Abstract | OBJECTIVE: 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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Authors | C Fiehn, F Kratz, G Sass, U Müller-Ladner, E Neumann |
Journal | Annals of the rheumatic diseases
(Ann Rheum Dis)
Vol. 67
Issue 8
Pg. 1188-91
(Aug 2008)
ISSN: 1468-2060 [Electronic] England |
PMID | 18408252
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- AWO54
- Albumins
- Antirheumatic Agents
- Drug Carriers
- Prodrugs
- Methotrexate
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Topics |
- Albumins
- Animals
- Antirheumatic Agents
(metabolism, therapeutic use)
- Arthritis, Experimental
(drug therapy, metabolism)
- Drug Carriers
- Methotrexate
(metabolism, therapeutic use)
- Mice
- Mice, Inbred DBA
- Prodrugs
(metabolism, therapeutic use)
- Random Allocation
- Toxicity Tests, Acute
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