Radiopaque microsphere-hydrogel composite for extended-release intratumoral immunotherapy in a large animal model.

Intratumoral injection of immune stimulants could potentially reverse the immunosuppressive tumor microenvironment, but the injected drug rapidly washes out into the systemic circulation. This results in systemic toxicity, and reduced efficacy, potentially requiring daily injections to generate an antitumor immune response. To address this problem, we developed an extended-release hydrogel that retains the immunotherapy agent at the injection site, and releases it over several days, even in highly vascular liver tumors. The extended-release hydrogel is a composite material containing drug-loaded microspheres (for sustained, tunable drug release), embedded in a radiopaque cross-linked hydrogel (for local retention). Using these new intratumoral drug carriers, we demonstrate the ability to safely deliver a wide range of different immunotherapy agents (cytokines, oligonucleotides, small molecules) into pig liver tumors, with no acute systemic toxicity. The microsphere gel reduces burst release by 7.8x (compared to microspheres), and increases half-life by > 15x (compared to hydrogel). Thus, the immunotherapy-loaded microsphere gel enables sustained intratumoral delivery of immune stimulants from a single injection, with low systemic toxicity.