Effective targeting of liposomes to liver and hepatocytes in vivo by incorporation of a Plasmodium amino acid sequence.
OBJECTIVE
Several species of the protozoan Plasmodium effectively target mammalian liver during the initial phase of host invasion. The purpose of this study was to demonstrate that a Plasmodium targeting amino acid sequence can be engineered into therapeutic nanoparticle delivery systems.


METHODS
A 19-amino peptide from the circumsporozoite protein of Plasmodium berghei was prepared containing the conserved region I as well as a consensus heparan sulfate proteoglycan binding sequence. This peptide was attached to the distal end of a lipid-polyethylene glycol bioconjugate. The bioconjugate was incorporated into phosphatidylcholine liposomes containing fluorescently labeled lipids to follow blood clearance and organ distribution in vivo.


RESULTS
When administered intravenously into mice, the peptide-containing liposomes were rapidly cleared from the circulation and were recovered almost entirely in the liver. Fluorescence and electron microscopy demonstrated that the liposomes were accumulated both by nonparenchymal cells and hepatocytes, with the majority of the liposomal material associated with hepatocytes. Accumulation of liposomes in the liver was several hundredfold higher compared to heart, lung, and kidney, and more than 10-fold higher compared to spleen. In liver slice experiments, liposome binding was specific to sites sensitive to heparinase.


CONCLUSIONS
Incorporation of amino acid sequences that recognize glycosaminoglycans is an effective strategy for the development of targeted drug delivery systems.
Longmuir
Kenneth J
KJ
Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California 92697, USA. longmuir@uci.edu
Robertson
Richard T
RT
Haynes
Sherry M
SM
Baratta
Janie L
JL
Waring
Alan J
AJ
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D055592:Biophysical Phenomena; D001703:Biophysics; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D005456:Fluorescent Dyes; D006497:Heparan Sulfate / Q000008:administration & dosage / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects*; D007275:Injections, Intravenous; D008055:Lipids / Q000737:chemistry; D008081:Liposomes; D008099:Liver / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D049329:Nanostructures; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D010713:Phosphatidylcholines / Q000737:chemistry; D010962:Plasmodium berghei / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D015202:Protein Engineering
D000962:Antimalarials; D004337:Drug Carriers; D005456:Fluorescent Dyes; D006497:Heparan Sulfate; D008055:Lipids; D008081:Liposomes; D010455:Peptides; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols