Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers

Abstract

Oral delivery is the most common method for drug administration. However, poor solubility, stability, and bioavailability of many drugs make achieving therapeutic levels via the gastrointestinal (GI) tract challenging. Drug delivery must overcome numerous hurdles, including the acidic gastric environment and the continuous secretion of mucus that protects the GI tract. Nanoparticle drug carriers that can shield drugs from degradation and deliver them to intended sites within the GI tract may enable more efficient and sustained drug delivery. However, the rapid secretion and shedding of GI tract mucus can significantly limit the effectiveness of nanoparticle drug delivery systems. Many types of nanoparticles are efficiently trapped in and rapidly removed by mucus, making controlled release in the GI tract difficult. This review addresses the protective barrier properties of mucus secretions, how mucus affects the fate of orally administered nanoparticles, and recent developments in nanoparticles engineered to penetrate the mucus barrier.

Figure 1

Schematic figure showing the thicknesses of the loosely adherent and firmly adherent mucus layers in vivo in the rat gastrointestinal tract. The loosely adherent mucus layer is removable by careful suction, whereas the firmly adherent mucus layer is not. The table presents values for mucus thickness as means ± SE for each group. Figure obtained from [18].

Figure 2

Summary schematic illustrating the fate of an ingested food bolus propelled through the GI tract via peristaltic contractions. Mucins in the loosely adherent layer adhere to the food, wrapping it in a ‘blanket’ of mucus. The shear thinning properties of the secreted mucins allow the bolus to pass without perturbing the firmly adherent layer and the epithelium. Enzymes and emulsifying lipids that can pass through the mucus will begin to digest the food, extracting nutrients. Water is continuously removed from any undigested material as it passes through the small intestine and colon.

Figure 3

Schematic model depicting the possible role of an extracellular lining of zwitterionic phospholipids in generating the hydrophobic barrier of the stomach to luminal acid. Figure adapted from [30].

Figure 4

Agglomerated Eudragit® particles coated with a mucus plug collected immediately following discharge from the proximal jejunum of the perfused rat colon (magnification ×60). Figure obtained from [40].

Figure 5

Qualitative enhanced green fluorescent protein (GFP) expression in the small and large intestinal tract of male Wistar rats cryosections after oral administrate of saline (A), naked GFP plasmid (B), gelatin nanoparticles encapsulating GFP plasmid (C) and the NiMOS encapsulating GFP plasmid (D). The bright-field and epifluorescence images of the tissue cryosections were obtained from small intestine and large intestine of rats after 5 days following a single 100 µg dose of plasmid administered orally in the control and NiMOS formulations. The letter “L” denotes the luminal side of the small and large intestine. Figure obtained from [79].

Figure 6

Snapshot of the concentration field during the displacement of a more viscous fluid (dark) by a fully-miscible, less viscous fluid (light). Figure obtained from [128].

Figure 7

Distribution of the mucus gel layer in front of the Peyer’s patch in (A) a control group and (B) the N-acetylcysteine (NAC) group. Periodic acid-Schiff staining shows a uniform, continuous layer of mucus gel in front of the Peyer’s patch that is then completely lacking after NAC treatment. L, lumen; GC, germinal center. Magnification, ×25. Figure adapted from [100].

Figure 8

Simultaneous uptake of equal numbers of CTB-coated (red) and control microparticles (green) into rabbit Peyer’s patch domes after 1 h exposure. Fluorescence microscopy of a representative cryostat section shows that both types of particles were taken up into the dome, but not into adjacent villi. Scale bar, 100 µm. Figure obtained from [2].

Figure 9

Fluorescent micrographs obtained from transversal cryosections of mice ileum intestine. In vivo intestinal ligated loop was incubated with 10 mg/mL of CellTrace BODIPY nanoparticles (NPs) diluted in PBS for 15, 30, 45, and 60 min (only showing 15 mins, trends similar across all time points). Micrographs were obtained from villus and Peyer’s patch (PP) areas. The letter L indicates the intestinal lumen, the muscularis mucosa is underscored with a white line (m), and the epithelial barrier is indicated by a blue line (E), around the Lamina propia (Lp in villus area) or the lymphoid tissue (Lt in PP area). Original magnification ×10. Figure adapted from [106].

Figure 10

Geometric ensemble effective diffusivity () at a time scale of 1 sec for polystyrene (PS), poly(lactic-co-glycolic acid) (PLGA), poly(sebacic acid) (PSA), and poly(sebacic acid)-co-poly(ethylene glycol) (PSA-PEG) in CVM. × denotes individual sample values (n = 3); – denotes the average. Figure adapted from [8].

Figure 11

A summary schematic illustrating the fate of mucus penetrating particles (MPP) and conventional mucoadhesive particles (CP) administered to the GI mucosal surface. MPP readily penetrate the loosely adherent mucus layer and enter the firmly adherent mucus layer. In contrast, CP are immobilized in the loosely adherent layer. Because MPP can enter the firmly adherent layer and thus are in closer proximity to cells, cells will be exposed to a greater dose of drug released from MPP compared to drug released from CP. As the loosely adherent layer is cleared, CP are removed, whereas MPP are retained longer within the firmly adherent layer and continue to release drugs to cells. Figure adapted from [5].