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Targeted drug delivery by in vivo coupling to endogenous albumin: An albumin-binding prodrug of methotrexate (MTX) is superior to MTX in the treatment of murine collagen-induced arthritis
  1. C Fiehn (c.fiehn{at}rheumazentrum-baden.de)
  1. Centre of Rheumatic Diseases, Germany
    1. F Kratz
    1. Tumor Biology Center, Freiburg, Germany
      1. G Sass
      1. MEDAC GmbH, Pharmaceutical Company, Wedel, Germany
        1. U Müller-Ladner
        1. Justus-Liebig-University of Gießen, Germany
          1. E Neumann (e.neumann{at}kerckhoff-klinik.de)
          1. Justus-Liebig-University of Gießen, Germany

            Abstract

            Objective: To examine the effect of an albumin-binding prodrug of methotrexate (MTX) in the treatment of murine collagen-induced arthritis (CIA).

            Methods: The prodrug AWO54 with the formula EMC-D-Ala-Phe-Lys-Lys-MTX binds selectively to the cysteine-34 position of endogenous albumin, which acts as a macromolecular drug carrier for MTX to the site of inflammation. The CIA model was used to evaluate the anti-arthritic effect of the compound after intravenous application.

            Results: The albumin-bound form of AWO54 was efficiently cleaved by cathepsin B and plasmin, two proteases that are over-expressed in rheumatoid arthritis, and release a MTX lysine derivative. AWO54 suppressed collagen-induced arthritis in a dose-dependent manner and was significantly superior to MTX. To obtain a similar effect only about 20% of the MTX-equivalent dose of AWO54 had to be given in comparison to MTX. The efficacy of the drug was tested in two different stages of CIA: While both, MTX and AWO54 inhibited arthritis in an early stage of the disease, in a later stage only AWO54 showed a significant inhibitory effect in comparison to control.

            Conclusion: Targeted drug delivery by in vivo coupling of a prodrug of MTX to endogenous albumin is superior to MTX in the treatment of CIA.

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