title: Functionalized STAT1 siRNA nanoparticles regress rheumatoid arthritis in a mouse model.
abstract: OBJECTIVE
  To develop and characterize an RGD peptide functionalized poly(lactide-co-glycolytic) acid (PLGA) nanosystem to deliver a STAT1 siRNA to joint tissues in a mouse model of rheumatoid arthritis.
  
  
  METHODS
  RGD-PLGA polymer was synthesized and used in preparing functionalized nanoparticles loaded with either tracking material or siRNA. The properties of the nanoparticles and stability of siRNA after encapsulation was assessed. Nanoparticle distribution was determined both noninvasively and based on analysis of dissected organs from arthritic and healthy mice. Arthritic mice were treated with weekly doses of STAT1 siRNA-loaded nanoparticles or controls. Clinical disease was assessed. Paws of arthritic mice were sectioned for histology or processed for RNA. STAT1, Mrc-1, and IL-10 mRNA abundance was determined by quantitative PCR.
  
  
  RESULTS
  Nanoparticles protected the siRNA from serum degradation. The presence of RGD peptide on the nanoparticles increased paw tissue uptake in arthritic mice. Furthermore, RGD functionalization increased lung delivery of nanoparticles in arthritic mice but not in control mice. Disease regressed in the STAT1 siRNA-treated animals and progressed in all control groups. STAT1 mRNA levels were decreased in paws of treated animals, while Mrc-1 and IL-10 mRNA levels were increased.
  
  
  CONCLUSIONS
  RGD functionalized PLGA nanoparticles encapsulating STAT1-targeted siRNAs are efficacious in the treatment of established arthritis, possibly through a selective inhibition of macrophage and dendritic cell activation.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E Montview Blvd, CO C238-V20, USA.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Scheinman
authors.forename: Ruchit
authors.initials: R
authors.lastname: Trivedi
authors.forename: Sam
authors.initials: S
authors.lastname: Vermillion
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry*; D016503:Drug Delivery Systems; D004355:Drug Stability; D020868:Gene Silencing; D015316:Genetic Therapy; D016753:Interleukin-10 / Q000378:metabolism; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D009842:Oligopeptides; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D016753:Interleukin-10; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C047981:arginyl-glycyl-aspartic acid