Tumor Microenvironment-Responsive Nanogel for Therapeutic Delivery of Interleukin-12

Various forms of immunotherapy have arisen and shown promise in treating cancer. The administration of cytokines such as Interleukin-12 (IL-12) was thought to robustly stimulate innate immunity, and increase the number of endogenous tumor specific cytotoxic T-cells. However, patients enrolled in clinical trials involving the administration of IL-12 were reported to have IFNγ toxicity, and suffered from multiple organ system complications and in some instances, death. To address this issue, a tumor microenvironment-responsive nanogel composed of modified hyaluronic acid has been developed. This hypoxia sensitive methacrylated hyaluronic acid (HS- MAHA) aims to actively release IL-12 in the presence of the hypoxic tumor microenvironment, and eliminate the systemic toxicity exhibited in the intravenous administration of recombinant human IL-12. The nanogel has also shown increased degradation in the presence of hyaluronidase, indicating an additional component of tumor microenvironmentsensitivity. The nanogel is able to differentiate CD4+ T-cells into the Th1 Phenotype in vitro, and recruit an increased number of tumor specific cytotoxic T-cells in vivo. The particles have shown sufficient accumulation in the tumor, while avoiding accumulation in the brain, heart, and lungs. Furthermore, the administration of antiPD1 antibody in combination with the nanogel containing IL-12 has shown delayed tumor growth in an aggressive B16-F10 melanoma model.M.S., Biomedical Engineering -- Drexel University, 201