纤维化
医学
细胞外基质
体内
胃肠道
药品
药物输送
病理
癌症研究
药理学
内科学
纳米技术
材料科学
生物
细胞生物学
生物技术
作者
Ling Li,Rachel L. Shapiro,Min Kyung Joo,Aditya Josyula,Henry T. Hsueh,Olaya Brewer Gutierrez,Gilad Halpert,Venkata S. Akshintala,Haiming Chen,Samuel D. Curtis,Marina Better,Charlotte Davison,Han Hu,Jose Antonio Almario,Steven N. Steinway,Kelton Hunt,Rico E. Del Sesto,Jessica Izzi,Kevan J. Salimian,Laura M. Ensign,Florin M. Selaru
标识
DOI:10.1053/j.gastro.2023.01.006
摘要
Tissue fibrosis results from uncontrolled healing responses leading to excessive mesenchymal cell activation and collagen and other extracellular matrix deposition. In the gastrointestinal tract, fibrosis leads to narrowing of the lumen and stricture formation. A drug treatment to prevent fibrosis and strictures in the gastrointestinal tract would be transformational for patient care. We aimed to develop a stricture treatment with the following characteristics and components: a small molecule with strong antifibrotic effects that is delivered locally at the site of the stricture to ensure correct lesional targeting while protecting the systemic circulation, and that is formulated with sustained-release properties to act throughout the wound healing processes.A high-throughput drug screening was performed to identify small molecules with antifibrotic properties. Next, we formulated an antifibrotic small molecule for sustained release and tested its antifibrotic potential in 3 animal models of fibrosis.Sulconazole, a US Food and Drug Administration-approved drug for fungal infections, was found to have strong antifibrotic properties. Sulconazole was formulated as sulconazole nanocrystals for sustained release. We found that sulconazole nanocrystals provided superior or equivalent fibrosis prevention with less frequent dosing in mouse models of skin and intestinal tissue fibrosis. In a patient-like swine model of bowel stricture, a single injection of sulconazole nanocrystals prevented stricture formation.The current data lay the foundation for further studies to improve the management of a range of diseases and conditions characterized by tissue fibrosis.
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