Journal
JOURNAL OF CONTROLLED RELEASE
Volume 316, Issue -, Pages 138-149Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2019.11.001
Keywords
Reactive oxygen species (ROS); Colitis; ROS-responsive microspheres; FK506; Dendritic cell migration
Funding
- National Research Foundation of Korea (NRF) - Korean Ministry of Science, ICT, and Future Planning [2015R1A5A2009124]
- Ministry of Education [2017R1D1A1B03027831]
- Korea Health Industry Development Institute (KHIDI) - Ministry of Health and Welfare, Republic of Korea [HI18C0453]
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Enteric-coated formulations using Eudragit (R) polymers have been extensively used for delivering drugs to the lower gastrointestinal tract. However, these drug-delivery systems cannot accurately deliver the therapeutic cargoes to colon because of early degradation of the polymers at alkaline pH of the small intestine. Here, we describe a precise method of delivering drugs to inflammation sites in colon using an oral drug delivery system. Tacrolimus (FK506)-loaded microspheres were prepared using a thioketal-based polymer that releases drug in response to reactive oxygen species (ROS), which are abundantly produced at the sites of inflammation in acute colitis. Orally-administered FK506-loaded thioketal microspheres (FK506-TKM) led to a substantial accumulation of FK506 in inflamed colon and effectively alleviated dextran-sulfate sodium (DSS)-induced murine colitis. At the molecular level, FK506-TKM significantly inhibited infiltration of CD4(+) and CD8(+) T lymphocytes in colon and differentiation of CD4(+) T cells into Th1 and Th17 cells in colon-draining mesenteric lymph nodes via restricting dendritic cell migration from colon. Our findings indicate orally-administered thioketal-based drug delivery system as a promising means of treating acute inflammatory bowel diseases.
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