Investigating the Alteration of Membrane Properties Caused by Doxorubicin: Application of Phospholipid Mono- and Bilayer Biomembrane Models

In this study, we examined the effects of doxorubicin (DOx) on DMPC monolayers formed at the air–water interface and bilayers formed at the gold-solution interface. Monolayer studies indicated DOx incorporation during compression. Polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) data showed limited interaction with DMPC polar headgroups. We also demonstrated that charged DOx molecules induce structural and functional modifications in zwitterionic DMPC-supported bilayers. Atomic force microscopy imaging showed an increase in the bilayer thickness and phase segregation with DOx. Electrochemical measurements supported this, revealing alterations in the dielectric properties of these films. PM-IRRAS studies of supported bilayers confirmed changes in lipid packing, specifically a decreased tilt angle of acyl chains in the presence of DOx, which correlated with elevated resistance observed via electrochemical impedance spectroscopy. Our findings demonstrate that DOx is inserted into the bilayer of zwitterionic DMPC (a membrane typical for healthy cells), causing its swelling and increasing its fluidity and barrier properties, contrasting with the predominant electrostatic interactions observed for cancer membrane models. These molecular-level insights are essential for advancing the development of effective anticancer therapies.