Partitioning of teniposide into membranes and the role of lipid composition.

We have examined the partitioning behavior of the anticancer agent teniposide (VM-26) into multilamellar vesicles composed of various phospholipid species. Partitioning was found to be sensitive to the composition of the liposomal membrane since changes in the head group or acyl chain constituents could dramatically alter the affinity of the drug for the bilayer. [3H]VM-26 partitioned most readily into 1,2-monounsaturated species of phosphatidylcholine (PC) with a molar partition coefficient (Kp) of 4290 for dioleoyl-PC at 37 degrees C. Inclusion of additional phospholipids having a different head group reduced partitioning in the order cardiolipin greater than phosphatidylglycerol greater than phosphatidylserine greater than phosphatidylethanolamine. The Kp for dioleoyl-PC with 33 mol% cardiolipin was reduced to 1370. Partitioning into completely saturated species of PC was much less than that for unsaturated species and was inversely proportional to the hydrocarbon chain length at temperatures either above or below the chain melting temperature. The Kp for fluid phase dimyristoyl-PC was 2300. Partitioning into dimyristoyl-PC or dioleoyl-PC at 37 degrees C (fluid) or dipalmitoyl-PC at 25 degrees C (gel) was reduced by the addition of 5-30 mol% cholesterol in proportion to its bilayer concentration. Etoposide (VP-16) at concentrations up to 10 mol% did not compete with [3H]VM-26 for association with dioleoyl-PC. Addition of calf serum or serum albumin could significantly reduce the association of [3H]VM-26 with the liposomes.