Journal
JOURNAL OF CONTROLLED RELEASE
Volume 150, Issue 1, Pages 77-86Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2010.10.002
Keywords
Inflammatory bowel diseases; TNF-alpha; RNA interference; siRNA; Oral delivery; Nanoparticles-in-microsphere oral system (NiMOS)
Funding
- National Institute of Diabetes, Digestive Diseases, and Kidney Diseases of the National Institutes of Health [R01-DK080477]
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The purpose of this study was to evaluate down-regulation of tumor necrosis factor (TNF)-alpha by oral RNA interference therapy. Control (scrambled sequence) or TNF-alpha specific small interfering RNA (siRNA) was encapsulated in type B gelatin nanoparticles and further entrapped in poly(epsilon-caprolactone) (PCL) microspheres to form a nanoparticles-in-microsphere oral system (NiMOS). Upon confirmation of the dextran sulfate sodium (DSS)-induced acute colitis model, mice were divided into several treatment groups receiving no treatment, blank NiMOS, NiMOS with scramble siRNA, or NiMOS with TNF-alpha silencing siRNA by oral ad ministration. Successful gene silencing led to decreased colonic levels of TNF-alpha, suppressed expression of other pro-inflammatory cytokines (e.g.. interleukin (IL)-1 beta, interferon (IFN)-gamma) and chemokines (MCP-1), an increase in body weight, and reduced tissue myeloperoxidase activity. Results of this study established the clinical potential of a NiMOS-based oral TNF-alpha gene silencing system for the treatment of inflammatory bowel disease as demonstrated in an acute colitis model. (C) 2010 Elsevier B.V. All rights reserved.
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