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Targeted drug delivery by in vivo coupling to endogenous albumin: an albumin-binding prodrug of methotrexate (MTX) is better than MTX in the treatment of murine collagen-induced arthritis
  1. C Fiehn1,
  2. F Kratz2,
  3. G Sass3,
  4. U Müller-Ladner4,
  5. E Neumann4
  1. 1
    Centre of Rheumatic Diseases, Baden-Baden, Germany
  2. 2
    Tumour Biology Centre, Freiburg, Germany
  3. 3
    MEDAC GmbH, Pharmaceutical Company, Wedel, Germany
  4. 4
    Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany
  1. Dr E Neumann, Justus-Liebig-University Giessen, Department of Internal Medicine and Rheumatology, Kerckhoff-Klinik GmbH, Department of Rheumatology and Clinical Immunology, Benekestr 2-8, 61231 Bad Nauheim, Germany; e.neumann{at}kerckhoff-klinik.de

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 overexpressed in rheumatoid arthritis, and release a MTX lysine derivative. AWO54 suppressed CIA in a dose-dependent manner and was significantly better than MTX. To obtain a similar effect only about 20% of the MTX-equivalent dose of AWO54 had to be given. 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 with control.

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

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Footnotes

  • Competing interests: None.

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