Treatment with liposome-bound recombinant human tumor necrosis factor-alpha suppresses parasitemia and protects against Plasmodium berghei k173-induced experimental cerebral malaria in mice.
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.
Postma
N S
NS
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Crommelin
D J
DJ
Eling
W M
WM
Zuidema
J
J
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D016779:Malaria, Cerebral / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000517:prevention & control*; D010962:Plasmodium berghei / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000627:therapeutic use
D000962:Antimalarials; D004337:Drug Carriers; D008081:Liposomes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha