Synergistic Effect of Paclitaxel and Epirubicin Coadministration─Insight into the Mechanisms of Interactions with Model Breast Cancer Cell Membranes.

Abstract

This study investigates the synergistic interaction mechanism of paclitaxel (PTX) and epirubicin (EPI) coadministration with model breast cancer cell membranes formed by monocomponent and ternary phospholipid monolayers composed of DPPC, cholesterol, and DMPS (4:4:2 molar ratio) at the air-water interface. These biomimetic membrane models were characterized using a combination of interface-sensitive techniques, including Langmuir monolayers, compression-expansion cycles, grazing incidence X-ray diffraction (GIXD), quartz crystal microbalance (QCM), and attenuated total reflection spectroscopy (ATR) for supported layers. These experimental methods were complemented by molecular dynamics (MD) simulations to gain molecular-level insights. The study confirms that neutral PTX interacts with all membrane components, while positively charged EPI exhibits significant interactions predominantly with the negatively charged DMPS lipid. Notably, the PTX + EPI combination demonstrated pronounced synergistic effects on both types of phospholipid monolayers, especially the ternary mixture, leading to significant membrane fluidization and the formation of irreversible aggregates. GIXD further corroborated the increased membrane fluidity and structural reorganization induced by the drug combination. QCM and ATR spectroscopy revealed substantial structural alterations and lipid rearrangement in the supported bilayers upon exposure to PTX + EPI. MD simulations suggest that these synergistic effects result from the formation of drug clusters within the lipid bilayer, influencing the physicochemical properties of the model biomembranes. These findings provide valuable insights into the interfacial interactions of anticancer drugs with lipid membrane materials, which can contribute to the development of improved combination therapies.