Phospholipid-cationic lipid interactions: influences on membrane and vesicle properties

Liposomes composed of synthetic dialkyl cationic lipids and zwitterionic ph ospholipids such as dioleoylphosphatidyl-ethanolamine have been studied ext ensively as vehicles for gene delivery, but the broader potentials of these cationic liposomes for drug delivery have not. An understanding of phospho lipid-cationic lipid interactions is essential for rational development of this potential. We evaluated the effect of the cationic lipid DOTAP (N-[1-( 2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium) on liposome physical prope rties such as size and membrane domain structure. DSC (differential scannin g calorimetry) showed progressive decrease and broadening of the phase tran sition temperature of dipalmitoylphosphatidylcholine (DPPC) with increasing fraction of DOTAP, in the range of 0.4-20 mol%. Laurdan (6-dodecanolyl-dim ethylamino-naphthalene), a fluorescent probe of membrane domain structure, showed that DOTAP and DPPC remained miscible at all ratios tested. DOTAP re duced the size of spontaneously-forming PC-containing liposomes, regardless of the acyl chain length and degree of saturation. The anionic lipid DOPG (dioleoylphosphatidylglycerol) had similar effects on DPPC membrane fluidit y and size. However, DOTAP/DOPC (50/50) vesicles were taken up avidly by OV CAR-3 human ovarian tumor cells, in contrast to DOPG/DOPC (50/50) liposomes . Overall, DOTAP exerts potent effects on bilayer physical properties, and may provide advantages for drug delivery. (C) 2001 Elsevier Science B.V. Al l rights reserved.