Oral TNF-α gene silencing using a polymeric microsphere-based delivery system for the treatment of inflammatory bowel disease.
The purpose of this study was to evaluate down-regulation of tumor necrosis factor (TNF)-α by oral RNA interference therapy. Control (scrambled sequence) or TNF-α 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-α silencing siRNA by oral administration. Successful gene silencing led to decreased colonic levels of TNF-α, suppressed expression of other pro-inflammatory cytokines (e.g., interleukin (IL)-1β, interferon (IFN)-γ) 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-α gene silencing system for the treatment of inflammatory bowel disease as demonstrated in an acute colitis model.
Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 110 Mugar Life Sciences Building, Boston, MA 02115, United States.
Christina
C
Kriegel
Mansoor
M
Amiji
D000284:Administration, Oral; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D005260:Female; D005780:Gelatin / Q000737:chemistry; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D053758:Nanoparticles / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D005780:Gelatin