Immunomodulatory and toxic effects of free and liposome-encapsulated tumor necrosis factor alpha in rats
Debs, R.J.; Fuchs, H.J.; Philip, R.; Brunette, E.N.; Düzgüneş, N.; Shellito, J.E.; Liggitt, D.; Patton, J.R.
Cancer Research 50(2): 375-380
1990
ISSN/ISBN: 0008-5472 PMID: 2295077 Document Number: 357364
Tumor necrosis factor alpha has potent immunomodulatory and antitumor activity, but its therapeutic applications may be limited by its significant host toxicity. We showed that liposome-encapsulated recombinant human tumor necrosis factor alpha (rHuTNF-alpha) retained full anticellular activity in vitro. We then assessed the immunomodulatory and toxic effects of two different doses of i.v. free or liposome-encapsulated rHuTNF-alpha in normal rats. Both free and liposome-encapsulated rHuTNF-alpha significantly enhanced alveolar macrophage- and blood monocyte-mediated interleukin 1 release and tumor cell lysis, as well as natural killer cell cytotoxicity, when compared to buffer-treated controls. However, administration of rHuTNF-alpha in liposomes substantially reduced tumor necrosis factor alpha-mediated toxicity. Animals receiving liposome-encapsulated rHuTNF-alpha showed significantly less tissue injury, gastric retention, and circulating leukocyte shifts than animals receiving free rHuTNF-alpha. In addition, liposome-based delivery significantly increased lung and liver uptake of rHuTNF-alpha. Therefore, liposome-encapsulated rHuTNF-alpha retains immunomodulatory activity, significantly reduces toxic inflammatory effects, and may allow targeting of tumor necrosis factor alpha to selected organs after i.v. administration.