Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment.
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.
Homma
Akie
A
Research Division, Chugai Pharmaceutical Co, Ltd, , Gotemba, Shizuoka, Japan. honmaake@chugai-pharm.co.jp
Sato
Haruhiko
H
Okamachi
Akira
A
Emura
Takashi
T
Ishizawa
Takenori
T
Kato
Tatsuya
T
Matsuura
Tetsu
T
Sato
Shigeo
S
Tamura
Tatsuya
T
Higuchi
Yoshinobu
Y
Watanabe
Tomoyuki
T
Kitamura
Hidetomo
H
Asanuma
Kentaro
K
Yamazaki
Tadao
T
Ikemi
Masahisa
M
Kitagawa
Hironoshin
H
Morikawa
Tadashi
T
Ikeya
Hitoshi
H
Maeda
Kazuaki
K
Takahashi
Koichi
K
Nohmi
Kenji
K
Izutani
Noriyuki
N
Kanda
Makoto
M
Suzuki
Ryochi
R
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
D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D008727:Methotrexate