Effect of pH on the interactions of doxorubicin with charged lipid monolayers containing 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine - An important component of cancer cell membranes

The phospholipid monolayer composed of 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) was used as a model cancer cell membrane for the studies of the interactions of an anticancer drug doxorubicin (DOx). The Langmuir experiments combined with Brewster angle microscopy (BAM) revealed that doxorubicin interacts with DMPS affecting the surface properties of the lipid monolayer. The pH-dependence of these interactions was clear especially at higher surface pressures, when the lipid film was well ordered. At pH 5.4 corresponding to cancer cell environment DOx incorporated into the phospholipid monolayer was partially squeezed out from the layer upon compression of the monolayer, while at pH 7.4 corresponding to healthy cell environment it remained bound in the film. Such different pH-dependent behavior was ascribed to the different nature of the drug-lipid interactions: predominantly electrostatic at pH 5.4 and also hydrophobic at pH 7.4. Cyclic voltammograms recorded under two different pH values for the electrodes modified with DMPS monolayers with incorporated DOx allowed to determine the surface concentration of the drug in the lipid layer. Larger amounts of the drug found for pH 7.4 confirmed the importance of hydrophobic interactions between DOx and hydrophobic chains of DMPS, which prevented the drug release from the lipid layer. The importance of electrostatic interactions between DOx and DMPS polar heads was also confirmed by the experiments, in which DMPS monolayers at the air-water interface were first pre-compressed to high surface pressure typical of real cell membranes and then exposed to DOx.