Nanoparticle-based therapeutic delivery of prohibitin to the colonic epithelial cells ameliorates acute murine colitis.
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.
Theiss
Arianne L
AL
Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia, USA. atheiss@emory.edu
Laroui
Hamed
H
Obertone
Tracy S
TS
Chowdhury
Indrajit
I
Thompson
Winston E
WE
Merlin
Didier
D
Sitaraman
Shanthi V
SV
D000208:Acute Disease; D000818:Animals; D018938:Caco-2 Cells; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D053758:Nanoparticles / Q000627:therapeutic use*; D000091402:Prohibitins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics; D012097:Repressor Proteins / Q000235:genetics* / Q000493:pharmacokinetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016328:NF-kappa B; C000717328:PHB protein, human; D000091402:Prohibitins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins