Abstract
The ether lipid, 1- O-octadecyl-2- O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH 3), has anticancer activity, but it has serious side-effects, including hemolysis, which prevent its optimal use. We surmised if ET-18-OCH 3 could be stably associated with liposomes, less free ET-18-OCH 3 would be available for lytic interaction with red cells. Liposome composition variables investigated included acyl chain saturation, phospholipid head group and mole ratio of Chol and ET-18-OCH 3. It was found that attenuation of hemolysis was strongly liposome composition dependent. Some ET-18-OCH 3 liposome compositions were minimally hemolytic. For example, whereas the HI 5 (drug concentration required to cause 5% human red cell lysis) was 5–6 μM for free ET-18-OCH 3, it was approximately 250 μM for DOPC (dioleoylphosphatidylcholine):Chol (cholesterol):DOPE-GA (glutaric acid derivatized DOPE):ET-18-OCH 3, (4:3:1:2) and 640 μM for DOPE (dioleyolphosphatidylethanolamine):Chol:DOPE-GA:ET-18-OCH 3 (4:3:1:2) liposomes. Efflux of carboxyfluorescein (CF) from liposomes and Langmuir trough determinations of mean molecular area of lipids in monolayers (MMAM) were used as indicators of membrane packing and stability. Incorporation of ET-18-OCH 3 in liposomes reduced the MMAM. Reduction in CF permeation was correlated with reduction in hemolysis. The most stable liposomes included components, such as cholesterol, DOPC and DOPE, which have complementary shapes to ET-18-OCH 3.
Published Version
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