- Research Article
- 10.1016/j.jcis.2025.139814
Molecular view of the interactions between the amphiphilic drug propranolol hydrochloride and model lipid membranes.
- Apr 15, 2026
- Journal of colloid and interface science
- Yixuan Yan + 7 more +7
Many clinically used drugs are amphiphiles, yet the effect of their amphiphilicity on their therapeutic activity is poorly understood. As cell membranes are the first barrier a drug encounters on route to its site of action, we propose that an amphiphilic drug's membrane activity will impact its clinical efficacy. Comprehensive quantitative detail on the membrane interactions of the amphiphilic β-blocker drug, (±) propranolol has been investigated, using a synergistic combination of surface area-pressure measurements, ellipsometry, Brewster angle microscopy and selective H/D contrast variation neutron reflectometry, and using Langmuir monolayers comprising zwitterionic, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) alone and with 30mol% of negatively charged, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-1'-rac-glycerol sodium (POPG). The interaction of propranolol with the lipid monolayers was resolved in terms of changes in lipid morphology, the extent of lipid loss from the membrane, and the drug's favoured location and orientation within the membrane. Propranolol is proposed to interact with the lipid monolayers in three stages: (1) electrostatic binding to the lipid head groups, (2) drug-mediated lipid loss from the membrane, and (3) the re-organisation of the drug's hydrophobic region within the membrane lipid chains. At steady state, and regardless of lipid packing, the monolayer contains more drug than lipid molecules. Further, the presence of negatively charged POPG does not enhance the cationic drug's interactions with the monolayer, most likely due to the differential solubilisation of membrane lipid in the aqueous subphase. Significantly, these results demonstrate how a drug's amphiphilic nature can determine its membrane activity and thereby impact its clinical efficacy.
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