title: Peritoneal Macrophage-Specific TNF-α Gene Silencing in LPS-Induced Acute Inflammation Model Using CD44 Targeting Hyaluronic Acid Nanoparticles.
abstract: The main goal of this study was to evaluate tumor necrosis factor-alpha (TNF-α) gene silencing in peritoneal macrophages upon activation with lipopolysaccharide (LPS), using CD44-targeting hyaluronic acid (HA)-based nanoparticles encapsulating TNF-α-specific small interfering RNA (siTNF-α). HA nanoparticles were formulated by blending hyaluronic acid-poly(ethylene imine) (HA-PEI), hyaluronic acid-hexyl fatty acid (HA-C6), and hyaluronic acid-poly(ethylene glycol) (HA-PEG) in 3:2:1 weight ratio, and encapsulating siTNF-α to form spherical particles of 78-90 nm diameter. Following intraperitoneal (IP) administration in LPS-treated C57BL/6 mice, the nanoparticles were actively taken up by macrophages and led to a significant downregulation of peritoneal TNF-α level. Downregulation of peritoneal macrophage-specific TNF-α also had a significant impact on other pro-inflammatory cytokine and chemokine levels in the serum. The C57BL/6 group of mice challenged with 5 mg/kg LPS had a significantly higher survival rate when they were treated with 3 mg/kg siTNF-α, either prior or simultaneously with the LPS administration, as compared to the LPS-challenged mice, which were treated with controls including the scrambled siRNA formulation. Overall, the results of this study demonstrate that CD44 targeting HA nanoparticles can selectively deliver siTNF-α to peritoneal macrophages leading to downregulation of pro-inflammatory cytokines in the peritoneal fluid and in the serum. This RNAi strategy could potentially provide an important therapeutic modality for acute inflammatory diseases, such as septic shock.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University , Boston, Massachusetts 02115, United States.|Alnylam Pharmaceuticals, Inc. , Cambridge, Massachusetts 02142, United States.
authors.forename: Verbena Y
authors.initials: VY
authors.lastname: Kosovrasti
authors.affiliation: Alnylam Pharmaceuticals, Inc. , Cambridge, Massachusetts 02142, United States.
authors.forename: Lubomir V
authors.initials: LV
authors.lastname: Nechev
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University , Boston, Massachusetts 02115, United States.|Faculty of Pharmacy, King Abdulaziz University , Jeddah, Saudi Arabia.
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
mesh_terms: D000818:Animals; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry*; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D018960:Hyaluronan Receptors; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid
keywords: CD44 targeting hyaluronic acid nanoparticles; LPS-induced inflammation; TNF-α silencing; peritoneal macrophages; siRNA