282380 Food-Associated Stimuli Impact On Particle Penetration Through Gastrointestinal Mucus Barrier

Wednesday, October 31, 2012
Hall B (Convention Center )
Hasan M. Yildiz and Rebecca L. Carrier, Chemical Engineering, Northeastern University, Boston, MA

Food-associated Stimuli Impact on Particle Penetration through Gastrointestinal Mucus Barrier

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

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

Introduction:

Mucus is a complex gel network comprised of mucins, lipids, salts, proteins, macromolecules and cellular debris. A heterogeneous mucus layer protects the gastrointestinal (GI) tract and other mucosal surfaces. Orally delivered drug and gene vectors must traverse through mucus in order to enter the circulatory system. However, the transport of these vectors and general barrier properties of mucus are not well characterized. The main objective of this project is to analyze the impact of food-derived lipids and bile salts as well as physiologically relevant stimuli, pH and [Ca+2], on particle transport across GI tract mucus. 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 nm amine-, carboxylate-, sulfate- and 100 nm carboxylate-modified particles were diluted in maleate buffer, bile salts (NaTDC) 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.-%. Calcium ion composition was adjusted by changing CaCI2 levels in maleate buffer, and medium pH was controlled by adjusting NaOH concentration. Particle diffusion was measured by tracking the positions of diluted 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 calculate time-averaged mean squared displacements (MSD) and effective diffusivities (Deff): MSD = [x(t+τ)-x(t)]2 + [y(t+τ)-y(t)]2 and Deff = 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 = Deff d2C/dx2 where C is the concentration of particles, t is time and x is position.

Results:

Lipids associated with fed state intestinal contents reduced particle transport rate through gastrointestinal mucus. Estimated fraction of dosed particle penetration was reduced by half for microspheres dosed with lipids. Surprisingly, particles dosed in Bile Salts have higher transport rates (~ 1.5 times faster diffusion rate) than particles dosed in Maleate Buffer. This could be related to BS adsorption changing the electrostatic interactions with the mucus network. Lower diffusion rates were also observed at higher calcium ion concentration. Acidity also plays important role on particle diffusion rates. pH elevation induced a dramatic decrease in effective diffusivities of microspheres.

Conclusions:

The observed impact of physicochemical stimuli: lipids, bile salts, pH, and [Ca+2] on particle transport support the significance of food contents on mucus barrier properties and the use of naturally changing factors in the GI tract to improve the effective transport of drug carriers for oral drug delivery. In addition, these factors could contribute to food effect on oral drug absorption, an important factor to oral drug delivery.


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