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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Development of an Oral Drug Delivery System Targeting Immune-Regulating Cells in Experimental Inflammatory Bowel Disease: A New Therapeutic Strategy

Hiroshi Nakase, Kazuichi Okazaki, Yasuhiko Tabata, Suguru Uose, Masaya Ohana, Kazushige Uchida, Yumi Matsushima, Chiharu Kawanami, Chikashi Oshima, Yoshito Ikada and Tsutomu Chiba
Journal of Pharmacology and Experimental Therapeutics January 2000, 292 (1) 15-21;
Hiroshi Nakase
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Kazuichi Okazaki
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Yasuhiko Tabata
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Suguru Uose
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Masaya Ohana
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Kazushige Uchida
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Yumi Matsushima
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Chiharu Kawanami
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Chikashi Oshima
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Yoshito Ikada
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Tsutomu Chiba
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Abstract

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-α, interleukin-1β, and interferon-γ in the colonic tissue. Serum Dx levels were not increased after oral administration of Dx microspheres. The tissue distribution of microspheres containing125I-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-α, interleukin-1β, and interferon-γ 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.

Footnotes

  • Send reprint requests to: Kazuichi Okazaki, M.D., Ph.D., Division of Gastroenterology and Endoscopic Medicine, Graduate School of Kyoto University, 54 Shogoinkawara-cho, Sakyoku, Kyoto, 606-8507, Japan. E-mail:okak{at}kuhp.kyoto-u.ac.jp

  • ↵1 This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Culture and Science of Japan (09670543, 11670495, and 10470134), a Grant-in-Aid for Research for the Future Program from the Japan Society for the Promotion of Science (JSPS-RFTF 97100201), and Supporting in Research Funds from the Japanese Foundation for Research and Promotion of Endoscopy (JFE-1997).

  • Abbreviations:
    UC
    ulcerative colitis
    IBD
    inflammatory bowel disease
    M cells
    microfold cells
    PDLLA
    poly(dl-lactic acid)
    Dx
    dexamethasone
    DSS
    dextran sodium sulfate
    MPO
    myeloperoxidase
    NO
    nitric oxide
    RT-PCR
    reverse-transcription polymerase chain reaction
    TNF-α
    tumor necrosis factor-α
    IL-1β
    interleukin-1β
    IFN-γ
    interferon-γ
    • Received June 10, 1999.
    • Accepted August 27, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 1
1 Jan 2000
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Development of an Oral Drug Delivery System Targeting Immune-Regulating Cells in Experimental Inflammatory Bowel Disease: A New Therapeutic Strategy

Hiroshi Nakase, Kazuichi Okazaki, Yasuhiko Tabata, Suguru Uose, Masaya Ohana, Kazushige Uchida, Yumi Matsushima, Chiharu Kawanami, Chikashi Oshima, Yoshito Ikada and Tsutomu Chiba
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 15-21;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Development of an Oral Drug Delivery System Targeting Immune-Regulating Cells in Experimental Inflammatory Bowel Disease: A New Therapeutic Strategy

Hiroshi Nakase, Kazuichi Okazaki, Yasuhiko Tabata, Suguru Uose, Masaya Ohana, Kazushige Uchida, Yumi Matsushima, Chiharu Kawanami, Chikashi Oshima, Yoshito Ikada and Tsutomu Chiba
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 15-21;
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