The anionic phospholipid-mediated membrane interaction of the anti-cancer 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 phospholipids and various zwitterionic phospholipids. Dilution of anionic lipids with zwitterionic lipids leads to decreased membrane association of the drug because electrostatic forces are very important in doxorubicin-membrane interaction. However, binding of doxorubicin to LUVET composed 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) and the N-methylethanolamine and N, N-dimethylethanolamine derivatives of PE. This preferential interaction is observed with all negatively charged 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 appears not to be due to the ability of PE to adopt inverted nonbilayer structures, but probably involves a combination of the ability of PE to form additional hydrogen bonds and of the intrinsic curvature of a bilayer containing PE because of its small headgroup. Implications of our finding for the in vivo membrane interaction and transport of the drug will be discussed.