THE ANIONIC PHOSPHOLIPID-MEDIATED MEMBRANE INTERACTION OF THE ANTICANCER DRUG DOXORUBICIN IS ENHANCED BY PHOSPHATIDYLETHANOLAMINE COMPARED TO OTHER ZWITTERIONIC PHOSPHOLIPIDS

The interaction of doxorubicin and lipids has been studied using large unilamellar vesicles (LUVET) composed of mixtures of anionic phosphol ipids and various zwitterionic phospholipids. Dilution of anionic lipi ds with zwitterionic lipids leads to decreased membrane association of the drug because electrostatic forces are very important in doxorubic in-membrane interaction. However, binding of doxorubicin to LUVET comp osed of anionic phospholipids combined with phosphatidylethanolamine ( PE) is much higher than binding to LUVET made of anionic lipids plus a range of other zwitterionic lipids such as phosphatidylcholine (PC) a nd the N-methylethanolamine and N,N-dimethylethanolamine derivatives o f PE. This preferential interaction is observed with all negatively ch arged phospholipids tested and is, in the case of phosphatidylserine ( PS), confirmed in monolayer experiments. The increase in surface area observed in a monolayer composed of PS and PE (1/3) was 3 times higher than in a monolayer of PS/PC (1/3). The preferential interaction appe ars not to be due to the ability of PE to adopt inverted nonbilayer st ructures, but probably involves a combination of the ability of PE to form additional hydrogen bonds and of the intrinsic curvature of a bil ayer containing PE because of its small headgroup. Implications of our finding for the in vivo membrane interaction and transport of the dru g will be discussed.