Delivery of cytokines by liposomes. II. Interleukin-2 encapsulated in long-circulating sterically stabilized liposomes: immunomodulatory and anti-tumor activity in mice.
We have recently demonstrated that recombinant human interleukin-2 (IL-2) can be successfully encapsulated in small (mean size, 65 nm), unilamellar, long-circulating, sterically stabilized liposomes (SSL, also known as Stealth liposomes). The present study was undertaken to assess in mice the immunomodulatory and anti-tumor effects of SSL-IL-2 in comparison with soluble, unmodified IL-2 and pegilated IL-2 (PEG-IL-2). The main findings were as follows: (a) SSL-IL-2 was significantly more effective than IL-2 in increasing leukocyte number in the blood and spleen (p < 0.05) and triggering spleen lymphokine-activated killer cell activity (p < 0.01; t test). (b) In mice with advanced metastatic carcinoma previously treated with chemotherapy (cyclophosphamide), the survival was two to six times greater following administration of SSL-IL-2 as compared with IL-2 (p < 0.05; log-rank test). Moreover, successful treatment with SSL-IL-2 required lower cumulative doses (1.25 x 10(5) vs. 2.5 x 10(5) CU) and fewer (two versus five) administrations. (c) PEG-IL-2 was a more potent immunostimulator than SSL-IL-2 in normal mice and as effective therapeutically as SSL-IL-2 in tumor-bearing mice. The former agent, however, often caused marked toxicity (up to 40% mortality in some experiments), including severe thrombocytopenia. These findings suggest that SSL-IL-2 is an immunopotentiating agent superior to IL-2 in both normal mice and in tumor-bearing mice pretreated with chemotherapy.
Kedar
E
E
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Braun
E
E
Rutkowski
Y
Y
Emanuel
N
N
Barenholz
Y
Y
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line / Q000276:immunology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004337:Drug Carriers; D005260:Female; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy*; D011092:Polyethylene Glycols
D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D007376:Interleukin-2; D008081:Liposomes; C067245:interleukin-2, polyethylene glycol-modified; D011092:Polyethylene Glycols; D003520:Cyclophosphamide