pH- and Temperature-responsive Hydrogels Based on Tertiary Amine-modified Polypeptides for Stimuli-responsive Drug Delivery

pH- and temperature-responsive hydrogels have attracted considerable attention due to their responsiveness to dual physiologically-relevant stimuli. In this study, we developed stimuli-responsive hydrogels based on monomethoxy poly(ethylene glycol) (mPEG)-polypeptide block copolymers containing various tertiary amine pendants (EEP-TAs). The EEP-TAs were synthesized via ring-opening copolymerization of alpha-amino acid N-carboxyanhydrides, and further modified post-polymerization with click chemistry. The EEP-TAs exhibited an alpha-helix-to-beta-sheet transition when the pH was increased from 4.0 to 7.4. At elevated polymer concentrations, aqueous solutions of the EEP-TAs underwent thermo-induced sol-gel phase transitions, which were dependent on the pH. The hydrogels almost fully degraded within 3 weeks in the subcutaneous layer of mice and exhibited good histocompatibility in vivo. Additionally, doxorubicin (DOX)-loaded hydrogels exhibited pH-responsive drug release profiles in vitro, which were composed of rapid release at acidic pH and more sustained release at neutral pH. Thus, these polypeptide hydrogels hold potential as depots for environment-responsive delivery of therapeutic agents.

Automated summary

pH- and temperature-responsive hydrogels based on mPEG-polypeptide block copolymers were developed in this study. The hydrogels exhibited an alpha-helix-to-beta-sheet transition at increased pH and underwent thermo-induced sol-gel phase transitions at elevated polymer concentrations, dependent on the pH. They demonstrated good histocompatibility and almost complete degradation in the subcutaneous layer of mice. The doxorubicin-loaded hydrogels showed pH-responsive drug release profiles with rapid release at acidic pH and sustained release at neutral pH, suggesting their potential as environment-responsive depots for drug delivery.