Development of an oral drug delivery system targeting immune-regulating cells in experimental inflammatory bowel disease: a new therapeutic strategy.
Several studies have indicated the involvement of macrophages and dendritic cells in active inflammatory bowel disease (IBD). Manipulation of these cells is considered a very important therapeutic strategy for patients with IBD. We evaluated the effect of a new drug delivery system targeting microfold cells and macrophages with poly(DL-lactic acid) microspheres containing dexamethasone (Dx). Colitis was induced in BALB/c mice by 5% dextran sodium sulfate. Dx microspheres (n = 10) and only Dx (n = 10) were orally administered to dextran sodium sulfate-treated mice. Thereafter, serum levels and tissue distributions of Dx were investigated. To estimate the efficacy of this drug delivery system, we measured the histological score, myeloperoxidase activity and nitric oxide production, and gene expressions of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma in the colonic tissue. Serum Dx levels were not increased after oral administration of Dx microspheres. The tissue distribution of microspheres containing (125)I-labeled Dx in inflamed colon was significantly higher than in other organs. The histological score, myeloperoxidase activity, and nitric oxide production of the group treated with Dx microspheres were significantly lower than of those treated with Dx alone. Gene expressions of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma were down-regulated in mice treated with Dx microspheres. Microspheres containing glucocorticoids such as Dx, which target microfold cells and macrophages, can facilitate mucosal repair in experimental colitis and could be an ideal agent for treatment of human IBD.
Nakase
H
H
Division of Gastroenterology and Endoscopic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Okazaki
K
K
Tabata
Y
Y
Uose
S
S
Ohana
M
M
Uchida
K
K
Matsushima
Y
Y
Kawanami
C
C
Oshima
C
C
Ikada
Y
Y
Chiba
T
T
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D003106:Colon / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003911:Dextrans; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D015870:Gene Expression; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D019344:Lactic Acid; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D009569:Nitric Oxide / Q000096:biosynthesis; D009195:Peroxidase / Q000378:metabolism; D011091:Polyesters; D011108:Polymers; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D003911:Dextrans; D007375:Interleukin-1; D011091:Polyesters; D011108:Polymers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019344:Lactic Acid; C033616:poly(lactide); D003907:Dexamethasone; D007371:Interferon-gamma; D009195:Peroxidase