Characterization of PLGA microspheres for the controlled delivery of IL-1 alpha for tumor immunotherapy

This paper describes the preparation and characterization of poly(lactic-co-glycolic acid) microspheres for the continuous delivery of a recombinant human interleukin-1 alpha (IL-1 alpha), a cytokine that is investigated for the immunotherapy of tumors. The polymers forming the microspheres were from two different sources, had a comonomer ratio of 50:50 or 75:25 (lactic/glycolic acid), and mel. wts. of 5-15 kDa, and were expected to degrade within a few weeks. IL-1 alpha, at nanogram quantities, was co-encapsulated with bovine serum albumin (BSA), at 10% wt. BSA/wt. polymer, to accelerate cytokine release. Microsphere characteristics, such as size, morphology, protein encapsulation efficiency, and degradation rates depended on polymer type. The microspheres degraded in a heterogeneous manner, from the center to the surface. Overall, protein release kinetics for both the cytokine and BSA, following the initial burst, were correlated with microsphere degradation profile, suggesting that protein release is controlled by matrix erosion. By biological and immunological assays, IL-1 alpha lost its activity during incubation, and the extent of cytokine inactivation was consistent with microsphere degradation rate. It is assumed that the pH drop within the fast-degrading microspheres is responsible for the reduced activity of the released IL-1 alpha. Preliminary experiments, using tumor-bearing mice, have shown significant longer survival rates of mice treated with IL-1 alpha carrying microspheres, on days 7 and 12 after tumor cell inoculation, while mice treated with empty microspheres, or soluble IL-1 alpha, died at similar rates to those observed in non-treated tumor-bearing mice. These results indicate the potential of controlled release approach in cytokine-based treatment protocols of tumors.