title: Effect of cholesterol on the uptake and intracellular degradation of liposomes by liver and spleen; a combined biochemical and gamma-ray perturbed angular correlation study.
abstract: We investigated the effect of cholesterol on the uptake and intracellular degradation of liposomes by rat liver and spleen macrophages. Multilamellar vesicles (MLV) consisting of distearoylphosphatidylcholine/phosphatidylserine (molar ratio 9:1) or distearoylphosphatidylcholine/cholesterol/phosphatidylserine (molar ratio 4:5:1) were labeled with [3H]cholesteryl hexadecyl ether and/or cholesteryl [14C]oleate. After i.v. injection the cholesterol-containing liposomes were eliminated less rapidly from the bloodstream and taken up to a lesser extent by the liver (macrophages) than the cholesterol-free liposomes. Assessment of the 3H/14C ratios in liver and spleen cells revealed that the cholesterol-containing liposomes are substantially more resistant towards intracellular degradation than the cholesterol-free liposomes. These results could be confirmed by measuring the release of 111In from liposomes after uptake by liver and spleen by means of gamma-ray perturbed angular correlation spectroscopy. Experiments with cultured Kupffer cells in monolayer also revealed that incorporation of cholesterol results in a decrease of the uptake and an increase of the intracellular stability of cholesteryl [14C]oleate-labeled liposomes. Finally, incubation of both types of liposomes with lysosomal fractions prepared from rat liver demonstrated a difference in susceptibility to lysosomal degradation: the cholesterol-free vesicles were much more sensitive to lysosomal esterase than the cholesterol-containing liposomes. These results may be relevant to the application of liposomes as a drug carrier system to liver and spleen (macrophages).
authors.affiliation: Laboratory of Physiological Chemistry, University of Groningen, The Netherlands.
authors.forename: F H
authors.initials: FH
authors.lastname: Roerdink
authors.forename: J
authors.initials: J
authors.lastname: Regts
authors.forename: T
authors.initials: T
authors.lastname: Handel
authors.forename: S M
authors.initials: SM
authors.lastname: Sullivan
authors.forename: J D
authors.initials: JD
authors.lastname: Baldeschwieler
authors.forename: G L
authors.initials: GL
authors.lastname: Scherphof
mesh_terms: D000818:Animals; D001673:Biodegradation, Environmental; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051381:Rats; D013057:Spectrum Analysis / Q000379:methods; D013154:Spleen / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002788:Cholesterol Esters; D008081:Liposomes; D002784:Cholesterol