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.
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.
Authors: Mark R Tanner; Xueyou Hu; Redwan Huq; Rajeev B Tajhya; Liang Sun; Fatima S Khan; Teresina Laragione; Frank T Horrigan; Pércio S Gulko; Christine Beeton Journal: Arthritis Rheumatol Date: 2015-01 Impact factor: 10.995
Authors: Jenna M Rosano; Nazanin Tousi; Robert C Scott; Barbara Krynska; Victor Rizzo; Balabhaskar Prabhakarpandian; Kapil Pant; Shivshankar Sundaram; Mohammad F Kiani Journal: Biomed Microdevices Date: 2009-05-19 Impact factor: 2.838