title: Suppression of experimental arthritis with self-assembling glycol-split heparin nanoparticles via inhibition of TLR4-NF-κB signaling.
abstract: It has been recently shown that Toll-like receptor4 mediated nuclear factor κB (TLR4-NF-κB) signaling plays a critical role in the pathogenesis of rheumatoid arthritis mediated by pro-inflammatory cytokines in arthritic synovium. Here we evaluate the therapeutic potential of glycol-split non-anticoagulant heparin/d-erythro-sphingosine nanoparticles (NAHNPs), which have shown strong inhibitory effect against TLR4 induced inflammation, in an experimental arthritis model. NAHNP significantly inhibited the production of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β in lipopolysaccharide (LPS)-induced primary mouse macrophages and DC2.4 dendritic cell line. The nanoparticles were administered to type II collagen-induced arthritis (CIA) mice by intraarticular injections once per day starting from onset of the disease symptoms. Treatment with NAHNP had a potent suppressive effect in CIA mice, observed with a decrease in arthritis score and footpad swelling. The animals treated with NAHNP significantly reduced levels of IgG1 and IgG2a antibodies against bovine type II collagen. Levels of proinflammatory cytokines--e.g., TNF-α, IL-6 and IL-1β in knee joints and sera were significantly inhibited compared to control mice. Moreover, nuclear localization of RelA in knee joints was significantly inhibited in NAHNP treatment, indicating down-regulation of the NF-κB signaling pathway. In addition, histological examination revealed significant suppression of inflammatory cell infiltration, joint destruction and synovial proliferation in synovium compared with control mice. These results suggest that selective inhibition of TLR4-NF-κB signaling with lipid modified heparin derivatives composited to nanostructures provides an effective therapeutic approach to inhibit chronic inflammation in an animal model of rheumatoid arthritis.
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hasan
authors.initials: H
authors.lastname: Babazada
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamashita
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshidaushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hashidam@pharm.kyoto-u.ac.jp.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D024043:Collagen Type II; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects; D006018:Glycols / Q000737:chemistry; D006493:Heparin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D007136:Immunoglobulins / Q000378:metabolism; D007596:Joints / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000187:drug effects*; D053758:Nanoparticles; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D024043:Collagen Type II; D016207:Cytokines; D006018:Glycols; D007136:Immunoglobulins; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D006493:Heparin
keywords: Arthritis; Heparin nanoparticles; Inflammation; NF-κB; Toll-like receptor 4