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.
Kriegel
Christina
C
Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 110 Mugar Life Sciences Building, Boston, MA 02115, United States.
Amiji
Mansoor
M
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