ABSTRACT
Background: Interleukin-1 alpha (IL-1α) is a pro-inflammatory cytokine that can activate immune effector cells and trigger anti-tumor immune responses. However, dose-limiting toxicities including cytokine storm and hypotension has limited its use in the clinic as a cancer therapy. We propose that polymeric microparticle (MP)-based delivery of IL-1α will suppress the acute pro-inflammatory side effects by allowing for slow and controlled release of IL-1α systemically, while simultaneously triggering an anti-tumor immune response. Methods: Polyanhydride copolymers composed of 1,6-bis-(p-carboxyphenoxy)-hexane:sebacic 20:80 (CPH:SA 20:80) was utilized to fabricate MPs. Recombinant IL-1α (rIL-1α) was encapsulated into CPH:SA 20:80 MPs (IL-1α-MPs) and the MPs were characterized by size, charge, loading efficiency, and in-vitro release and activity of IL-1α. IL-1α-MPs were injected intraperitonially into head and neck squamous cell carcinoma (HNSCC)-bearing C57Bl/6 mice and monitored for changes in weight, tumor growth, circulating cytokines/chemokines, hepatic and kidney enzymes, blood pressure, heart rate, and tumor-infiltrating immune cells. Results: CPH:SA IL-1α-MPs demonstrated sustained release kinetics of IL-1α (100% protein released over 8-10 days) accompanied by minimal weight loss and systemic inflammation compared to rIL-1α-treated mice. Blood pressure measured by radiotelemetry in conscious mice demonstrates that rIL-1α-induced hypotension was prevented in IL-1α-MP-treated mice. Liver and kidney enzymes were within normal range for all control and cytokine-treated mice. Both rIL-1α and IL-1α-MP-treated mice showed similar delays in tumor growth and similar increases in tumor-infiltrating CD3+ T cells, macrophages, and dendritic cells. Conclusions: CPH:SA-based IL-1α-MPs generated a slow and sustained systemic release of IL-1α resulting in reduced weight loss, systemic inflammation, and hypotension accompanied by an adequate anti-tumor immune response in HNSCC-tumor bearing mice. Therefore, MPs based on CPH:SA formulations may be promising as delivery vehicles for IL-1α to achieve safe, effective, and durable antitumor responses for HNSCC patients.
