COMBINATION OF ANTITUMOR ETHER LIPID WITH LIPIDS OF COMPLEMENTARY MOLECULAR SHAPE REDUCES ITS HEMOLYTIC-ACTIVITY

Because the therapeutic use of the antitumor ether lipid ctadecyl-2-O- methyl-sn-glycero-3-phosphorylcholine (ET-18-OCH3) is restricted by it s hemolytic activity we explored the use of lipid packing parameters t o reduce this toxicity by creating structurally optimized ET-18-OCH3 l iposomes. We postulated that combination of ET-18-OCH3, which is simil ar in structure to lysophosphatidylcholine, with lipid molecules of co mplementary molecular shape (opposite headgroup/chain volume) would li kely yield a stable lamellar phase from which ET-18-OCH3 exchange to r ed blood cell membranes would be curtailed. To quantitate the degree o f shape complementarity, we used a Langmuir trough and measured the me an molecular area per molecule (MMAM) for monolayers comprised of ET-1 8-OCH3, the host lipids, and binary mixtures of varying mole percentag e ET-18-OCH3. The degree of complementarity was taken as the reduction in MMAM from the value expected based on simple additivity of the ind ividual components. The greatest degree of shape complementarity was o bserved with cholesterol: the order of complementarity for the ET-18-O CH3-lipid mixtures examined was cholesterol much greater than DOPE > P OPC approximate to DOPC. Phosphorus NMR and TLC analysis of aqueous su spensions of ET-18-OCH3 (40 mol%) with the host lipids revealed them t o all be lamellar phase. For ET-18-OCH3 at 40 mol% in liposomes, the h emolytic activity followed the trend of the reduction in MMAM and was least for the ET-18-OCH3/cholesterol system (H-50 = 661 mu M ET-18-OCH 3) followed by ET-18-OCH3/DOPE (H-50 = 91 mu M) and mixtures with POPC and DOPC which were comparable at H-50 = 26 mu M and 38 mu M, respect ively: the H-50 concentration for free ET-18-OCH3 was 16 mu M. This ex perimental strategy for designing optimized liposomes with a reduction in exchange, and hence toxicity, may be useful for other amphipathic/ lipophilic drugs that are dimensionally compatible with lipid bilayers . (C) 1997 Elsevier Science B.V.