Institute of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou 325027, PR China.
Institute of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou 325027, PR China.
Acta Biomater. 2018 Jun;73:275-284. doi: 10.1016/j.actbio.2018.04.019. Epub 2018 Apr 13.
Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but it displays a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity). We report here an intravitreally injectable thermosensitive glycosylated TA (TA-SA-Glu) hydrogel, formed by covalently conjugating glucosamine (Glu) with succinate TA (TA-SA), for treating uveitis. The TA-SA-Glu hydrogelator forms a supramolecular hydrogel spontaneously in aqueous solution with a minimal gelation concentration of 0.25 wt%. Structural analysis revealed that hydrogen bonds assisted by hydrophobic interaction resulted in self-assembled nanofibers. Rheology analysis demonstrated that this TA-SA-Glu hydrogel exhibited a typical thixotropic property. Sustained release of both TA-SA-Glu and TA from the hydrogel occurred throughout the 3-day in vitro release study. The obtained TA-SA-Glu hardly caused cytotoxicity against ARPE-19 and RAW264.7 cells after 24 h of incubation at drug concentration up to 600 μM. In particular, TA-SA-Glu exhibited a comparable anti-inflammatory efficacy to TA in terms of inhibiting the production of nitric oxide, tumor necrosis factor-α, and interleukin-6 in activated RAW264.7 macrophages. Following a single intravitreal injection, 69 nmol TA-SA-Glu hydrogel caused minimal apparent retinal toxicity, whereas the TA suspension displayed significant effects in terms of localized retinal toxicity. A single intravitreal injection of TA-SA-Glu hydrogel was more effective in controlling inflammatory response than that of the TA suspension treatment, particularly in down-regulating the pro-inflammatory Th1 and Th17 effector responses for treating experimental autoimmune uveitis. This study strongly indicates that supramolecular TA-SA-Glu hydrogels may represent a new option for posterior uveitis management.
Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but suffers a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity). We generated an injectable glycosylated triamcinolone acetonide hydrogelator (TA-SA-Glu) hydrogel for treating uveitis. Following a single intravitreal injection, the proposed TA-SA-Glu hydrogel hardly caused apparent retinal toxicity at a dosage of 69 nmol per eye. Furthermore, TA-SA-Glu hydrogel was more effective in controlling non-infectious uveitis over than a TA suspension, particularly in terms of down-regulating the pro-inflammatory Th1 and Th17 effector responses for treating experimental autoimmune uveitis (EAU). This study strongly indicates that TA-SA-Glu supramolecular hydrogels may represent a new option for the management of various intraocular inflammations.
玻璃体内/眼周注射曲安奈德（TA）混悬液是一种常见的葡萄膜炎治疗方法，但存在严重副作用的高风险（例如，眼内压升高、视网膜毒性）。我们在此报告一种可玻璃体内注射的温敏糖基化 TA（TA-SA-Glu）水凝胶，它通过将葡糖胺（Glu）与琥珀酸 TA（TA-SA）缩合而形成，用于治疗葡萄膜炎。TA-SA-Glu 水凝胶形成剂在水溶液中自发形成超分子水凝胶，最小凝胶浓度为 0.25wt%。结构分析表明，氢键辅助疏水相互作用导致自组装纳米纤维。流变学分析表明，这种 TA-SA-Glu 水凝胶表现出典型的触变特性。在体外释放研究的 3 天内，水凝胶中 TA-SA-Glu 和 TA 均持续释放。在药物浓度高达 600µM 的情况下，获得的 TA-SA-Glu 在孵育 24 小时后对 ARPE-19 和 RAW264.7 细胞几乎没有细胞毒性。特别是，TA-SA-Glu 在抑制活化的 RAW264.7 巨噬细胞中一氧化氮、肿瘤坏死因子-α和白细胞介素-6 的产生方面，表现出与 TA 相当的抗炎功效。单次玻璃体内注射 69nmol TA-SA-Glu 水凝胶引起的明显视网膜毒性最小，而 TA 混悬液则显示出明显的局部视网膜毒性。单次玻璃体内注射 TA-SA-Glu 水凝胶在控制炎症反应方面比 TA 混悬液治疗更有效，特别是在下调促炎 Th1 和 Th17 效应器反应方面，用于治疗实验性自身免疫性葡萄膜炎。这项研究强烈表明，超分子 TA-SA-Glu 水凝胶可能为后部葡萄膜炎的治疗提供一种新的选择。
