title: Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment.
abstract: Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA-MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA-MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, , Gotemba, Shizuoka, Japan. honmaake@chugai-pharm.co.jp
authors.forename: Akie
authors.initials: A
authors.lastname: Homma
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
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: Tatsuya
authors.initials: T
authors.lastname: Tamura
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: Ryochi
authors.initials: R
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D007270:Injections, Intra-Articular; D007717:Knee / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D010003:Osteoarthritis / Q000139:chemically induced / Q000188:drug therapy*; D020370:Osteoarthritis, Knee / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D011917:Rats, Inbred Lew; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D008727:Methotrexate