Synthesis and optimization of hyaluronic acid–methotrexate conjugates to maximize benefit in the treatment of osteoarthritis
| Autor: | Takenori Ishizawa, Koichi Takahashi, Kentaro Asanuma, Shigeo Sato, Kenji Nohmi, Ryohchi Suzuki, Tadashi Morikawa, Tomoyuki Watanabe, Yoshinobu Higuchi, Akie Homma, Tatsuya Tamura, Makoto Kanda, Noriyuki Izutani, Takashi Emura, Kazuaki Maeda, Hironoshin Kitagawa, Haruhiko Sato, Tadao Yamazaki, Masahisa Ikemi, Hitoshi Ikeya, Tetsu Matsuura, Tatsuya Kato, Akira Okamachi, Hidetomo Kitamura |
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| Rok vydání: | 2010 |
| Předmět: |
Male
musculoskeletal diseases Knee Joint Clinical Biochemistry Pharmaceutical Science Osteoarthritis Pharmacology Biochemistry Cell Line chemistry.chemical_compound In vivo Synovial Fluid Drug Discovery Hyaluronic acid medicine Animals Humans Hyaluronic Acid Molecular Biology Organic Chemistry Fibroblasts medicine.disease Cathepsins Rats Methotrexate chemistry Rats Inbred Lew Drug delivery Antifolate Molecular Medicine Drug carrier Conjugate medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 18:1062-1075 |
| ISSN: | 0968-0896 |
| Popis: | We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like synoviocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis. |
| Databáze: | OpenAIRE |
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