Rheumatoid arthritis (RA) is a chronic inflammatory arthropathy affecting approximately 1% of the general population worldwide. The disease is characterized by symmetrical inflammation of the synovial lining of diarthrodial joints, leading to cartilage and bone destruction and resulting in significant morbidity. Despite advances in RA treatment, many patients fail to respond to current therapy. Over half of the patients who initially respond eventually cease therapy due to secondary loss of efficacy and/or life-threatening toxicities. Many of these patients will ultimately require costly joint replacement to improve and maintain their daily activities. These problems highlight the need for continued development of additional therapies for RA. Unlike conventional drugs, nanosystems allow targeted delivery of a small but concentrated amount of therapeutic agents specifically to the desired site of inflammation. In addition, these nanosystems allow non-invasive and quantitative image-based readouts of drug effects, which ultimately translate to improved outcomes while minimizing systemic side effects. Using perfluorocarbon nanoparticles that target the integrin ?v?3 on neovasculature, we delivered the anti-angiogenic drug fumagillin to arthritic mice. Our preliminary data indicate that ?v?3-targeted perfluorocarbon nanoparticles halt the progression of inflammatory arthritis in a mouse model of RA. To further explore the use of nanoparticles for therapy and non-invasive evaluation of early treatment response in inflammatory arthritis, we propose the following aims:
Specific Aim 1 : Develop systemic targeted nanomedicine strategies to halt or reverse inflammation in a mouse model of arthritis. Using a collagen-induced arthritis (CIA) model, we have determined that systemic injection of ?v?3-targeted nanoparticles carrying fumagillin into arthritic mice led to >50% decrease in joint inflammation. These preliminary studies suggest that targeted nanoparticles may represent a novel way to treat RA and other types of inflammatory arthritis. However, many issues regarding the therapeutic agent selection, the dose, the administration strategy, and the use of adjunctive treatment remain unresolved. In this aim, we will test how different nanoparticle formulations, targeting and administration strategies will impact on the progression of inflammation in murine CIA.
Specific Aim 2 : Develop intra-articular nanomedicine strategies to halt and inhibit cartilage and bone erosions. Intra-articular injection is an attractive alternative in treating RA because of the much lower total dose of medication given by local delivery. Yet despite the limitations of systemic administration of disease modifying drugs, intra-articular injections have not been actively investigated because of the rapid clearance of drugs from the joint and the short-lived beneficial effect. Due to their size, nanoparticles are well suited for intra-articular use because the drugs entrapped in the outer surfactant layer are restricted to the joint space, allowing specific and local delivery of drugs without systemic effects. We will develop nanoparticle formulations that target proliferative synovium to reverse pannus formation and inhibit cartilage and bone erosions in a rabbit model of inflammatory arthritis and evaluate these in combination with systemic nanoparticle approaches. In conjunction, we will develop MR molecular imaging technologies based on targeted nanoparticles to track early therapeutic responses in a rabbit model of inflammatory arthritis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-NANO-M (01))
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Mao, Su-Yau
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Goette, Matthew J; Keupp, Jochen; Rahmer, Jürgen et al. (2015) Balanced UTE-SSFP for 19F MR imaging of complex spectra. Magn Reson Med 74:537-43
Yan, Huimin; Zhou, Hui-Fang; Hu, Ying et al. (2015) Suppression of experimental arthritis through AMP-activated protein kinase activation and autophagy modulation. J Rheum Dis Treat 1:5
Pan, Dipanjan; Schirra, Carsten O; Wickline, Samuel A et al. (2014) Multicolor computed tomographic molecular imaging with noncrystalline high-metal-density nanobeacons. Contrast Media Mol Imaging 9:13-25
Schmieder, Anne H; Wang, Kezheng; Zhang, Huiying et al. (2014) Characterization of early neovascular response to acute lung ischemia using simultaneous (19)F/ (1)H MR molecular imaging. Angiogenesis 17:51-60
Tomlinson, Ryan E; Schmieder, Anne H; Quirk, James D et al. (2014) Antagonizing the αv β3 integrin inhibits angiogenesis and impairs woven but not lamellar bone formation induced by mechanical loading. J Bone Miner Res 29:1970-80
Pham, Christine T N; Thomas, Dennis G; Beiser, Julia et al. (2014) Application of a hemolysis assay for analysis of complement activation by perfluorocarbon nanoparticles. Nanomedicine 10:651-60
Lanza, Gregory M; Moonen, Chrit; Baker Jr, James R et al. (2014) Assessing the barriers to image-guided drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6:1-14
Zhou, Hui-fang; Yan, Huimin; Hu, Ying et al. (2014) Fumagillin prodrug nanotherapy suppresses macrophage inflammatory response via endothelial nitric oxide. ACS Nano 8:7305-17
Zhou, Hui-fang; Yan, Huimin; Pan, Hua et al. (2014) Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis. J Clin Invest 124:4363-74
Lanza, Gregory M; Pan, Dipanjan (2014) Molecular imaging with computed tomography. Contrast Media Mol Imaging 9:1-2

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