title: Arthritic joint-targeting small interfering RNA-encapsulated liposome: implication for treatment strategy for rheumatoid arthritis.
abstract: RNA interference, mediated by small interfering RNA (siRNA), is effective in silencing genes with a high degree of specificity. To explore the therapeutic potential of systemically administered siRNA for rheumatoid arthritis (RA), we tested the complex of siRNA and the recently developed wrapsome (siRNA/WS) containing siRNA-encapsulated liposome in mice with collagen-induced arthritis (CIA). Mice with CIA received an intravenous injection of Cy5-labeled siRNA/WS. Fluorescence stereoscopic microscopy and flow cytometry were used to assess the siRNA/WS tissue distribution. The efficacy of siRNA-targeting tumor necrosis factor (TNF)-α/WS in CIA was evaluated by arthritis score. TNF-α mRNA levels in the joints were measured by real-time reverse transcriptase-polymerase chain reaction. The intensity of Cy5 fluorescence was higher in arthritic joints than in nonarthritic sites in Cy5-siRNA/WS-treated mice and remained higher up to 48 h after injection, compared with that in naked Cy5-siRNA-treated mice. Cy5 fluorescence intensity was higher in synovial cells than in splenocytes, bone marrow cells, and peripheral blood leukocytes. The majority of Cy5-positive synovial cells were CD11b⁺ with only a few CD3⁺ cells. Treatment with TNF-α siRNA/WS resulted in significant decreases in severity of arthritis and TNF-α mRNA level in the joints compared with control siRNA/WS. In conclusion, the use of our WS allowed efficient and targeted delivery of siRNAs to arthritic joints. The siRNA/WS was mainly incorporated into CD11b⁺ cells, including macrophages and neutrophils, in the inflamed synovium, suggesting its potential therapeutic effects in RA by silencing the expression of inflammatory molecules produced by these cells.
authors: Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Yukiko
authors: Y
authors: Komano
authors: Nobuhiro
authors: N
authors: Yagi
authors: Ikumi
authors: I
authors: Onoue
authors: Kayoko
authors: K
authors: Kaneko
authors: Nobuyuki
authors: N
authors: Miyasaka
authors: Toshihiro
authors: T
authors: Nanki
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D003094:Collagen; D016503:Drug Delivery Systems; D007596:Joints / Q000187:drug effects*; D008081:Liposomes; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D039481:CD11b Antigen; D017252:CD3 Complex; D008081:Liposomes; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen