Abstract
Our study describes liposomes (conventional or sterically stabilized) as carrier systems for recombinant human tumor necrosis factor-α (rhTNF-α) to increase its protective efficacy againstPlasmodium berghei-induced experimental cerebral malaria (ECM) in mice. rhTNF-α 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-α by reaction with N-succinimidylS-acetylthioacetate. Intravenous injection of liposome-bound rhTNF-α substantially enhanced protection against ECM as compared with injection of free rhTNF-α. A similar protective efficacy against ECM was obtained by treatment with rhTNF-α coupled to either conventional or sterically stabilized liposomes. Encapsulation of rhTNF-α into liposomes did not improve the protective efficacy of rhTNF-α against P. berghei-induced ECM. Parasitemia was suppressed by treatment with either free or liposome-bound rhTNF-α in mice protected against ECM, but not in rhTNF-α-treated mice developing ECM. These data suggest that the effect of rhTNF-α on parasitemia plays a role in establishing protection against ECM. Our studies indicate that liposome-bound rhTNF-α exhibits an enhanced protective efficacy against ECM compared with free rhTNF-α. It is hypothesized that thiolation of rhTNF-α and coupling to the liposomal bilayer stabilizes the bioactive trimeric configuration of rhTNF-α.
Footnotes
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Send reprint requests to: D.J.A. Crommelin, Department of Pharmaceutics, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. E-mail:D.J.A.Crommelin{at}pharm.uu.nl
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↵1 Current address: Department of Medical Microbiology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
- Abbreviations:
- Chol
- cholesterol
- PEG
- polyethylene glycol
- ECM
- experimental cerebral malaria
- EPC
- egg phosphatidylcholine
- HSA
- human serum albumin
- MPB-PE
- maleimido-4-(p-phenylbutyrate)-phosphatidylethanolamine
- PEG-DSPE
- distearoylphosphatidylethanolamine-polyethylene glycol 2000
- SATA
- N-succinimidyl S-acetylthioacetate
- rhTNF-α
- recombinant human tumor necrosis factor-α
- rhTNFα-ATA
- acetylthioacetyl-rhTNF-α
- Received April 28, 1998.
- Accepted July 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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