title: Intranasal brain delivery of cationic nanoemulsion-encapsulated TNFα siRNA in prevention of experimental neuroinflammation.
abstract: Neuroinflammation is a hallmark of acute and chronic neurodegenerative disorders. The main aim of this study was to evaluate the therapeutic efficacy of intranasal cationic nanoemulsion encapsulating an anti-TNFα siRNA, for potential anti-inflammatory therapy. TNFα siRNA nanoemulsions were prepared and characterized for particle size, surface charge, morphology, and stability and encapsulation efficiency. Qualitative and quantitative intracellular uptake studies by confocal imaging and flow cytometry, respectively, showed higher uptake compared to Lipofectamine® transfected siRNA. Nanoemulsion significantly lowered TNFα levels in LPS-stimulated cells. Upon intranasal delivery of cationic nanoemulsions almost 5 fold higher uptake was observed in the rat brain compared to non-encapsulated siRNA. More importantly, intranasal delivery of TNFα siRNA nanoemulsions in vivo markedly reduced the unregulated levels of TNFα in an LPS-induced model of neuroinflammation. These results indicate that intranasal delivery of cationic nanoemulsions encapsulating TNFα siRNA offered an efficient means of gene knockdown and this approach has significant potential in prevention of neuroinflammation.
  
  
  BACKGROUND
  Neuroinflammation is often seen in patients with neurodegenerative disorders and tumor necrosis factor-alpha (TNFα) plays a significant role in contributing to neuronal dysfunction. As a result, inhibition of TNFα may alleviate disease severity. In this article, the authors investigated using a cationic nanoemulsion system carrying TNFα siRNA intra-nasally to protect against neuroinflammation. This new method may provide a future approach in this clinical setting.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA USA; Novartis Institute of Biomedical Research, Cambridge, MA USA.
authors.forename: Sunita
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA USA.
authors.forename: Srujan K
authors.initials: SK
authors.lastname: Gandham
authors.affiliation: Novartis Institute of Biomedical Research, Cambridge, MA USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Panicucci
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA USA. Electronic address: m.amiji@neu.edu.
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004655:Emulsions / Q000008:administration & dosage; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics; D008055:Lipids; D008264:Macrophages; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010316:Particle Size; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000235:genetics*
chemical_list: D000893:Anti-Inflammatory Agents; D004655:Emulsions; D008055:Lipids; C086724:Lipofectamine; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha
keywords: Brain delivery; Cationic nanoemulsion; Gene silencing; Neuroinflammation; Small interfering RNA; Tumor necrosis factor-alpha