Catherine Taylor Nordgård

Oligosaccharides As Modulators of Rheology in Complex Mucous Systems

Mucus rheology is integral to physiological function with the exact secretion rheology resulting from the macromolecular components, both mucin and nonmucin, and the interactions between these macromolecules. Here we present data demonstrating that low-molecular-weight guluronic acid oligomers extracted from alginate are able to disrupt intermolecular interactions in both purified and native mucous systems, resulting in rheological changes that are compatible with a lower cross-link density and thus reduced resistance to deformation. Additionally, these changes are associated with altered physiological function, raising the possibility of the use of such oligomers in biomedical applications.

Alterations in Mucus Barrier Function and Matrix Structure Induced by Guluronate Oligomers

The effect of guluronate oligomers on the barrier properties of mucous matrices was investigated in terms of the mobility of nanoparticles in mucous matrices by fluorescence recovery after photobleaching (FRAP), cellular uptake of nanoparticles in mucus secreting cells (HT29-MTX), and mucin matrix architecture by scanning electron microscopy (SEM). Guluronate oligomers improved nanoparticle mobility in both native and highly purified mucus matrices and improved cellular uptake of nanoparticles through a mucus layer. Addition of guluronate oligomers to mucin matrices resulted in a decrease in the density of network cross-links and an increase in matrix pore size. Based on these data, we conclude that guluronate oligomers are able to improve nanoparticle mobility in several mucus matrices and alter network architecture in mucin matrices in a manner that suggests a reduction in barrier function. As such, there may be a potential application for guluronate oligomers in mucosal delivery of nanomedicines.

Dynamic responses in small intestinal mucus: Relevance for the maintenance of an intact barrier.

Mucus in the small intestine acts as both a lubricant and a barrier to reduce mucosal exposure to damaging agents, and must perform these functions in a highly mechanically dynamic environment, both in terms of luminal shear and gut wall contractility. Here we investigate the dynamic responses of ex vivo pig small intestinal mucus to applied shear of different magnitudes over different timescales. At low levels of applied stress of 1Pa, which is of the order of magnitude of that induced by gut wall contractility, the mucus demonstrates stress hardening responses to the applied deformation. This hardening behavior is lost at higher levels of applied stress. Such hardening behavior is likely to contribute to the ability of small intestinal mucus to maintain a barrier at the mucosal surface in the mechanically dynamic gut environment.

Co association of mucus modulating agents and nanoparticles for mucosal drug delivery

Abstract Nanoparticulate drug delivery systems (nDDS) offer a variety of options when it comes to routes of administration. One possible path is crossing mucosal barriers, such as in the airways and in the GI tract, for systemic distribution or local treatment. The main challenge with this administration route is that the size and surface properties of the nanoparticles, as opposed to small molecular drugs, very often results in mucosal capture, immobilization and removal, which in turn results in a very low bioavailability. Strategies to overcome this challenge do exist, like surface ‘stealth’ modification with PEG. Here we review an alternative or supplemental strategy, co‐association of mucus modulating agents with the nDDS to improve bioavailability, where the nDDS may be surface modified or unmodified. This contribution presents some examples on how possible co‐association systems may be achieved, using currently marketed mucolytic drugs, alternative formulations or novel agents. Graphical abstract Figure. No Caption available.