高亲和选择素的新型分子探针的构建及其诊疗类风湿关节炎的实验研究

Rheumatoid arthritis (RA) is a long lasting autoimmune disorder and disabling disease with the main character of chronic inflammatory lesions that primarily affects joints. While the cause of rheumatoid arthritis is not clear, it is believed to involve a combination of genetic and environmental factors. Treatment of RA is a challenge in the clinic. How to detect and diagnosis of RA as well as the followed therapy in its early stage are the key for the combat against this disease. It’s urgent needed to develop an ideal tool for the detection and monitoring such progress specially for the lack of efficient real time method for RA. In this project, we for the first time design a novel multimodal probe for simultaneous optical imaging and MR imaging and treatment of RA. The biomarker is seletin, which is highly expressed in the inflammation sites. Based on the established dendritic polyglycerorls (dPGS), which is highly biocompatible and presents the function for multivalent selectin binding and the inhibition of complement activation, we construct the novel optical/MR probe as the imaging and therapeutical agent. With an ingenious design of connection, celecoxib is conjugated to form the theranostic probe, which can be delivered and released in the inflammation site. We examine the probe with various RA cell and animal in vitro. The biological activities are evaluated for their specificities and sensitivenesss for the detection and imaging for RA. Further mechanism experiments are explored to understand why the novel probe can be applied for the detection and therapy of RA. These results of this project will provide a novel tool for real time imaging and therapeutically evaluation of RA, and open an avenue for the development of novel antiflammation drug and theranostic drug.

类风湿关节炎（RA）是一种以关节组织慢性炎症病变为主要特征的致残性疾病，其病因复杂，临床尚无法彻底根治，如何早期发现和诊断RA，并在病变的早期阶段进行药物干预和治疗，是防控RA的关键。本课题针对RA早期发现和诊疗难的迫切需求，基于介导炎性反应的细胞黏附分子选择素的高表达，在高亲和结合选择素的树枝状甘油硫酸酯dPGS上构建具有光磁复合性能的新型分子探针，通过活体动物模型和光磁成像，考察RA炎症发生、发展过程中的特性；通过巧妙设计连接塞来昔布，实现对抗炎药物的靶向递送，并通过不同炎性细胞、动物模型和光磁成像研究，明确新型分子探针诊疗RA的特异性和敏感性。本项目是在我们良好的前期工作基础上，利用多模态成像技术的优势互补，验证新型分子探针在不同RA模型中的有效性，有望同时实现对RA的早期发现和诊断，实时成像和预后评价，为研究和开发新型的靶向抗炎药物和诊疗一体化药物提供理论基础和科学依据。

类风湿关节炎RA是一种慢性炎症疾病，其病因复杂，临床缺乏有效诊疗手段和干预策略。本项目针对RA早期发现和诊疗难的迫切需求，选择了多个炎性分子标志物，并基于介导炎性反应的细胞黏附分子选择素、Cox2的高表达，在高亲和结合选择素的dPGS上构建新型诊疗分子探针。在前期良好工作基础之上，通过巧妙科学设计，利用生物正交反应，在靶向亲和组件上共价连接具有独特光学性质和信号放大作用的AIE分子和/或ESIPT荧光团以及光磁复合分子，构筑了多个新颖结构的分子影像探针，采用光学、核磁共振、质谱等手段进行了结构表征和确证；搭建了多种细胞学模型；开展了分子探针的生物活性评价、细胞成像、在体成像等研究；发现了具有自主知识产权的多个新型多功能分子影像探针，实现了分子探针信号的有效放大和生物学应用；通过活体动物模型，考察了细胞和活体的选择素以及炎性因子水平，用以明确了RA发生、发展过程中的时空运动特性；共价连接抗RA一线药物吲哚美辛、塞来昔布，制备了新型的多功能、多模态分子探针和影像诊疗药物，并深入研究了其在体内外的生物活性，探究了新型分子诊疗药物靶向炎症的分子机制。本项目的顺利实施，发现了多个具有自主知识产权的新型分子探针，完成了其设计、制备、路线优化、生物学评价等研究；本课题紧跟分子影像学热点领域，探索了如何构筑靶向分子探针的应用基础问题。项目执行来，我们按照研究计划进行的相关研究内容探索，实现了预期研究目标。迄今为止，我们牵头获得省部级奖励2项，申报发明专利5项，其中授权3项，在国际学术期刊上发表了署名本项NSFC资助的SCI论文28篇，为新型分子探针的构筑、炎症的早期发现和诊断、实时成像和评价、开发新型的靶向抗炎药物和诊疗一体化药物提供了良好理论基础和科学依据。

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