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Research Article

Synergistic effect of antiangiogenic nanotherapy combined with methotrexate in the treatment of experimental inflammatory arthritis

    Hui-fang Zhou

    Division of Rheumatology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8045, Saint Louis, MO 63110, USA

    ,
    Grace Hu

    Division of Cardiology, Washington University School of Medicine, Saint Louis, MO, USA

    ,
    Samuel A Wickline

    Division of Cardiology, Washington University School of Medicine, Saint Louis, MO, USA

    ,
    Gregory M Lanza

    Division of Cardiology, Washington University School of Medicine, Saint Louis, MO, USA

    &
    Published Online:https://doi.org/10.2217/nnm.10.78

    Aim: This study examines the effect of combining the antiangiogenic effect of αvβ3-targeted fumagillin nanoparticles with the conventional antirheumatic drug methotrexate for the treatment of inflammatory arthritis. Method: Arthritis was induced in mice by K/BxN serum transfer, and disease activity was monitored by clinical score and change in ankle thickness. Groups of mice received nanoparticles or methotrexate as single therapy or nanoparticles and methotrexate as combination therapy. Results: We found that animals treated with a pulse dose of fumagillin nanoparticles followed by methotrexate had significantly improved and sustained clinical response compared with those treated with either agent alone. Histological analysis confirmed a significant decrease in inflammatory cell influx, bone erosions, cartilage damage and angiogenesis with the combination therapy. Conclusion: Analysis of plasma cytokine levels suggests that fumagillin nanoparticles enhanced the systemic anti-inflammatory effects of methotrexate. Antiangiogenic nanotherapy may represent a promising approach for the treatment of inflammatory arthritis when combined with a conventional antirheumatic drug.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Sizova L: Approaches to the treatment of early rheumatoid arthritis with disease-modifying antirheumatic drugs. Br. J. Clin. Pharmacol.66(2),173–178 (2008).
    • Van Der Bijl AE, Goekoop-Ruiterman YP, De Vries-Bouwstra JK et al.: Infliximab and methotrexate as induction therapy in patients with early rheumatoid arthritis. Arthritis Rheum.56(7),2129–2134 (2007).
    • Zhou H-F, Chan HW, Wickline SA, Lanza GM, Pham CT: αvβ3-targeted nanotherapy suppresses inflammatory arthritis in mice. Faseb J.23(9),2978–2985 (2009).▪▪ First study to show that αvβ3-targeted nanoparticles conjugated to fumagillin accumulate specifically in inflamed joints and suppress the progression of experimental arthritis.
    • Duda DG, Jain RK, Willett CG: Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J. Clin. Oncol.25(26),4033–4042 (2007).▪▪ Presents the rationale and current understanding of antiangiogenics and their therapeutic potential in combination with chemoradiotherapy.
    • Culy C: Bevacizumab: antiangiogenic cancer therapy. Drugs Today (Barc)41(1),23–36 (2005).
    • Fukumura D, Jain RK: Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc. Res.74(2–3),72–84 (2007).
    • Winter PM, Caruthers SD, Zhang H, Williams TA, Wickline SA, Lanza GM: Antiangiogenic synergism of integrin-targeted fumagillin nanoparticles and atorvastatin in atherosclerosis. JAAC Cardiovasc. Imaging1(5),624–634 (2008).▪▪ Shows that integrin-targeted fumagillin nanoparticles can induce sustained antiangiogenic response in a model of atherosclerosis when combined with a statin.
    • Adkison AM, Raptis SZ, Kelley DG, Pham CT: Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J. Clin. Invest.109(3),363–371 (2002).
    • Schnell MA, Hardy C, Hawley M, Propert KJ, Wilson JM: Effect of blood collection technique in mice on clinical pathology parameters. Human Gene Ther.13(1),155–161 (2002).
    • 10  Storgard CM, Stupack DG, Jonczyk A, Goodman SL, Fox RI, Cheresh DA: Decreased angiogenesis and arthritic disease in rabbits treated with an αvβ3 antagonist. J. Clin. Invest.103(1),47–54 (1999).
    • 11  Bulte JWM, Lanza GM, Fuhrhop RW et al.: Gd-DTPA perfluorocarbon emulsions as a novel paramagnetic particulate contrast medium: T1 and T2 relaxometry. Presented at: Proceedings of International Society for Magnetic Resonance in Medicine 6th Annual Meeting. Sydney, Australia, 18–24 April (1998) (Abstract 209).
    • 12  Lena N, Imbert AM, Brunet P, Cano JP, Carcassonne Y: Kinetics of methotrexate and its metabolites in red blood cells. Cancer Drug Deliv.4(2),119–127 (1987).
    • 13  Chan ES, Cronstein BN: Methotrexate – how does it really work? Nat. Rev. Rheumatol.6(3),175–178 (2010).▪ Details the complex and multifaceted mechanisms that make methotrexate efficacious in the treatment of inflammatory disorders.
    • 14  Varner JA, Brooks PC, Cheresh DA: Review: The integrin αvβ3: angiogenesis and apoptosis. Cell Adhes. Commun.3(4),367–374 (1995).
    • 15  Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W, Folkman J: Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation99(13),1726–1732 (1999).
    • 16  Brdlik CM, Crews CM: A single amino acid residue defines the difference in ovalicin sensitivity between type I and II methionine aminopeptidases. J. Biol. Chem.279(10),9475–9480 (2004).
    • 17  De Bandt M, Grossin M, Weber AJ et al.: Suppression of arthritis and protection from bone destruction by treatment with TNP-470/AGM-1470 in a transgenic mouse model of rheumatoid arthritis. Arthritis Rheum.43(9),2056–2063 (2000).▪ Early report showing that TNP-470, a soluble form of fumagillin, can prevent the development of experimental arthritis.
    • 18  Herbst RS, Madden TL, Tran HT et al.: Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer. J. Clin. Oncol.20(22),4440–4447 (2002).
    • 19  Neurath MF, Hildner K, Becker C et al.: Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): A mechanism for methotrexate-mediated immunosuppression. Clin. Exp. Immunol.115(1),42–55 (1999).
    • 20  Szekanecz Z, Besenyei T, Paragh G, Koch AE: New insights in synovial angiogenesis. Joint Bone Spine77(1),13–19 (2009).
    • 21  Szekanecz Z, Besenyei T, Szentpetery A, Koch AE: Angiogenesis and vasculogenesis in rheumatoid arthritis. Curr. Opin. Rheum.22(3),299–306 (2010).▪ Provides a current understanding of the role of angiogenesis in rheumatoid arthritis, and summarizes the possibilities of therapeutic intervention.
    • 101  BRISTOL-MYERS SQUIBB PHARMA COMPANY: US6511648 (2003).
    • 201  Image J: image processing and analysis in Java http://rsb.info.nih.gov/ij