Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland.
Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland.
Gastroenterology. 2023 May;164(6):937-952.e13. doi: 10.1053/j.gastro.2023.01.006. Epub 2023 Jan 16.
BACKGROUND & AIMS: 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.
组织纤维化是由失控的愈合反应导致的，其导致间充质细胞过度激活以及胶原和其他细胞外基质的沉积。在胃肠道中，纤维化会导致管腔变窄和狭窄形成。预防胃肠道纤维化和狭窄的药物治疗将对患者护理产生变革性影响。我们旨在开发一种具有以下特征和成分的狭窄治疗方法：一种具有强大抗纤维化作用的小分子，在狭窄部位局部给药，以确保正确的病变靶向，同时保护全身循环，并且具有缓释特性，可在整个伤口愈合过程中发挥作用。
进行了高通量药物筛选，以鉴定具有抗纤维化特性的小分子。接下来，我们将一种抗纤维化小分子制成缓释制剂，并在 3 种纤维化动物模型中测试其抗纤维化潜力。
发现美国食品和药物管理局批准用于真菌感染的药物舒康唑具有很强的抗纤维化特性。舒康唑被制成舒康唑纳米晶体用于缓释。我们发现，舒康唑纳米晶体在皮肤和肠道组织纤维化的小鼠模型中，通过更频繁的给药提供了更好或等效的纤维化预防效果。在类似患者的猪肠狭窄模型中，单次注射舒康唑纳米晶体可预防狭窄形成。
目前的数据为进一步研究奠定了基础，以改善一系列以组织纤维化为特征的疾病和病症的管理。
