Projects

Diffusivity of drugs and nanoparticles across intestinal mucus

Student: Savidra Lucatero
Department: Chemical Engineering
Advisor: Rebecca Carrier

Abstract

A number of orally administered medications exhibit low absorption and bioavailability due to either poor solubility and/or degradation and current research focus on optimized systems for oral drug delivery. Drug absorption is impeded by mucus, a viscous layer coating the inner wall of the gastrointestinal tract and being a main barrier for diffusive transport of drug molecules. A 50% decrease in the apparent permeability of various drugs has been observed in the presence of mucus. We are working with functionalized iron oxide nanoparticles to evaluate the effect of size, charge and lipophilicity on permeability across intestinal mucus and to characterize their binding to mucus molecules, and its dependence on the charge, size, and polarity.

Absorption of drugs along the gastrointestinal tract has been a matter of research for years, and the pharmaceutical industry invests around 75 billion dollars yearly looking for advanced drug delivery systems. In general, some of the goals in traditional oral drug therapies include, to achieve an enhanced drug bioavailability, a reduced toxicity, and to produce more uniform plasma drug levels. The absorbed drugs goes across the intestinal wall before reaching the circulatory blood, lymph or any other receptors in the body. Grossly, any absorbed molecule has to permeate the viscous mucus first and the ephitelial layer secondly, and these barriers readily impede the passage of the drug molecules.

The viscoelastic behavior and gel-like properties of mucus make it a main barrier for diffusive transport of drug molecules, significantly reducing their passage to target sites within the body. In general, mucus retards the diffusion of molecules by physical obstruction and entanglement of fibers in the gel, by intermolecular interactions between the drug and the mucous components and/or by sequestration of water molecules within the fibrillar network, which reduces the water available for diffusion. A ~50% decrease in the apparent permeability of various drugs has been observed in the presence of mucus.

Some physicochemical properties of drugs known to affect their permeability across the intestinal wall include size, charge and lipophobicity, and we are interested in evaluating the effect of these parameters on the permeability of drugs and nanoparticles across intestinal mucus. Our second goal deals with the binding of drugs and nanoparticles to mucin molecules, and its dependence on the charge, size, and polarity. Regarding the first objective, we intend to use a diffusion cell chamber, model drugs with different physicochemical properties and nanoparticles with functionalized surfaces, both displaying differences in size, charge and hydrophobicity. To characterize the nature of interactions between functionalized nanoparticles and mucus, we pretend to combine electron microscopy and atomic force microscopy to quantitatively characterize binding of drug molecules and nanoparticles to mucin, and possibly identify if it is regio-specific. We will also look for a relationship between the mucin binding and the physicochemical properties of drugs and the surface characteristics of nanoparticles.