inflammation at the injection site. Anionic characteristics of hydrogels allow efficient loading of cationic model protein, lysozyme, through electrostatic interaction. Lysozyme-loaded polypeptide block copolymer sols readily formed a viscoelastic gel in vivo and sustained lysozyme release for at least a week. Overall, results demonstrate an elegant approach to control release of certain charged proteins and have a myriad of therapeutic possibilities in protein therapeutics.