Sustained delivery of IL-1 Ra from biodegradable microspheres reduces the number of murine B16 melanoma lung metastases.
The interleukin-1 receptor antagonist (IL-1Ra) 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 B16 cells revealed the microspheres to be capable of sustained IL-1Ra 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 tumors 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.
Lavi
Galia
G
Department of Biotechnology Engineering, Bldg. 39, Room 222, Ben-Gurion University of the Negev, Beer Sheva, 84105 Israel.
Voronov
Elena
E
Dinarello
Charles A
CA
Apte
Ron N
RN
Cohen
Smadar
S
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D053590:Interleukin 1 Receptor Antagonist Protein / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015203:Reproducibility of Results; D012995:Solubility
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D011108:Polymers; D011994:Recombinant Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid