title: Synthesis and optimization of hyaluronic acid-methotrexate conjugates to maximize benefit in the treatment of osteoarthritis.
abstract: 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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Akie
authors.initials: A
authors.lastname: Homma
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tamura
authors.forename: Akira
authors.initials: A
authors.lastname: Okamachi
authors.forename: Takashi
authors.initials: T
authors.lastname: Emura
authors.forename: Takenori
authors.initials: T
authors.lastname: Ishizawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kato
authors.forename: Tetsu
authors.initials: T
authors.lastname: Matsuura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hidetomo
authors.initials: H
authors.lastname: Kitamura
authors.forename: Kentaro
authors.initials: K
authors.lastname: Asanuma
authors.forename: Tadao
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Masahisa
authors.initials: M
authors.lastname: Ikemi
authors.forename: Hironoshin
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Morikawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeya
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Maeda
authors.forename: Koichi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Nohmi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Izutani
authors.forename: Makoto
authors.initials: M
authors.lastname: Kanda
authors.forename: Ryohchi
authors.initials: R
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D007719:Knee Joint / Q000187:drug effects / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D010003:Osteoarthritis / Q000188:drug therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D013582:Synovial Fluid / Q000166:cytology
chemical_list: C000611759:DK226 compound; D006820:Hyaluronic Acid; D002403:Cathepsins; D008727:Methotrexate