Size selectivity of intestinal mucus to diffusing particulates is dependent on surface chemistry and exposure to lipids

Hasan M Yildiz,Craig A Mckelvey,Patrick J Marsac,Rebecca L Carrier

doi:10.3109/1061186x.2015.1086359

Hasan M Yildiz, Craig A Mckelvey + Show 2 more

Open Access

https://doi.org/10.3109/1061186x.2015.1086359

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Abstract

Intestinal mucus provides a significant barrier to transport of orally delivered drug carriers, as well as other particulates (e.g. food, microbes). The relative significance of particle size, surface chemistry, and dosing medium to mucus barrier properties is not well characterized, but important in designing delivery systems targeted to the intestinal mucosa. In this study, multiple particle tracking (MPT) was used to study diffusion of 20–500 nm diameter carboxylate- and polyethylene glycol-(PEG-)functionalized polystyrene model carriers through intestinal mucus. The impact of exposure to mucus in buffer versus a partially digested triglyceride mixture was explored. Effective diffusivity of particles in intestinal mucus decreased with an increasing particle size less than and more than theoretically (Stokes–Einstein) expected in a homogenous medium when dosed in buffer and model-fed state intestinal contents, respectively. For example, effective diffusivity decreased 2.9- versus 20-fold with increase in the particle size from 100 to 500 nm when dosed to mucus in buffer versus lipid-containing medium. Functionalization with PEG dramatically decreased sensitivity to lipids in a dosing medium. The results indicate that reduction of particle size may increase particle transport through intestinal mucus barriers, but these effects are strongly dependent on intestinal contents and particle surface chemistry.

Highlights

Mucus lines wet epithelial surfaces in the body, and as such is an important barrier to penetration of molecular, particulate, and microbial species
Size dependence of particle transport across intestinal mucus The size selectivity of gastrointestinal mucus was explored by investigating diffusion of 20, 40, 100, 200, and 500 nm diameter carboxylate-modified particles using multiple particle tracking
The heterogeneous mesh network of intestinal mucus results in decreased transport rates with increasing particle size from 20 to 500 nm, but the size selectivity depends on the particle surface chemistry and the presence of food-associated lipids in the dosing medium

Summary

Introduction

Mucus lines wet epithelial surfaces in the body, and as such is an important barrier to penetration of molecular, particulate, and microbial species. Oral delivery is the most utilized route for drug administration.[4] Small molecule (< 500 Da) drugs are candidates for oral delivery due to potential to be absorbed in the GI tract.[5] Oral delivery of proteins has been explored using polymeric nanoparticle carriers to provide protection against the harsh acidic environment in the stomach and hydrolytic degradation in the gastrointestinal tract.[6,7] Particle size plays a central role in oral delivery of nanoparticles. The mobility of larger particles in cervical mucus was enhanced by coating the particles with polyethyleneglycol (PEG).[10,11] These findings suggest that while relative mucus mesh and particle size is an important factor in controlling particle penetration at mucosal surfaces, there are other important phenomena to consider, including the impact of the heterogeneous nature of the pore network and intermolecular interactions, impacting the complex permeability properties of mucus gels. The impact of particle size on transport of particles through intestinal mucus has not been exhaustively studied, yet is significant to the design of oral particulate carrier systems

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