Nanoparticle-based therapeutic delivery of prohibitin to the colonic epithelial cells ameliorates acute murine colitis.

Abstract

BACKGROUND:

Intestinal epithelial expression of antioxidants and nuclear factor kappa B (NF-κB) contribute to mucosal barrier integrity and epithelial homeostasis, two key events in the pathogenesis of inflammatory bowel disease (IBD). Genetic restoration of intestinal epithelial prohibitin 1 (PHB) levels during experimental colitis reduces the severity of disease through sustained epithelial antioxidant expression and reduced NF-κB activation. To determine the therapeutic potential of restoring epithelial PHB during experimental colitis in mice, we assessed two methods of PHB colonic mucosal delivery: adenovirus-directed administration by enema and poly(lactic acid) nanoparticle (NPs) delivery by gavage.

METHODS:

As a proof-of-principle to demonstrate the therapeutic efficacy of PHB, we utilized adenovirus-directed administration by enema. Second, we used NPs-based colonic delivery of biologically active PHB to demonstrate therapeutic use for human IBD. Colitis was induced by oral administration of dextran sodium sulfate (DSS) in water for 6-7 days. Wildtype mice receiving normal tap water served as controls.

RESULTS:

Both methods of delivery resulted in increased levels of PHB in the surface epithelial cells of the colon and reduced severity of DSS-induced colitis in mice as measured by body weight loss, clinical score, myeloperoxidase activity, proinflammatory cytokine expression, histological score, and protein carbonyl content.

CONCLUSIONS:

This is the first study to show oral delivery of a biologically active protein by NPs encapsulated in hydrogel to the colon. Here we show that therapeutic delivery of PHB to the colon reduces the severity of DSS-induced colitis in mice. PHB may represent a novel therapeutic target in IBD.

• Authors: Arianne L Theiss, Hamed Laroui, Tracy S Obertone, Indrajit Chowdhury, Winston E Thompson, Didier Merlin, Shanthi V Sitaraman
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 17 Issue 5 Pg. 1163-76 (May 2011) ISSN: 1536-4844 [Electronic] England
• PMID: 20872832 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Chemical References

• NF-kappa B
• PHB protein, human
• Prohibitins
• Recombinant Fusion Proteins
• Repressor Proteins
• Tumor Necrosis Factor-alpha
• Green Fluorescent Proteins

Topics

• Acute Disease
• Animals
• Caco-2 Cells
• Colitis (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Drug Delivery Systems (methods)
• Green Fluorescent Proteins (genetics)
• Humans
• Intestinal Mucosa (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• NF-kappa B (metabolism)
• Nanoparticles (therapeutic use)
• Prohibitins
• Recombinant Fusion Proteins (genetics, pharmacokinetics)
• Repressor Proteins (genetics, pharmacokinetics)
• Tumor Necrosis Factor-alpha (metabolism)