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This study investigates the interfacial interactions between the selected methylxanthines, theophylline (Theo) and its derivative theophylline-7-acetic acid (TheoAcid), and model pulmonary surfactants. Chronic obstructive pulmonary disease (COPD) and asthma treatments utilizing these drugs are often limited by a narrow therapeutic window and systemic toxicity. We explore the biophysical feasibility of localized inhalation delivery by analyzing physicochemical drug effects on two-dimensional (2D) monolayers of DPPC, DPPG, and their binary mixture (8:2 molar ratio) at the air-water interface. Structural reorganization was interrogated using Brewster angle microscopy (BAM), grazing incidence X-ray diffraction (GIXD), and polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). Results demonstrate that while theophylline exerts a mild influence, theophylline-7-acetic acid significantly disrupts the organization of the lipid models. The surface properties of phospholipid membranes probed by the Langmuir technique change significantly when exposed to theophylline-7-acetic acid. GIXD analysis reveals a drug-induced transition from rectangular to hexagonal molecular packing in the DPPG monolayers. Furthermore, PM-IRRAS identifies preferential interactions with phosphate head groups, leading to changes in hydration and interfacial fluidization. The increased effect of TheoAcid compared to that of theophylline is attributed to possible electrostatic interactions, especially with negatively charged DPPG layers. These findings were also bridged to three-dimensional (3D) systems using fluorescence microscopy of giant unilamellar vesicles (GUVs), which confirmed drug-induced phase separation and morphological changes. Together, these results provide information about the physicochemical mechanisms of methylxanthine-lung surfactant interactions, offering critical insights into the stability of pulmonary interfaces under drug exposure.
Kołomyjska et al. (Thu,) studied this question.