{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:28:54Z","timestamp":1787243334889,"version":"build-2736575974"},"reference-count":61,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Foundation of Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application","award":["2024KFKT05"],"award-info":[{"award-number":["2024KFKT05"]}]},{"name":"Key Project of the Natural Science Foundation of the Department of Education of Anhui Province","award":["2022AH051226"],"award-info":[{"award-number":["2022AH051226"]}]},{"name":"Key Project of the Natural Science Foundation of the Department of Education of Anhui Province","award":["2022AH051231"],"award-info":[{"award-number":["2022AH051231"]}]},{"name":"Open Project of Anhui Engineering Technology Research Center of Biochemical Pharmaceutical","award":["2023SYKFD08"],"award-info":[{"award-number":["2023SYKFD08"]}]},{"name":"Foundation of Anhui Innovative Center for Drug Basic Research of Metabolic Diseases","award":["YZJ2026005"],"award-info":[{"award-number":["YZJ2026005"]}]},{"name":"Anhui Province New Era Education Quality Project","award":["2024yjsxxsfkc044"],"award-info":[{"award-number":["2024yjsxxsfkc044"]}]},{"name":"College Students\u2019 Innovative Entrepreneurial Training Plan Program","award":["S202510368002"],"award-info":[{"award-number":["S202510368002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Imperatorin (IPT) is a natural furanocoumarin featuring robust anti-inflammatory, antifibrotic and antioxidant activities. However, poor aqueous solubility and insufficient oral bioavailability restrict its clinical application. Multiple gastrointestinal barriers, including the mucus barrier, limited epithelial penetration and P-glycoprotein-triggered drug efflux, are major obstacles hindering IPT oral absorption. Methods: N-acetylcysteine (NAC)-functionalized TPGS conjugates were synthesized first. Using Pluronic\u00ae F108 and Lipoid\u00ae S-100 as a matrix, imperatorin@N-acetylcysteine-TPGS\/Pluronic\u00ae F108\/Lipoid\u00ae S-100 (IPT@NAC-TFS) micelles were fabricated. We characterized their physicochemical features and in vitro release behavior. The Caco-2\/HT29-MTX-E12 co-culture cell model was adopted to explore mucus permeation, cellular uptake and transepithelial transport mechanisms. In vivo intestinal distribution and pharmacokinetic tests in rats were carried out to confirm the oral absorption-enhancing effect of micelles. Results: Optimized micelles displayed a uniform shape and favorable encapsulation efficiency. Low CMC maintained structural stability upon gastrointestinal dilution. NAC modification conferred mucus-penetrating capacity on micelles. TPGS simultaneously improved epithelial barrier permeability and inhibited drug efflux, switching IPT transport mode. The micelles effectively cleared intracellular ROS, recovered SOD activity and lowered MDA levels in BLM-impaired MLg fibroblasts. In vivo results revealed enhanced intestinal drug accumulation, with the relative oral bioavailability of IPT increased by 6.07-fold. Conclusions: IPT@NAC-TFS micelles overcome multiple gastrointestinal barriers for oral IPT delivery. Combining mucus penetration, efflux suppression and antioxidative capacity, this system offers a promising strategy to develop oral formulations of poorly soluble antifibrotic natural products.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081036","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:05:19Z","timestamp":1787241919000},"page":"1036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["N-Acetylcysteine-Functionalized Mixed Micelles Overcome Multiple Intestinal Barriers to Improve Oral Bioavailability and Antioxidant Protection of Imperatorin"],"prefix":"10.3390","volume":"18","author":[{"given":"Yu","family":"Zhang","sequence":"first","affiliation":[{"name":"Drug Research and Development Center, School of Pharmacy, Wannan Medical University, Wuhu 241002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Guo","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haonan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Drug Research and Development Center, School of Pharmacy, Wannan Medical University, Wuhu 241002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiale","family":"Liu","sequence":"additional","affiliation":[{"name":"Drug Research and Development Center, School of Pharmacy, Wannan Medical University, Wuhu 241002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Drug Research and Development Center, School of Pharmacy, Wannan Medical University, Wuhu 241002, 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Diseases, Wannan Medical University, Wuhu 241002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Hou","sequence":"additional","affiliation":[{"name":"Drug Research and Development Center, School of Pharmacy, Wannan Medical University, Wuhu 241002, China"},{"name":"Anhui Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wannan Medical University, Wuhu 241002, China"},{"name":"Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wannan Medical University, Wuhu 241002, China"},{"name":"Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wannan Medical University, Wuhu 241002, 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