Unveiling the Interactions of Doxorubicin with the Lipid Components of Liposomes for Its Delivery

The characterization of drug/lipid interactions is key to developing novel and more efficient drug delivery systems. In this work, we combine electrochemical measurements, attenuated total reflection (ATR) spectroscopy, and molecular dynamics simulations to unveil the interacting mechanisms of doxorubicin (DOX) with lipid monolayers and bilayers containing a cytidine derivative nucleolipid, which serve as a model system of previously developed liposomes for DOX delivery. The nucleolipid was included in the liposome formulation to take advantage of its molecular recognition capabilities and its capacity to anchor gold nanoparticles. The compression isotherms of the Langmuir monolayers and interfacial capacitance measurements on a gold electrode modified with hybrid bilayers in the presence of DOX demonstrate the interaction of the drug with the nucleolipid polar heads. This is confirmed by computational simulations of a solvated DOX/bilayer complex, which show that the adsorption process is driven by stacking and electrostatic interactions involving the aromatic and nonaromatic moieties of DOX, respectively. Moreover, both ATR spectra of supported bilayers on silicon and simulations show that the presence of DOX does not significantly affect the tilt angles of the lipids. The system studied in this work is a promising therapeutic option for cancer treatment. The combined methodology applied to this study can serve as a reference for other studies of drug-carrier interactions.