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Methotrexate prodrugs sensitive to reactive oxygen species for the improved treatment of rheumatoid arthritis. | LitMetric

Methotrexate prodrugs sensitive to reactive oxygen species for the improved treatment of rheumatoid arthritis.

Eur J Med Chem

Center for Nanomedicine & Theranostics, Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK, 2800, Kongens Lyngby, Denmark. Electronic address:

Published: August 2018

AI Article Synopsis

Article Abstract

Methotrexate (MTX) is the standard of care in the treatment of rheumatoid arthritis (RA), a common autoimmune disease that is characterized by chronic inflammation in the synovial membrane of joints. Unfortunately, MTX suffers from high discontinuation rates due to a large variability in efficacy and, in particular, adverse effects. As inflammation is associated with elevated levels of reactive oxygen species (ROS) like HO, we propose to improve treatment through site-selective delivery of MTX to inflammatory tissue by use of a HO sensitive MTX prodrug. To establish proof proof-of-concept, two novel HO sensitive, thiazolidinone-based MTX prodrugs were synthesized and evaluated for this purpose. MTX-γ-thiazolidinone (MTX-γ-TZ) exhibited the most promising properties - good to high chemical and metabolic stability, excellent aqueous solubility, while being activated when subjected to patho-physiological concentrations of HO. In vivo, MTX-γ-TZ exhibited comparable efficacy to MTX in a murine collagen type II-induced arthritis (CIA) model while treated mice showed indications of reduced toxicity as their body weight decreased less towards the end of the study, compared to the MTX-treated group.

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Source
http://dx.doi.org/10.1016/j.ejmech.2018.07.045DOI Listing

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