Vol. 288, Issue 1, 114-120, January 1999

Treatment with Liposome-Bound Recombinant Human Tumor Necrosis Factor- Suppresses Parasitemia and Protects against Plasmodium berghei k173-Induced Experimental Cerebral Malaria in Mice

N. S. Postma, D. J. A. Crommelin, W. M. C. Eling¹ and J. Zuidema

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

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