Sustained delivery of IL-1Ra from biodegradable microspheres reduces the number of murine B16 melanoma lung metastases

The interleukin-I receptor antagonist (IL-1 Ra) is approved for treating rheumatoid arthritis and has the potential to treat metastatic cancers involving excess amounts of the pro-inflammatory cytokine, interleukin-1 beta (IL- 1). To maintain sustained delivery and improve its therapeutic efficacy, IL-1Ra was encapsulated with stabilizers in biodegradable poly-(lactic/glycolic acid) (PLGA) microspheres. In vitro cytokine release and bioactivity studies in cultured melanoma B 16 cells revealed the microspheres to be capable of sustained IL- I Ra release on a daily level that could inhibit cell proliferation for at least 7 days. The level of IL-1Ra released from the microspheres was revealed in rat serum. Significant amounts of IL-1Ra were released over the course of 2 weeks, at levels sufficient for the inhibition of exogenously-administered IL-1 beta. In mice injected with B16 melanoma cells, the sustained IL-1Ra delivery from biodegradable microspheres inhibited tumor growth and significantly prolonged mice survival. Furthermore, the rumors were less vascularized and after amputation of the primary tumor, the number of lung metastases was reduced by 70%, as compared to the control groups. Thus, we show that biodegradable microspheres represent an efficient system for sustaining IL-1Ra delivery and improving its therapeutic efficacy. As such, the system can be integrated into therapeutic protocols for treating metastatic cancers. (C) 2007 Elsevier B.V. All rights reserved.