title: MRI-assessed therapeutic effects of locally administered PLGA nanoparticles loaded with anti-inflammatory siRNA in a murine arthritis model.
abstract: Rheumatoid arthritis is characterized by systemic inflammation of synovial joints leading to erosion and cartilage destruction. Although efficacious anti-tumor necrosis factor α (TNF-α) biologic therapies exist, there is an unmet medical need for safe and more efficient treatment regimens for disease remission. We evaluated the anti-inflammatory effects of poly(dl-lactide-co-glycolide acid) (PLGA) nanoparticles loaded with small interfering RNA (siRNA) directed against TNF-α in vitro and in vivo. The siRNA-loaded PLGA nanoparticles mediated a dose-dependent TNF-α silencing in lipopolysaccharide-activated RAW 264.7 cells in vitro. The severity of collagen antibody-induced arthritis in DBA/1J mice was assessed by paw scoring and compared to the degree of magnetic resonance imaging (MRI)-quantified joint effusion and bone marrow edema. Two intra-articular treatments per joint with nanoparticles loaded with TNF-α siRNA (1 μg) resulted in a reduction in disease activity, evident by a significant decrease of the paw scores and joint effusions, as compared to treatment with PLGA nanoparticles loaded with non-specific control siRNA, whereas the degree of bone marrow edema in the tibial and femoral head remained unchanged. When the siRNA dose was 5 or 10 μg, there was no difference between the specific and the non-specific siRNA treatment groups. These findings suggest that MRI is a promising method for evaluation of early disease progression and treatment in murine arthritis models. In addition, proper siRNA dosing seems to be important for a positive therapeutic outcome in vivo. However, further studies are needed to fully clarify the mechanism(s) underlying the observed anti-inflammatory effects of the siRNA-loaded nanoparticles.
authors.affiliation: Department of Biomedical Engineering, Eindhoven University of Technology, P.O. Box 513, Building W-Hoog 4.11, 5600 MB Eindhoven, The Netherlands. b.teboekhorst@maastrichtuniversity.nl
authors.forename: Bernard C M
authors.initials: BC
authors.lastname: te Boekhorst
authors.forename: Linda B
authors.initials: LB
authors.lastname: Jensen
authors.forename: Stefano
authors.initials: S
authors.lastname: Colombo
authors.forename: Amir K
authors.initials: AK
authors.lastname: Varkouhi
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Hanne M
authors.initials: HM
authors.lastname: Nielsen
authors.forename: Gustav J
authors.initials: GJ
authors.lastname: Strijkers
authors.forename: Camilla
authors.initials: C
authors.lastname: Foged
authors.forename: Klaas
authors.initials: K
authors.lastname: Nicolay
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000628:therapy*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002460:Cell Line; D004337:Drug Carriers / Q000008:administration & dosage; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D005269:Femur; D020868:Gene Silencing; D019344:Lactic Acid / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D053758:Nanoparticles / Q000008:administration & dosage*; D011100:Polyglycolic Acid / Q000008:administration & dosage; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D013977:Tibia; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D004337:Drug Carriers; D005229:Fatty Acids, Monounsaturated; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane