Liposomes incorporating a Plasmodium amino acid sequence target heparan sulfate binding sites in liver.
Previous studies demonstrated that intravenously administered liposomes, incorporating a peptide from the Plasmodium circumsporozoite protein, accumulate rapidly and selectively in mouse liver. The present investigation was designed to determine the molecular components in liver responsible for liposome targeting. Studies of liver tissue slices demonstrated that immunoreactivity for heparan sulfate proteoglycan (HSPG), but not other tested proteoglycans, was distributed along sinusoidal borders of liver; this immunoreactivity appeared associated with nonparenchymal cells of the sinusoids and with the basolateral portion of hepatocytes. Peptide-containing liposomes bound to liver tissue in a pattern similar to the distribution of heparan sulfate immunoreactivity, either after intravenous injection of liposomes in vivo or after incubation of liposomes with liver slices in vitro. Control liposomes, without the peptide, displayed very light binding without a pattern. Pretreatment of liver slices with heparinase, but not chondroitinase or hyaluronidase, eliminated peptide-containing liposome binding, but did not affect binding of control liposomes. Coincubation of peptide-containing liposomes with heparin, but not with other glycosaminoglycans, markedly inhibited liposome binding to liver slices. N-desulfated and O-desulfated heparins individually were less effective inhibitors of liposome binding than was heparin. These results indicate that liposomes containing a peptide from Plasmodium target liver tissue by binding to HSPGs in the extracellular matrix.
Robertson
Richard T
RT
Department of Anatomy & Neurobiology, 113 Irvine Hall, School of Medicine, University of California, Irvine, California 92697-1280, USA. rtrobert@uci.edu
Baratta
Janie L
JL
Haynes
Sherry M
SM
Longmuir
Kenneth J
KJ
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004337:Drug Carriers; D005260:Female; D006497:Heparan Sulfate / Q000378:metabolism*; D007150:Immunohistochemistry; D008081:Liposomes; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010961:Plasmodium / Q000737:chemistry*; D015800:Protozoan Proteins / Q000737:chemistry*
D004337:Drug Carriers; D006497:Heparan Sulfate; D008081:Liposomes; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan