An injectable hydrogel using an immunomodulating gelator for amplified tumor immunotherapy by blocking the arginase pathway

Abstract

Arginase 1 (ARG1) inactivates T cells by degrading L-arginine, severely reducing the immunotherapeutic efficacy. Effectively blocking the ARG1 pathway remains a challenge. L-norvaline is a very cheap and negligible side effects inhibitor of ARG1. However, its blockage efficacy for ARG1 is impeded by its high half-maximal-inhibitory concentration (IC50) requiring high drug loading content of L-norvaline in carriers. Moreover its high water solubility results in bursting and uncontrolled release. Herein we reported an injectable hydrogel strategy via an L-norvaline-based immunomodulating gelator that could effectively block ARG1 pathway. The designed gelator was a diblock copolymer containing L-norvaline-based polypeptide block, which could construct a thermally responsive injectable hydrogel by its self-gelation in tumor microenvironments. The hydrogel not only ensures high drug loading of L-norvaline, but also ensures controlled release of L-norvaline through responsive peptide bond cleavage, thereby solving the problems encountered by L-norvaline. The injectable hydrogel in combination with doxorubicin hydrochloride demonstrated a potent immunotherapy for removal of primary tumors, suppression of abscopal tumors and inhibition of pulmonary metastasis by combining the blockage of ARG1 pathway and the immunogenic cell death. Our immunomodulating gelator strategy provides a robust injectable hydrogel platform to efficiently reverse ARG1 immunosuppressive environments for amplified immunotherapy. STATEMENT OF SIGNIFICANCE: We designed an injectable hydrogel via an L-norvaline-based immunomodulating gelator. The designed gelator, a diblock copolymer containing an L-norvaline-based polypeptide block, enabled a thermally responsive injectable hydrogel by its self-gelation in tumor microenvironments. The injectable hydrogel not only guarantees high drug loading of L-norvaline, but also ensures controlled release of L-norvaline through responsive peptide bonds cleavage, thereby solving the problems encountered by L-norvaline. By further introducing doxorubicin hydrochloride in the hydrogel for inducing immunogenic cell death, the hydrogel showed remarkable immunotherapeutic efficacy towards ablation of primary tumors, suppression of abscopal tumors and inhibition of pulmonary metastasis. Our immunomodulating gelator strategy provides a new concept to efficiently reverse Arginase 1 immunosuppressive environments for amplified immunotherapy.

Keywords: Gelator; Hydrogel; Immunomodulation; Tumor environments; Tumor therapy.