Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment

被引：64

作者：

Homma, Akie ^{[1
]}

Sato, Haruhiko ^{[1
]}

Okamachi, Akira ^{[1
]}

Emura, Takashi ^{[1
]}

Ishizawa, Takenori ^{[1
]}

Kato, Tatsuya ^{[1
]}

Matsuura, Tetsu ^{[1
]}

Sato, Shigeo ^{[1
]}

Tamura, Tatsuya ^{[1
]}

Higuchi, Yoshinobu ^{[1
]}

Watanabe, Tomoyuki ^{[1
]}

Kitamura, Hidetomo ^{[1
]}

Asanuma, Kentaro ^{[1
]}

Yamazaki, Tadao ^{[1
]}

Ikemi, Masahisa ^{[2
]}

Kitagawa, Hironoshin ^{[2
]}

Morikawa, Tadashi ^{[2
]}

Ikeya, Hitoshi ^{[2
]}

Maeda, Kazuaki ^{[2
]}

Takahashi, Koichi ^{[2
]}

Nohmi, Kenji ^{[2
]}

Izutani, Noriyuki ^{[2
]}

Kanda, Makoto ^{[2
]}

Suzuki, Ryochi ^{[2
]}

机构：

[1] Chugai Pharmaceut Co Ltd, Div Res, Shizuoka 4128513, Japan

[2] Denki Kagaku Kogyo KK, Res Ctr, Tokyo 1948560, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 13期

关键词：

Hyaluronic acid; Methotrexate; Osteoarthritis; Targeting drug delivery system; ANTIGEN-INDUCED ARTHRITIS; MOLECULAR-WEIGHT; RHEUMATOID-ARTHRITIS; THERAPEUTIC TARGETS; KNEE OSTEOARTHRITIS; SYNOVIAL-FLUID; ALPHA-PEPTIDES; DRUG-DELIVERY; SIDE-CHAIN; DERIVATIVES;

D O I：

10.1016/j.bmc.2009.04.063

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：4647 / 4656

页数：10

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