Examining the Impact of Food-Associated Stimuli On Particle Penetration Through Gastrointestinal Mucus Barrier

Examining the Impact of Food-associated Lipids on Particle Penetration through Gastrointestinal Mucus Barrier

Hasan Yildiz, yildiz.h@husky.neu.edu

Rebecca L. Carrier, rebecca@coe.neu.edu

Introduction:

Mucus, a complex network including glycoproteins known as mucins, lipids, and cellular and serum macromolecules, provides a barrier through which orally delivered drugs and nutrients must diffuse in order to enter the circulatory system. A heterogeneous mucus layer protects the gastrointestinal (GI) tract and other mucosal surfaces. However, the transport of these vectors and general barrier properties of mucus are not well characterized. In this investigation, the impact of lipid content associated with fed state intestinal contents on particle transport across gastrointestinal mucus was explored. The influence of surface chemistry on particle transport rates was examined using carboxylate- and peg modified nanoparticles of various sizes in GI tract. These post-prandial stimuli could potentially be used to control drug carrier transport or prevent pathogen invasion.

Materials and Methods:

Particle transport across porcine intestinal mucus from pig jejunum was investigated. 200- and 500-nm carboxylate- and peg modified particles were diluted in maleate buffer and simulated fed intestinal contents (“FED state”) including maleate buffer, bile salts/phospholipids (lecithin) and a lipid mixture containing soybean oil and monoglycerol for a particle concentration of 0.0025 wt.-%. Particle diffusion was measured by tracking the positions hundreds of individual microspheres using real- time multiple particle tracking technique (MPT). Olympus IX51 was used to detect particles at 40 X magnification and videomicroscopy. Positions of particle centroids were used to determine time-averaged mean squared displacements (MSD) and effective diffusivities (D_eff): MSD = [x(t+τ)-x(t)]² + [y(t+τ)-y(t)]² and D_eff = MSD/(4τ) where x and y are positional data and τ is the time scale. Particle effective diffusion coefficients were then used to estimate the fraction of nanoparticles expected to penetrate an intestinal mucus layer with a given thickness using a numerical integration of Fick's second law : dC/dt = D_eff d²C/dx² where C is the concentration of particles, t is time and x is position.

Results:

FED State intestinal contents significantly decrease particle mobility. At τ=10 s, transport rates of 200- and 500-nm carboxylate-modified nanoparticles were reduced 3- and 2.5-fold respectively within FED State in comparison to maleate buffer. Estimated fraction of dosed particle penetration was reduced nearly by half for carboxylate-modified microspheres dosed with lipids. Trivial impact of lipids was observed for PEG-modified particles. Less than 1- fold reduction was seen on the transport rates of 200- and 500-nm peg-modified nanoparticles at τ=10 s. The effect of surface chemistry on nanoparticle diffusion is significant.  200-, and 500-nm pegylated particle transport rate increased ~30- and 10-fold at τ=10 s compared with corresponding carboxylate- modified particles of the same size in FED State. Nearly % 60 percent of 200 nm- pegylated particles would penetrate GI mucus with a thickness 10 µm where only %10 of same size carboxylate-modified particles could penetrate mucus barrier.

Conclusions:

These results strongly support the potential role of food-associated lipids with fed state contents on the intestinal mucus barrier and motivate in-depth investigation of these phenomena for developing therapeutic strategies.  Promising results provide the influence of surface chemistry, especially rapid transport of PEG-modified particles to improve the effective transport of drug carriers for oral drug delivery and for the development of therapeutic applications.