Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract

Oral delivery, a patient-friendly means of drug delivery, is preferred for local administration of intestinal therapeutics. Lipidoid nanoparticles, which have been previously shown to deliver siRNA to intestinal epithelial cells, have potential to treat intestinal disease. It is unknown, however, wh...

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Autores principales: Ball, Rebecca L., Bajaj, Palak, Whitehead, Kathryn A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794865/
https://www.ncbi.nlm.nih.gov/pubmed/29391566
http://dx.doi.org/10.1038/s41598-018-20632-6
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author Ball, Rebecca L.
Bajaj, Palak
Whitehead, Kathryn A.
author_facet Ball, Rebecca L.
Bajaj, Palak
Whitehead, Kathryn A.
author_sort Ball, Rebecca L.
collection PubMed
description Oral delivery, a patient-friendly means of drug delivery, is preferred for local administration of intestinal therapeutics. Lipidoid nanoparticles, which have been previously shown to deliver siRNA to intestinal epithelial cells, have potential to treat intestinal disease. It is unknown, however, whether the oral delivery of these particles is possible. To better understand the fate of lipid nanoparticles in the gastrointestinal (GI) tract, we studied delivery under deconstructed stomach and intestinal conditions in vitro. Lipid nanoparticles remained potent and stable following exposure to solutions with pH values as low as 1.2. Efficacy decreased following exposure to “fed”, but not “fasting” concentrations of pepsin and bile salts. The presence of mucin on Caco-2 cells also reduced potency, although this effect was mitigated slightly by increasing the percentage of PEG in the lipid nanoparticle. Mouse biodistribution studies indicated that siRNA-loaded nanoparticles were retained in the GI tract for at least 8 hours. Although gene silencing was not initially observed following oral LNP delivery, confocal microscopy confirmed that nanoparticles entered the epithelial cells of the mouse small intestine and colon. Together, these data suggest that orally-delivered LNPs should be protected in the stomach and upper intestine to promote siRNA delivery to intestinal epithelial cells.
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spelling pubmed-57948652018-02-12 Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract Ball, Rebecca L. Bajaj, Palak Whitehead, Kathryn A. Sci Rep Article Oral delivery, a patient-friendly means of drug delivery, is preferred for local administration of intestinal therapeutics. Lipidoid nanoparticles, which have been previously shown to deliver siRNA to intestinal epithelial cells, have potential to treat intestinal disease. It is unknown, however, whether the oral delivery of these particles is possible. To better understand the fate of lipid nanoparticles in the gastrointestinal (GI) tract, we studied delivery under deconstructed stomach and intestinal conditions in vitro. Lipid nanoparticles remained potent and stable following exposure to solutions with pH values as low as 1.2. Efficacy decreased following exposure to “fed”, but not “fasting” concentrations of pepsin and bile salts. The presence of mucin on Caco-2 cells also reduced potency, although this effect was mitigated slightly by increasing the percentage of PEG in the lipid nanoparticle. Mouse biodistribution studies indicated that siRNA-loaded nanoparticles were retained in the GI tract for at least 8 hours. Although gene silencing was not initially observed following oral LNP delivery, confocal microscopy confirmed that nanoparticles entered the epithelial cells of the mouse small intestine and colon. Together, these data suggest that orally-delivered LNPs should be protected in the stomach and upper intestine to promote siRNA delivery to intestinal epithelial cells. Nature Publishing Group UK 2018-02-01 /pmc/articles/PMC5794865/ /pubmed/29391566 http://dx.doi.org/10.1038/s41598-018-20632-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ball, Rebecca L.
Bajaj, Palak
Whitehead, Kathryn A.
Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract
title Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract
title_full Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract
title_fullStr Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract
title_full_unstemmed Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract
title_short Oral delivery of siRNA lipid nanoparticles: Fate in the GI tract
title_sort oral delivery of sirna lipid nanoparticles: fate in the gi tract
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794865/
https://www.ncbi.nlm.nih.gov/pubmed/29391566
http://dx.doi.org/10.1038/s41598-018-20632-6
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