CHARACTERIZATION OF PLGA MICROSPHERES FOR THE CONTROLLED DELIVERY OF IL-1-ALPHA FOR TUMOR-IMMUNOTHERAPY

This paper describes the preparation and characterization of poly(lact ic-co-glycolic acid) microspheres for the continuous delivery of a rec ombinant human interleukin-1 alpha (IL-1 alpha), a cytokine that is in vestigated for the immunotherapy of tumors. The polymers forming the m icrospheres 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 q uantities, was co-encapsulated with bovine serum albumin (BSA), at 10% wt. BSA/wt. polymer, to accelerate cytokine release. Microsphere char acteristics, such as size, morphology, protein encapsulation efficienc y, and degradation rates depended on polymer type. The microspheres de graded in a heterogeneous manner, from the center to the surface. Over all, protein release kinetics for both the cytokine and BSA, following the initial burst, were correlated with microsphere degradation profi le, suggesting that protein release is controlled by matrix erosion. B y biological and immunological assays, IL-1 alpha lost its activity du ring incubation, and the extent of cytokine inactivation was consisten t with microsphere degradation rate. It is assumed that the pH drop wi thin the fast-degrading microspheres is responsible for the reduced ac tivity of the released IL-1 alpha. Preliminary experiments, using tumo r-bearing mice, have shown significant longer survival rates of mice t reated with IL-1 alpha carrying microspheres, on days 7 and 12 after t umor cell inoculation, while mice treated with empty microspheres, or soluble IL-1 alpha, died at similar rates to those observed in non-tre ated tumor-bearing mice. These results indicate the potential of contr olled release approach in cytokine-based treatment protocols of tumors .