Journal article
Methotrexate Prodrugs Sensitive to Reactive Oxygen Species for the Improved Treatment of Rheumatoid Arthritis
Department of Chemistry, Technical University of Denmark1
Organic Chemistry, Department of Chemistry, Technical University of Denmark2
Technical University of Denmark3
MC2 Therapeutics ApS4
Capdelta Group ApS5
University of Copenhagen6
Department of Micro- and Nanotechnology, Technical University of Denmark7
Colloids and Biological Interfaces, Department of Micro- and Nanotechnology, Technical University of Denmark8
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 H2O2, we propose to improve treatment through site-selective delivery of MTX to inflammatory tissue by use of a H2O2 sensitive MTX prodrug. To establish proof proof-of-concept, two novel H2O2 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 H2O2. 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
Language: | English |
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Publisher: | Elsevier BV |
Year: | 2018 |
Pages: | 738-746 |
ISSN: | 17683254 and 02235234 |
Types: | Journal article |
DOI: | 10.1016/j.ejmech.2018.07.045 |
ORCIDs: | Clausen, Mads H. , Andersen, Nikolaj S. and Andresen, Thomas Lars |