Crucial Impact of Residue Chirality on the Gelation Process and Biodegradability of Thermoresponsive Polypeptide Hydrogels.

Thermosensitive polypeptide hydrogels have gained considerable attention in potential biomedical applications, of which the polymer structure may be tuned by residue chirality. In this study, polypeptide-based block copolymers with different chiralities were synthesized by ring-opening polymerization of γ-ethyl-l-glutamate N-carboxyanhydride and/or γ-ethyl-d-glutamate N-carboxyanhydride using amino-terminated monomethoxy poly(ethylene glycol) as a macroinitiator. All mPEG-polypeptide copolymers underwent sol-gel transition with an increase in temperature. The block copolymers with mixed enantiomeric residues of γ-ethyl-l-glutamate (ELG) and γ-ethyl-d-glutamate (EDG) in the polypeptide blocks exhibited lower critical gelation concentrations and lower critical gelation temperatures compared with those composed of pure ELG or EDG residues. We established that the difference in gelation properties between the copolymers was derived from the distinction of the secondary structures. We further demonstrated the influence of polypeptide chirality on the degradability and biocompatibility of hydrogels in vivo. Our findings provide insights into the design of hydrogels having tailored secondary conformation, gelation property, and biodegradability.