The Anticancer Drugs Doxorubicin and Vincristine Differently Impact the Stiffness of Langmuir Monolayers that Mimic the Cell Membrane of Cardiomyocytes

Doxorubicin (<i>Dox</i>) and vincristine (<i>Vin</i>) are commonly prescribed drugs for cancer chemotherapy. However, they can also lead to cardiotoxicity as a side effect. To investigate the interaction of both medications with the lipid structure of the cardiomyocyte membrane, we assembled mixed lipid Langmuir monolayers mimicking the <i>inner</i> and <i>outer</i> leaflets of cardiomyocyte membranes and their physiological environment. Surface pressure isotherms and maximum insertion pressure measurements probed the interaction of the lipid mixtures with the drugs in the subphase, and Brewster angle microscopy (BAM) was employed to visualize the lipid domain formation. The viscoelastic properties of the monolayers were quantified by using compression-expansion experiments. Sum-frequency generation (SFG) spectroscopy was employed to probe the average lipid conformation and interfacial water structure, ascertaining the biochemical characteristics of the drug-lipid interaction. The results show that both drugs intercalate between lipids at low pressures, expanding the monolayers, but with <i>Vin</i> having a modest effect on the <i>inner</i> monolayer only. <i>Dox</i> had a major interaction with both lipid monolayers at pressures of up to 30 mN/m. This interaction reduces the significant lipids' conformational disorder of the <i>outer</i> monolayer through adsorption and insertion of the drug within the lipids, but in the <i>inner</i> monolayer, the drug insertion did not affect the more ordered lipid conformation. In contrast, <i>Vin</i> only interacted with membrane lipids at limited pressures (<10 mN/m), which are rather nonphysiological conditions for a cell. The results showed a different behavior of the complex elastic modulus for the <i>outer</i> monolayer (<i>Dox</i>: 12% decrease; <i>Vin</i>: 17% increase), while both drugs produced a decrease for the <i>inner</i> monolayer (<i>Dox</i>: 30%; <i>Vin</i>: 10%). Thus, <i>Dox</i> and <i>Vin</i> have opposite effects on the elasticity of the <i>outer</i> leaflet, which may explain the synergic effect of <i>Vin</i> in alleviating <i>Dox</i> cardiotoxicity.