title: 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.
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.
  
  
  CONCLUSIONS
  Targeted drug delivery by in vivo coupling of a prodrug of MTX to endogenous albumin is better than MTX in the treatment of CIA.
authors.affiliation: Centre of Rheumatic Diseases, Baden-Baden, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Fiehn
authors.forename: F
authors.initials: F
authors.lastname: Kratz
authors.forename: G
authors.initials: G
authors.lastname: Sass
authors.forename: U
authors.initials: U
authors.lastname: Müller-Ladner
authors.forename: E
authors.initials: E
authors.lastname: Neumann
mesh_terms: D000418:Albumins; D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004337:Drug Carriers; D008727:Methotrexate / Q000378:metabolism / Q000627:therapeutic use* / Q000031:analogs & derivatives; D051379:Mice; D008811:Mice, Inbred DBA; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D011897:Random Allocation; D023382:Toxicity Tests, Acute
chemical_list: C530579:AWO54; D000418:Albumins; D018501:Antirheumatic Agents; D004337:Drug Carriers; D011355:Prodrugs; D008727:Methotrexate