基于没食子有效部位设计组装抗溃疡性结肠炎的诊疗一体化药物载体

Ulcerative colitis (UC) has the characteristics of long duration, easy recurrence and extensive lesions, which has been listed as one of the intractable diseases by the World Health Organization. Due to the difficulty in delivering the common UC drugs and their significant side effects, it is crucial to design and assemble diagnosis and treatment integrated pharmaceutical carrier for the treatment of UC. Kui Jie’an is a traditional proved prescription widely used in Xinjiang Uygur Autonomous Region. Our previous study found that gallotannin is the effective fraction in Kui Jie’an to treat UC. Besides, gallotannin could be selectively adsorbed in UC lesion site and easily form layer-by-layer self-assembly. Our application is to design and assemble gallotannin into pharmaceutical carrier of diagnosis and treatment integration in UC therapy. This application intends to carry out work in the following three aspects: 1. Explore the mechanism of selective adsorption of gallotannin in UC lesion site from drug accumulation, electric attraction, receptor up-regulation, etc. 2. Screen activity by directionally capturing targeted composition (group) to search for the active ingredients for anti-UC. 3. Establish gallotannin-based pharmaceutical carrier with targeting ability, magnetic performance, visibility and effectivity by employing ferriferous oxide and masalazine as templates via one-step complexation and self-assembly membraning strategy. The implementation of our application will expand the utilization of effective fraction of natural medicine from the aspect of harmaceutics and help reinvigorate traditional Uygur medicine.

溃疡性结肠炎（UC）的病程长，易反复，病变范围广，药物难以递送且副作用明显，被世界卫生组织列为现代难治病之一。如何设计组装诊疗一体化药物载体是UC治疗的关键环节。溃结安系新疆维吾尔医医院广泛使用抗UC的传统验方，前期研究发现，没食子鞣质系溃结安抗UC的有效部位，此外，没食子鞣质具有选择性吸附在UC病灶和易于层层自组装的性质。本申请拟将没食子鞣质设计组装成UC诊疗一体化药物载体。为实现以上想法，本申请拟开展以下三方面工作：1.从药物物理富集、电荷吸引和受体上调等方面探讨没食子鞣质产生UC病灶选择性吸附的由来。2.通过定向捕获目标成分（群）进行活性筛选，寻找抗UC的物质基础。3.将四氧化三铁和美沙拉嗪制成模板，通过一步络合自组装成膜的方法，将没食子鞣质构建成具有靶向性、有效性、磁性和可视性的药物载体。本申请的实施将从药剂学的角度拓展天然药物有效部位的用途，帮助经典维药焕发新的光彩。

没食子已经有1100余年的使用历史，前期本小组发现没食子提取物有良好的制剂成型潜力。本工作揭示了没食子和五倍子治疗溃疡性结肠炎的物质基础和作用机理，确定了先导化合物。本着通过简单的方法制备高端多功能制剂的理念，开展了以下三方面的研究，一是没食子治疗溃疡性结肠炎的机理探讨；二是没食子提取物治疗溃疡性结肠炎的诊疗一体化制剂制备与活性检测；三是没食子提取物治疗胃溃疡的诊疗一体化制剂制备与活性检测。本工作内容是通过体内外实验筛选出没食子抗炎活性成分的基础上，从肠黏膜完整性、氧化应激和炎症角度探讨其治疗溃疡性结肠炎的机理。采用简单的方法提取没食子提取物，并通过自组装技术制备没食子提取物-铁离子络合微胶囊。用液相色谱法对微胶囊进行了质谱、扫描电子显微镜等表征。本小组成功制备了没食子提取物-铁离子络合微胶囊。有趣的是，通过体外和体内粘附实验，微囊更有可能积聚在炎症表面，并有效缓解溃疡性结肠炎的症状。此外本工作以造影剂铋离子为原料，通过牺牲模板法技术层层自组装形成聚合物中空微囊的机理及性能研究。建立多药合一的聚合物自组装平台，分析微囊在胃溃疡疾病中的诊断与治疗作用。本工作得到了LC-MS 纯化制备获得的五倍子中11种成分，药理学验证发现没食子酸乙酯一方面可以抑制细胞质中IKKβ的磷酸化，IKKβ的磷酸化水平的降低导致NF-κB的亚基p65从细胞质进入细胞核及其磷酸化的水平下降。得到了粒径均匀(3±0.5µm)的没食子提取物和金属螯合空心微球。体外释药研究发现，空心微球在生理环境下分解缓慢。在pH 1.5时，约93.5%的BiG@MCs在4-8小时降解完全。本工作扩大了传统上用于治疗痢疾的没食子提取物的临床应用，通过制备没食子提取物-铁离子络合微胶囊并显示没食子提取物对UC的保护作用，为从富含单宁的天然产物中开发微胶囊提供了有益参考。