INFLUENCE OF CHOLESTEROL ON THE ASSOCIATION OF PLASMA-PROTEINS WITH LIPOSOMES

The in vivo association of blood proteins with large unilamellar lipos omes composed of saturated phosphatidylcholines was analyzed to determ ine the effect of membrane fluidity and hydrocarbon chain length on li posome-plasma protein interactions and liposome clearance. Liposomes c omposed of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphati dylcholine (DPPC), distearoylphosphatidylcholine (DSPC), and diarachid oylphosphatidylcholine (DAPC) were administered via the lateral tail v ein of CD-1 mice and were subsequently isolated from the blood at 2 mi n postinjection. The protein binding ability (P-B, grams of protein bo und per mole total lipid) of the liposomes was quantified and related to their circulation half-lives. Liposomes composed of long-chain satu rated 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 P-B values an d enhanced circulation lifetimes for this lipid system. This cholester ol effect plateaued at 30 mol % cholesterol, corresponding to the loss of the gel-liquid crystalline phase transition, and resulted in P-B v alues of 23-28 grams of protein per mole of total lipid. The types of blood proteins binding to DSPC liposomes were not significantly altere d by the inclusion of cholesterol. This is the first demonstration of rapid clearance of neutral large unilamellar liposomes having high lev els of bound protein.