Chemically synthetic polypeptides are a class of unique biodegradable polymers with excellent biocompatibility, controllable chemical compositions and secondary structures analogous to natural peptides. We synthesized a series of poly(ethylene glycol) (PEG)-polypeptide amphiphilic block copolymers via the ring opening polymerization of α-amino acid-N-carboxyanhydride (NCA) using amino-terminated PEG as a macroinitiator. Through adjusting the hydrophilic/hydrophobic balance of the PEG-polypeptide block copolymers, injectable, temperature-responsive hydrogels were obtained from the copolymer aqueous solutions at elevated polymer concentrations. The thermal gelation behavior and biodegradation of the hydrogels can be tuned by residue chirality and polymer secondary conformation. Moreover, diverse stimuli-sensitivities, such as pH- and reactive oxygen species (ROS)-responsiveness, are able to be further imparted to the hydrogels by the incorporation of functional amino acid residues or pendant groups. In our recent studies, the injectable PEG-polypeptide hydrogels were investigated as topical delivery systems for antitumor immunotherapy or immune-based combination therapy. For instance, PEG-poly(γ-ethyl-L-glutamate) hydrogels were used as local depots for sustained co-delivery of chemotherapeutics and immunostimulating agents, including cytokines, IDO inhibitor and/or immune checkpoint blockade antibodies. It was found that the intratumoral delivery of doxorubicin induced the immunogenic cell death of tumor cells in situ, which significantly enhanced the antitumor immune response of the immunomodulating agents and prolonged animal survival time. Notably, the incorporation of functional amino acid residues in the polypeptide segments of hydrogels such as ROS-responsive and IDO-inhibiting residues contributed to the improvement of immunosuppressive tumor microenvironment, and thus further increased antitumor immune effects.

Injectable, stimuli-responsive polypeptide hydrogels as topical delivery systems for antitumor immunotherapy

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