Nanoparticle Digestion Simulator Reveals pH-Dependent Aggregation in the Gastrointestinal Tract

Abstract

Determining the physicochemical properties of ingested nanoparticles within the gastrointestinal tract (GIT) is critical for evaluating the impact of environmental exposure and potential for nanoparticle drug delivery. However, it is challenging to predict nanoparticle physicochemical properties at the point of intestinal absorption due to the changing chemical environments within the GIT. Herein, a dynamic nanoparticle digestion simulator (NDS) was constructed to examine nanoparticle evolution due to changing pH and salt concentrations in the stomach and upper intestine. This multicompartment, flow-through system simulates digestion by transferring gastrointestinal fluids and digestive secretions at physiologically relevant time scales and flow rates. Pronounced differences in aggregation and aggregate stability were observed with silver nanoparticles (citrate-coated) with an initial hydrodynamic diameter (Dh) of 24.6 ± 0.4 nm examined under fasted (pH 2) and fed (pH 5) gastric conditions using nanoparticle tracking analysis (NTA) for size distributions and transmission electron microscopy with energy dispersive X-ray spectroscopy (TEM–EDX) for morphology and elemental composition. Under fasted stomach conditions, particles aggregated to Dh = 130 ± 10 nm and remained as large aggregates in the upper intestinal compartments (duodenum and jejunum) ending with Dh = 110 ± 20 nm and a smaller mode at 59 ± 8 nm. In contrast, under fed conditions, nanoparticles aggregated to 60 ± 10 nm in the stomach, then disaggregated to individual nanoparticles (26 ± 2 nm) in the intestinal compartments. The NDS provides an analytical approach for studying nanoparticle physicochemical modifications within the GIT and the impacts of intentionally and unintentionally ingested nanoparticles.

Transformation, Absorption and Toxicological Mechanisms of Silver Nanoparticles in the Gastrointestinal Tract Following Oral Exposure

“…Electrostatically charged polymers, such as polyvinylpyrrolidone (PVP), are frequently used to modify the surface of AgNPs by enhancing the repulsive force between neighboring particles to ensure colloidal stability . However, the repulsive force may be weakened by the salinity and pH of digestive juices, causing AgNPs to aggregate. − Representatively, chloride in the gastric fluid is a key element promoting the aggregation of AgNPs in the stomach. The reaction between Cl – and Ag + leached from AgNPs leads to the formation of AgCl in proximity to particles, thereby reducing the repulsive force of the particles and increasing the aggregation rate. , By contrast, the effect of food components, such as oil, starch, and protein, on the aggregation and disaggregation of AgNPs appears to be more convoluted .…”

“…It has been demonstrated that AgNPs have a high stability in authentic saliva, most likely as a result of the adsorption of enzymes or other biomolecules on the NP surface, which inhibits aggregation . Instead, AgNPs were seen to first aggregate in the gastric phase of the simulated gastrointestinal digestion and then disaggregate back into well-dispersed particles in the intestinal phase; however, it is unknown why this took place. , …”

“…Typically, PVP is one of the most often used polymers to stabilize AgNPs, depending on its amphiphilic nature . Ault et al demonstrated that citrate-coated AgNPs, as opposed to PVP-coated AgNPs, aggregated in the duodenum and jejunum, suggesting that PVP coating is helpful to stabilize AgNPs in the intestines . Besides, by acting as a steric barrier, covalent attachment of molecules like thiolated poly­(ethylene glycol) (PEG) on the surface can limit the dissolution rate of AgNPs .…”

A Novel Strategy for Visualizing, Tracing, and Measuring the Gastrointestinal Absorption of Silver Nanoparticles

“…[ 3,9,11 ] In order to investigate the gastrointestinal fate of AgNPs, plenty of studies have examined the transformation of AgNPs in artificial GIT fluids through simulating the digestion process from the mouth to the intestine. [ 12–18 ] These in vitro approaches provide an important insight into what AgNPs experience in the GIT before intestinal absorption or excretion from the body, but using simulated digestion models cannot reproduce the complex and dynamic interplay between AgNPs, microenvironment matrices, and cells in the GIT.…”

Changes of physico-chemical properties of nano-biomaterials by digestion fluids affect the physiological properties of epithelial intestinal cells and barrier models

“…This interaction may dramatically modify NBMs’ properties. For instance, the exposure may lead to dissolution [ 42 ], aggregation/agglomeration [ 43 ], and formation of bio-molecular corona [ 44 ] that may change over time. Monitoring such biotransformations is crucial to understand the NBMs biological fate in the gut environment and the impact on their toxicity [ 19 , 45 ].…”