Macromolecular glucocorticoid prodrug improves the treatment of dextran sulfate sodium-induced mice ulcerative colitis

被引:33
作者
Ren, Ke [1 ]
Yuan, Hongjiang [1 ]
Zhang, Yijia [1 ]
Wei, Xin [1 ]
Wang, Dong [1 ]
机构
[1] Univ Nebraska Med Ctr, Dept Pharmaceut Sci, Omaha, NE 68198 USA
关键词
Inflammatory bowel diseases; Dextran sulfate sodium; Glucocorticoid; ELVIS; HPMA copolymer; Prodrug; INFLAMMATORY-BOWEL-DISEASE; MOUSE MODELS; RHEUMATOID-ARTHRITIS; KAPPA-B; MECHANISMS; CORTICOSTEROIDS; EPIDEMIOLOGY; GROWTH; CONJUGATE; INDUCTION;
D O I
10.1016/j.clim.2015.03.027
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
A macromolecular prodrug (P-Dex) of dexamethasone (Dex) was developed to improve the treatment of inflammatory bowel disease (IBD). Colonic inflammation was induced by feeding mice with dextran sulfate sodium. Mice were treated with daily i.p. injection of free Dex or single i.v. injection of P-Dex, PBS or free polymer. Both P-Dex and free Dex could lower disease activity index and histology scores when compared to the controls. A single injection of P-Dex with 1/4 equivalent Dex dose had a better therapeutic effect than daily free Dex treatment. Mechanism study found that P-Dex could target the inflamed colon, and be retained by epithelial cells and local inflammatory infiltrates, suggesting that the improved efficacy of P-Dex may be attributed to its inflammation targeting, subcellular processing and activation. Collectively, these data support our hypothesis that the development of macromolecular prodrug of glucocorticoid may have the potential to improve the clinical management of IBD. (C) 2015 Elsevier Inc. All rights reserved.
引用
收藏
页码:71 / 81
页数:11
相关论文
共 43 条
[1]   MECHANISMS OF DISEASE Inflammatory Bowel Disease [J].
Abraham, Clara ;
Cho, Judy H. .
NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (21) :2066-2078
[2]   A METAANALYSIS OF THE EFFECT OF ORAL AND INHALED CORTICOSTEROIDS ON GROWTH [J].
ALLEN, DB ;
MULLEN, ML ;
MULLEN, B .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1994, 93 (06) :967-976
[3]   Glucocorticosteroids: current and future directions [J].
Barnes, Peter J. .
BRITISH JOURNAL OF PHARMACOLOGY, 2011, 163 (01) :29-43
[4]   Traditional corticosteroids for induction of remission in Crohn's disease [J].
Benchimol, E., I ;
Seow, C. H. ;
Steinhart, A. H. ;
Griffiths, A. M. .
COCHRANE DATABASE OF SYSTEMATIC REVIEWS, 2008, (02)
[5]  
Byrne FR, 2006, CURR OPIN DRUG DISC, V9, P207
[6]  
COOPER HS, 1993, LAB INVEST, V69, P238
[7]   Epidemiology and Natural History of Inflammatory Bowel Diseases [J].
Cosnes, Jacques ;
Gower-Rousseau, Corinne ;
Seksik, Philippe ;
Cortot, Antoine .
GASTROENTEROLOGY, 2011, 140 (06) :1785-U118
[8]   DEXTRAN SULFATE SODIUM-INDUCED COLITIS OCCURS IN SEVERE COMBINED IMMUNODEFICIENT MICE [J].
DIELEMAN, LA ;
RIDWAN, BU ;
TENNYSON, GS ;
BEAGLEY, KW ;
BUCY, RP ;
ELSON, CO .
GASTROENTEROLOGY, 1994, 107 (06) :1643-1652
[9]  
Dieleman LA, 1998, CLIN EXP IMMUNOL, V114, P385
[10]   Inflammatory bowel disease: evolutionary concepts in biology, epidemiology, mechanisms and therapy [J].
Fiocchi, Claudio .
CURRENT OPINION IN GASTROENTEROLOGY, 2013, 29 (04) :347-349