461881 Lipid Nanoemulsions Impact Transport Across Mucosal Surfaces
Lipids are endogenously present in mucus at a mass ratio up to 2% and contribute significantly to mucus rheological properties of mucus. Our lab has demonstrated that ingested lipids present in the intestinal lumen, originating from food or lipid-based nanoemulsion delivery systems, for example, significantly strengthen the intestinal mucus barrier to nanoparticle and microbe transport. These observations motivated exploration of the impact of exposure to lipid nanoemulsions on transport of molecular species across the intestinal mucosal surface. We utilized electron paramagnetic resonance (EPR) to study the diffusion and microenvironment characteristics of low molecular weight paramagnetic probe molecules serving as model drugs. Interestingly, EPR spectra indicate that molecular transport in mucus gels is considerably impacted by exposure to lipids, with neutral molecules remaining associated with lipid phases within mucus, positive species being immobilized at the interface of hydrophilic and lipid domains, and negative species being expelled into the aqueous phase within the mucus gel. These results support the conclusion that intestinal mucus can pose a significant barrier to penetration on the molecular scale (< 1 nm), and that significance of mucus barriers to molecular species, as with nanoparticles, is strongly dependent upon charge and dramatically altered by food-associated lipids. To further explore the potential significance of intestinal mucus impact on drug absorption, we utilized ion-selective electrodes to investigate the behavior of supersaturated drug solutions, as are frequently created by certain drug delivery technologies, in intestinal mucus. Intestinal mucus significantly delays the onset of drug precipitation from a supersaturated solution, enabling a prolonged high driving force for drug absorption. Taken together, our results indicate that the intestinal mucus hydrogel can significantly impact the access of nano-scale drug carriers as well as molecular species to the underlying epithelium, and that the barrier posed by this hydrogel is considerably altered in the presence of lipids characteristic of ingested food or nano-emulsion drug delivery systems. The findings strongly support investigation of the impact of the intestinal mucus barrier in design of novel oral delivery technologies.