The effect of a water-soluble tris-galactoside terminated cholesterol derivative on the in vivo fate of small unilamellar vesicles in rats.
When the water-soluble cholesterol derivative, N-[tris [(beta-D-galactopyranosyloxy)methyl]methyl]-N alpha-[4-(5-cholesten-3 beta-yloxy)succinyl]glycinamide (tris-gal-chol) (Kempen et al. (1984) J. Medicin. Chem. 27, 1306-1312) is added as an aqueous micellar solution to a dispersion of small unilamellar phospholipid vesicles it rapidly associates with the vesicles, without causing significant leakage of liposome contents. Incorporation of 10 mol% tris-gal-chol in the liposomal membrane caused a substantial increase in the rate and extent of rat liver uptake and a shift in intrahepatic distribution of an intravenously administered dose of liposomes. For neutral liposomes composed of equimolar amounts of cholesterol and sphingomyelin incorporation of tris-gal-chol led to a 7-fold increase in total liver uptake, which was mainly accounted for by an increase in uptake by the Kupffer cells (12-fold) and by only a small increase in uptake by the hepatocytes (1.4-fold). The increased liver uptake is blocked by preinjection of N-acetyl-D-galactosamine and not affected by preinjection of N-acetyl-D-glucosamine. This indicates that the increased interaction of liposomes as a result of tris-gal-chol incorporation is mediated by galactose-specific recognition sites on both Kupffer cells and hepatocytes. Targeting of liposomes to the asialoglycoprotein receptor of the hepatocytes is thus frustrated by the highly active galactose-specific receptor on Kupffer cells. Comparable results on lactosylceramide incorporation into liposomes were recently reported by us (Spanjer et al. (1984) Biochim. Biophys. Acta 774, 49-55).
D000116:Acetylgalactosamine / Q000494:pharmacology; D000117:Acetylglucosamine / Q000494:pharmacology; D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism*; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008823:Micelles; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution
D002788:Cholesterol Esters; D007328:Insulin; D008081:Liposomes; D008823:Micelles; C042924:N-(tris((beta-galactopyranosyloxy)methyl)methyl)-N(alpha)-(4-(5-cholesten-3 beta-yloxy)succinyl)glycinamide; D000116:Acetylgalactosamine; D000117:Acetylglucosamine