(496i) Oral Delivery of siRNA Lipid Nanoparticles: Fate in the GI Tract. 

The ideal administration route of siRNA therapeutics for intestinal diseases would be oral delivery with a stable drug delivery vehicle able to withstand the environment of the gastrointestinal (GI) tract. Herein, we explore the use of lipidoid nanoparticles (LNPs) for oral siRNA delivery to the intestines. LNPs with siRNA have the potential to benefit patients who suffer from intestinal maladies that are associated with the upregulation of specific proteins. LNPs have previously been shown to potently deliver siRNA to Caco-2 intestinal cells and several other cells types in vitro and in vivo. Specifically, this study looks at the influence of pH and digestive enzymes on LNP efficacy in Caco-2 cells, LNP oral biodistribution in mice, and ability to enter small intestine and colon cells. LNPs remained potent and stable in a range of pH solutions. Initially, LNPs in solution with the human fed concentration of pepsin and bile salts led to reductions in efficacy. Fortunately, LNPs maintained stability and potency in the fasted pepsin and bile salt concentrations. High LNP uptake was seen in Caco-2 cells 3 hours post-transfection and the nanoparticles did not adversely influence intestinal cell permeability or tight junction arrangement. Mouse oral biodistribution studies revealed LNPs with Cy5.5 labeled siRNA remained in the GI tract for at least 8 hours. The orally delivered LNPs did not readily cross the intestinal barrier to enter other organs such as the kidneys or liver. Confocal microscopy confirmed siRNA LNP entry within mouse small intestine and colon epithelial cells after oral administration. Overall, LNPs show promise for oral siRNA delivery to intestinal cells in order to help patients suffering from intestinal diseases.