Treatment with liposome-bound recombinant human tumor necrosis factor-alpha suppresses parasitemia and protects against Plasmodium berghei k173-induced experimental cerebral malaria in mice.

Abstract

Our study describes liposomes (conventional or sterically stabilized) as carrier systems for recombinant human tumor necrosis factor-alpha (rhTNF-alpha) to increase its protective efficacy against Plasmodium berghei-induced experimental cerebral malaria (ECM) in mice. rhTNF-alpha was either covalently coupled to the outer surface of preformed liposomes or encapsulated into the liposomes. For coupling to the liposomes, reactive thiol groups were introduced in rhTNF-alpha by reaction with N-succinimidyl S-acetylthioacetate. Intravenous injection of liposome-bound rhTNF-alpha substantially enhanced protection against ECM as compared with injection of free rhTNF-alpha. A similar protective efficacy against ECM was obtained by treatment with rhTNF-alpha coupled to either conventional or sterically stabilized liposomes. Encapsulation of rhTNF-alpha into liposomes did not improve the protective efficacy of rhTNF-alpha against P. berghei-induced ECM. Parasitemia was suppressed by treatment with either free or liposome-bound rhTNF-alpha in mice protected against ECM, but not in rhTNF-alpha-treated mice developing ECM. These data suggest that the effect of rhTNF-alpha on parasitemia plays a role in establishing protection against ECM. Our studies indicate that liposome-bound rhTNF-alpha exhibits an enhanced protective efficacy against ECM compared with free rhTNF-alpha. It is hypothesized that thiolation of rhTNF-alpha and coupling to the liposomal bilayer stabilizes the bioactive trimeric configuration of rhTNF-alpha.