Chen Tzu-Yang, Tseng Ching-Li, Lin Chih-An, Lin Hua-Yang, Venkatesan Parthiban, Lai Ping-Shan
Department of Chemistry, National Chung Hsing University, Taichung 40227, Taiwan.
Graduate Institute of Biomedical Materials & Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan.
Pharmaceutics. 2021 Aug 30;13(9):1366. doi: 10.3390/pharmaceutics13091366.
Dry eye syndrome (DES) is a common ocular disease worldwide. Currently, anti-inflammatory agents and immunosuppressive drugs, such as cyclosporine A, have been widely used to treat this chronic condition. However, the multifactorial etiology of DES, poor tolerance, low bioavailability, and prolonged treatment to response time have limited their usage. In this study, nimesulide, a cyclooxygenase (COX)-2 selective inhibitor, was conjugated with hyaluronic acid (HA), and the HA-nimesulide conjugates were expected to increase the solubility and biocompatibility for alleviating the DES in the benzalkonium chloride (BAC)-induced goblet cell-loss dry eye model. The therapeutic efficacy of HA-nimesulide was assessed using fluorescein staining, goblet cell density by conjunctival impression cytology, and histology and immunohistochemistry of corneal tissues. Compared to commercial artificial tears and Restasis, the HA-nimesulide conjugates could promote goblet cell recovery and enhance the regeneration of the corneal epithelium. Importantly, immunofluorescent staining studies demonstrated that the HA-nimesulide conjugates could decrease the number of infiltrating CD11b-positive cells after two weeks of topical application. In the anti-inflammatory test, the HA-nimesulide conjugates could inhibit the production of pro-inflammatory cytokines and prostaglandin E (PGE2) in the lipopolysaccharide (LPS)-stimulated Raw 264.7 cell model. In conclusion, we demonstrated that HA-nimesulide conjugates had anti-inflammatory activity, and promoted goblet cell recovery and corneal epithelium regeneration when used as topical eye drops; accordingly, the HA-nimesulide conjugates could potentially be effective for the treatment of DES.
干眼综合征（DES）是一种全球常见的眼部疾病。目前，抗炎药和免疫抑制药物，如环孢素A，已被广泛用于治疗这种慢性病。然而，DES的多因素病因、耐受性差、生物利用度低以及治疗至反应时间长限制了它们的使用。在本研究中，将环氧化酶（COX）-2选择性抑制剂尼美舒利与透明质酸（HA）偶联，预期HA-尼美舒利偶联物可提高溶解度和生物相容性，以缓解苯扎氯铵（BAC）诱导的杯状细胞丢失型干眼模型中的DES。通过荧光素染色、结膜印迹细胞学检测杯状细胞密度以及角膜组织的组织学和免疫组织化学评估HA-尼美舒利的治疗效果。与市售人工泪液和Restasis相比，HA-尼美舒利偶联物可促进杯状细胞恢复并增强角膜上皮再生。重要的是，免疫荧光染色研究表明，局部应用两周后，HA-尼美舒利偶联物可减少浸润的CD11b阳性细胞数量。在抗炎试验中，HA-尼美舒利偶联物可抑制脂多糖（LPS）刺激的Raw 264.7细胞模型中促炎细胞因子和前列腺素E（PGE2）的产生。总之，我们证明HA-尼美舒利偶联物具有抗炎活性，用作局部滴眼液时可促进杯状细胞恢复和角膜上皮再生；因此，HA-尼美舒利偶联物可能对DES治疗有效。
