Influence of cholesterol on the association of plasma proteins with liposomes.
The in vivo association of blood proteins with large unilamellar liposomes composed of saturated phosphatidylcholines was analyzed to determine the effect of membrane fluidity and hydrocarbon chain length on liposome-plasma protein interactions and liposome clearance. Liposomes composed of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), and diarachidoylphosphatidylcholine (DAPC) were administered via the lateral tail vein of CD-1 mice and were subsequently isolated from the blood at 2 min postinjection. The protein binding ability (PB, grams of protein bound per mole total lipid) of the liposomes was quantified and related to their circulation half-lives. Liposomes composed of long-chain saturated phospholipids that exist in the gel (frozen) state at 39 degrees C (DPPC,DSPC and DAPC) bound large quantities of blood proteins, in excess of 48 g of protein per mole total lipid, and were found to be rapidly cleared from the circulation. The incorporation of cholesterol into DSPC liposomes resulted in significantly decreased PB values and enhanced circulation lifetimes for this lipid system. This cholesterol effect plateaued at 30 mol % cholesterol, corresponding to the loss of the gel-liquid crystalline phase transition, and resulted in PB values of 23-28 grams of protein per mole of total lipid. The types of blood proteins binding to DSPC liposomes were not significantly altered by the inclusion of cholesterol. This is the first demonstration of rapid clearance of neutral large unilamellar liposomes having high levels of bound protein.
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Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada.
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D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004134:Dimyristoylphosphatidylcholine / Q000378:metabolism; D005260:Female; D006207:Half-Life; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D008560:Membrane Fluidity; D051379:Mice; D010713:Phosphatidylcholines / Q000378:metabolism; D011485:Protein Binding
D001798:Blood Proteins; D008081:Liposomes; D010713:Phosphatidylcholines; C044819:1,2-diarachidonoyl-glycero-3-phosphocholine; D015060:1,2-Dipalmitoylphosphatidylcholine; D002784:Cholesterol; C010942:1,2-distearoyllecithin; D004134:Dimyristoylphosphatidylcholine