壳聚糖-雷公藤多苷接枝共聚微球包衣减轻 DSS 诱导的实验性结肠炎通过抑制 TLR4/NF-κB 信号通路。
Eudragit-coated chitosan-tripterygium glycoside conjugate microspheres alleviate DSS-induced experimental colitis by inhibiting the TLR4/NF-κB signaling pathway.
机构信息
Department of Clinical Laboratory, Jiujiang No. 1 People's Hospital, Jiujiang, Jiangxi Province 332000, China.
Department of Gastroenterology, digestive disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China; Gastroenterology Institute of Jiangxi Province, Nanchang, Jiangxi Province 330006, China; Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, Jiangxi Province 330006, China; JiangXi Clinical Research Center for Gastroenterology, Nanchang, Jiangxi Province 330006, China.
出版信息
Biomed Pharmacother. 2023 Feb;158:114194. doi: 10.1016/j.biopha.2022.114194. Epub 2023 Jan 3.
OBJECTIVE
Tripterygium glycoside (TG) is a fat-soluble extract of Tripterygium wilfordii, with anti-inflammatory properties associated with TLR signaling pathways. This study constructed a targeted delivery system for experimental colitis, namely, eudragit (EuL)-coated chitosan (Ch)-TG conjugate microspheres (Ch-TG-MS/EuL), and evaluated its therapeutic efficacy and underlying mechanisms.
METHODS
Ch-TG-MS was fabricated using emulsification cross-linking technique and then coated with EuL to create Ch-TG-MS/EuL. Drug release properties were assessed using a dialysis model. Additionally, the therapeutic benefits of Ch-TG-MS/EuL on colonic inflammation and its specific effect on TLR4/NF-κB signaling in intestinal mucosa were evaluated in vivo using a DSS-induced murine colitis model.
RESULTS
The Ch-TG-MS/EuL microspheres appeared as yellow powders with a slightly enlarged shape, rough surface, and adhesions. The Ch-TG-MS/EuL formulations also exhibited high entrapment efficiency and drug loading rate. High-performance liquid chromatography revealed that Ch-TG-MS/EuL exhibited a less intense peak than free TG, confirming that the drug is contained within the formulation. Free TG displayed explosive release within the first 5 h of administration, while Ch-TG-MS/EuL prevented the pre-mature release of TG and exhibited controllable release up to 24 h. In vivo, noticeable amelioration of intestinal mucosal tissue destruction was achieved with Ch-TG-MS/EuL compared to free TG. Additionally, immunohistochemical and western blotting results revealed that Ch-TG-MS/EuL markedly down-regulated the expression of intestinal mucosal TLR4, MyD88, and NF-κB p65. Hence, Ch-TG-MS/EuL may ameliorate the colon inflammatory response by inhibiting the hyperactivation of TLR4/NF-κB signaling.
CONCLUSION
Novel Ch-TG-MS/EuL preparation may represent a colonic delivery system for UC therapeutics by inhibiting TLR4/NF-κB hyperactivation.
DATA AVAILABILITY
All experimental data supporting the conclusions of this study are available from the corresponding author on reasonable request.
目的
雷公藤苷（TG）是从雷公藤中提取的一种脂溶性提取物，具有与 TLR 信号通路相关的抗炎特性。本研究构建了一种实验性结肠炎的靶向递药系统，即载有雷公藤苷的壳聚糖（Ch）-雷公藤苷微球（Ch-TG-MS）/Eudragit（EuL），并评价了其治疗效果及潜在机制。
方法
采用乳化交联技术制备 Ch-TG-MS，然后用 EuL 包被形成 Ch-TG-MS/EuL。采用透析法评估药物释放性能。此外，在 DSS 诱导的小鼠结肠炎模型中，评估了 Ch-TG-MS/EuL 对结肠炎症的治疗作用及其对肠道黏膜 TLR4/NF-κB 信号通路的特异性作用。
结果
Ch-TG-MS/EuL 微球呈黄色粉末状，形状略有增大，表面粗糙，有粘连。Ch-TG-MS/EuL 制剂也表现出较高的包封效率和载药量。高效液相色谱法表明，Ch-TG-MS/EuL 的峰强度低于游离 TG，证实药物存在于制剂中。游离 TG 在给药后前 5 h 内呈现爆发式释放，而 Ch-TG-MS/EuL 则阻止了 TG 的过早释放，并能持续 24 h 进行控制释放。体内研究表明，与游离 TG 相比，Ch-TG-MS/EuL 能显著改善肠道黏膜组织破坏。此外，免疫组化和 Western blot 结果表明，Ch-TG-MS/EuL 明显下调了肠道黏膜 TLR4、MyD88 和 NF-κB p65 的表达。因此，Ch-TG-MS/EuL 可能通过抑制 TLR4/NF-κB 信号的过度激活来改善结肠炎症反应。
结论
新型 Ch-TG-MS/EuL 制剂可能通过抑制 TLR4/NF-κB 的过度激活，成为治疗 UC 的结肠递药系统。
数据可用性
所有支持本研究结论的实验数据均可根据合理要求向通讯作者索取。
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