PHASE-BEHAVIOR OF STEALTH-LIPID-LECITHIN MIXTURES

The application of liposomes in the drug delivery is severely limited due to their short blood circulation lifetimes. Recently, however, liposomes containing special lipids have shown up to several orders of magnitude reduced clearance rates in blood. The most important parameters for achieving avoidance of the uptake by macrophages and/or disintegration by plasms proteins is, in addition to small diameter (preferentially 80-200 nm) and appropriate fluidity of the membrane, the presence of bulky and charged polar heads. After preliminary improvements of liposome blood circulation times by using some glycolipids the longest circulation times, that is up to 50% of the dose/liposomes after 1 day as compared to < 1% of conventional liposomes, were achieved when diocylamphiphiles with particular polymeric polar heads were introduced into bilayers as the "Stealth" component at concentrations < 10 mol%. Those lipids have, in general, negatively charged polar heads with a bulky polymeric chain and whose thermal motion greatly enhances the repulsive steric interaction. It seems, that this steric stabilization of the liposome against the attack of plasma proteins and opsonization is much more effective than previous attempts, which used mainly the rigidification of the membrane (using high temperature lipids, increased amount of cholesterol, some particular negatively charged glycolipids, polymerization, etc,) and small size liposomes. In addition, it seems that the conditions of small size and special membrane compositions are not a necessary condition in these formulations in which the polymer chains shield as a flexible umbrella the liposome underneath. Because of their large polar heads and relatively high hydrophilicity these "Stealth lipids" are not necessarily bilayer forming lipids investigated were the phase behavior of mixtures of ogglecithin and 1900PEGilated di-C(m) phosphatidylethanolamine which forms liposomes at X(EPC)mol > .6 and micellar systems at X(EPC)mol < .4.