BIODISTRIBUTION AND TUMOR-LOCALIZATION OF STEALTH LIPOSOMAL TUMOR-NECROSIS-FACTOR-ALPHA IN SOFT-TISSUE SARCOMA-BEARING RATS

The blood residence half-life and organ distribution of recombinant hu man tumor necrosis factor-alpha (TNF-alpha) encapsulated in sterically stabilized liposomes, were investigated in rats bearing a soft tissue sarcoma in the hind leg. We studied the decay in blood concentration of ''empty'' liposomes using the aqueous marker (67)gallium-desferal, as well as the blood concentration of soluble TNF-alpha and liposome e ncapsulated TNF-alpha using I-125. Encapsulation efficacy of TNF-alpha was 24%. The pharmacokinetics of TNF-alpha, were markedly altered aft er encapsulation in liposomes, with a 33-fold increase in mean residen ce time of TNF-alpha in the blood, and a concomitant 14-fold increase in the area under the plasma concentration vs. time curve for liposoma l TNF-alpha. Although the liposomes exhibit Stealth characteristics, u ptake by mononuclear phagocyte-rich organs (e.g., liver and spleen) wa s noticeable, especially at later time points. Encapsulation of TNF-al pha in sterically stabilized liposomes resulted in a marked increase i n localization of the cytokine in tumor measured as total uptake over time. However, peak TNF-alpha concentration levels in tumor were not s ignificantly enhanced compared with free TNF-alpha. Besides the augmen ted localization of TNF-alpha after encapsulation in sterically stabil ized liposomes, a diminished toxicity was observed. (C) 1998 Wiley-Lis s, Inc.