Department of Ophthalmology, The Affiliated Hospital of Qingdao University, NO. 16 Jiangsu Road, Qingdao, Shandong Province 266000, China.
State Key Laboratory of Bio-fibers and Eco-textiles, Institute of Marine Biobased Materials, College of materials Science and Engineering, Qingdao University, Qingdao, Shandong Province 266071, China.
Int J Biol Macromol. 2024 Nov;279(Pt 2):135290. doi: 10.1016/j.ijbiomac.2024.135290. Epub 2024 Sep 2.
Fungal keratitis (FK) is recognized as a stubborn ocular condition, caused by intense fungal invasiveness and heightened immune reaction. The glycosaminoglycan chondroitin sulfate exhibits properties of immunomodulation and tissue regeneration. In prior investigations, oxidized chondroitin sulfate (OCS) ameliorated the prognosis of FK in murine models. To further improve the curative efficacy, we used the antifungal drug natamycin to functionalize OCS and prepared oxidized chondroitin sulfate-natamycin (ON) eye drops. The structure of ON was characterized by FTIR, UV-vis, and XPS, revealing that the amino group of natamycin combined with the aldehyde group in OCS through Schiff base reaction. Antifungal experiments revealed that ON inhibited fungal growth and disrupted the mycelium structure. ON exhibited exceptional biocompatibility and promoted the proliferation of corneal epithelial cells. Pharmacokinetic analysis indicated that ON enhanced drug utilization by extending the mean residence time in tears. In murine FK, ON treatment reduced the clinical score and corneal fungal load, restored corneal stroma conformation, and facilitated epithelial repair. ON effectively inhibited neutrophil infiltration and decreased the expression of TLR-4, LOX-1, IL-1β, and TNF-α. Our research demonstrated that ON eye drops achieved multifunctional treatment for FK, including inhibiting fungal growth, promoting corneal repair, enhancing drug bioavailability, and controlling inflammatory reactions.
真菌性角膜炎（FK）是一种顽固的眼部疾病，由强烈的真菌感染和增强的免疫反应引起。糖胺聚糖硫酸软骨素具有免疫调节和组织再生的特性。在之前的研究中，氧化硫酸软骨素（OCS）改善了 FK 在小鼠模型中的预后。为了进一步提高疗效，我们使用抗真菌药物那他霉素对 OCS 进行功能化，制备了氧化硫酸软骨素-那他霉素（ON）滴眼液。ON 的结构通过傅里叶变换红外光谱（FTIR）、紫外-可见光谱（UV-vis）和 X 射线光电子能谱（XPS）进行了表征，结果表明那他霉素的氨基与 OCS 中的醛基通过席夫碱反应结合。抗真菌实验表明，ON 抑制了真菌的生长并破坏了菌丝体结构。ON 表现出优异的生物相容性并促进了角膜上皮细胞的增殖。药代动力学分析表明，ON 通过延长在泪液中的平均停留时间来提高药物的利用度。在 FK 小鼠模型中，ON 治疗降低了临床评分和角膜真菌负荷，恢复了角膜基质形态，并促进了上皮修复。ON 有效抑制了中性粒细胞浸润，并降低了 TLR-4、LOX-1、IL-1β 和 TNF-α 的表达。我们的研究表明，ON 滴眼液实现了 FK 的多效治疗，包括抑制真菌生长、促进角膜修复、提高药物生物利用度和控制炎症反应。
