Exploring the impact of various zwitterionic surface modifications on the mucus diffusion and membrane permeability of lipid-based nanocarriers

This study investigates the effect of structural differences among six zwitterionic surfactants on the performance of lipid-based nanoemulsions. Nanoemulsions were prepared using a standardized formulation approach to minimize compositional variability, thereby isolating the influence of surfactant type. The headgroups of the zwitterionic surfactants, phosphorylcholine, carnitine, amine oxide, betaine, and sulfobetaine, were evaluated for their impact on key parameters including physical stability, cytotoxicity, mucus diffusion, and cellular uptake within the overall surfactant structure. Results revealed significant variations in nanoemulsion performance depending on the zwitterionic surfactant structure. Formulations containing the surfactant cocamidopropyl hydroxysultaine exhibited moderate cytotoxicity but demonstrated superior diffusion through porcine mucus and enhanced uptake by human cells. In contrast, n-dodecylphosphocholine-based nanoemulsions showed excellent stability across all tested biorelevant media coupled with low cytotoxicity. Lipid-based nanocarriers formulated with lauryldimethylamine oxide combined good stability in biorelevant media with high mucus diffusion and moderate cellular uptake. Lauryl betaine-based systems displayed low hemolytic and moderate cytotoxic activities, but showed limited mucus penetration and cellular uptake. This study elucidates critical differences among various zwitterionic surfactants and highlights their suitability for liquid pharmaceutical formulations in the nanoscale range.