In vitro and in vivo models for the study of oral delivery of nanoparticles

Abstract

Oral delivery is an attractive route to deliver therapeutics via nanoparticles due to its ease of administration and patient compliance. This review discusses laboratory techniques for studying oral delivery of nanoparticles, which offer protection of cargo through the gastrointestinal tract. Some of the difficulties in modeling oral delivery include the harsh acidic environment, variable pH, and the tight monolayer of endothelial cells present throughout the gastrointestinal tract. The use of in vitro techniques including the Transwell ® system, simulated gastric/intestinal fluid, and diffusion chambers addresses these challenges. When studying effects after oral delivery in vivo, bioimaging of nanoparticle biodistribution using radioactive markers has been popular. Functional assays such as immune response and systemic protein concentration analysis can further define the merits of the oral delivery systems. As biologics become increasingly more important in chronic therapies, nanoparticle-mediated oral delivery will assume greater prominence, and more sophisticated in vitro and in vivo models will be required.

Fig. 1

(A) Mounted rat colonic tissue [55]. (B) Transmission electron micrograph of the apical part of two Caco-2 cells with microvilli and tight junction labeled [54]. (C) TEM image of M cells identified by lack of microvilli at their apical surface in an in vitro CaCo-2 and Raji coculture. (D) M cells identified in fixed cell monolayers by SEM analysis [59]. (E) Coculture of 90% Caco-2 and 10% HT29-MTX grown for 16 days on a Transwell insert and stained with PAS (stains acidic mucosubstances pink). This figure shows the mucus layer with thickness of 2–10 μm [58].

Fig. 2

A schematic of the gut-on-a-chip system showing the porous ECM-coated membrane lined with epithelial cells (CaCo-2 cells) facing the upper channel and vacuum chambers to apply peristaltic forces on both sides of the microchannel [62].

Fig. 3

(A) Drawing of the GI tract of the common brushtail possum and gamma scintigraphy scans of GI tract after oral dosing with small (75–125 μm) radio-labeled with 99mTc exchange resin from 3 to 32 h [79]. (B) Gamma scintigraphy scans of chitosan nanoparticles in the human GI tract; at 3 min the particles remain intact, after 12 min the particle has disintegrated and the particles are moving into the small intestine, after 1 h the granules have attached to the intestinal mucosa in the lower jejunum, and after 1 h 45 min most of the granules have become detached [90]. (C) Localization of an enteric-coated magnetic tablet as determined by gamma scintigraphy from [99mTc]-DTPA labeling. Pictured is the x- and y-plane of the small intestine (SI) and stomach at the 111 min of acquisition [83].

Fig. 4

Biodistribution of ^99mTc-pertechnetate-labeled chitosan (^99mTc-CS) and ¹²³iodine-labeled aspart-insulin (¹²³I-aspart-insulin) nanoparticles after oral administration to a rat [86].

Fig. 5

IVIS images of Spraque–Dawley rats after oral administration of (A) Cy5.5-NHS (fluorescent label alone); (B) nano-scaled Cy5.5-conjugated ZnO nanoparticles; (C) submicron-scaled Cy5.5-conjugated ZnO nanoparticles after 1, 2, 3, 5, and 7 h [89].