巨噬细胞趋向诊疗一体化探针干扰TNF-α治疗炎症性肠病研究

Inflammatory bowel disease (IBD) is a nonspecific and chronic inflammatory bowel disease. Poor therapeutic effect and its nature of relapse limited disease prognosis.It is still challenge to evaluate disease activity clinically. Recent studies showed that innate immunity played a key role in IBD pathogenesis. Macrophages were one of the most important immune cells in IBD. Macrophages and its cytokine TNF-α have been recognized as both diagnostic and therapeutic targets as well. Our previous studies have shown a MRI-based approach for tacking intestinal macrophages in IBD model. Based on those results, we will establish a kind of biomimetic nanoprobe targeting IBD with immune trend to macrophages. The nanoprobe was cored on a PEI/Si-RNA complex, modified with dual imaging groups and coated with biomimetic leukocyte membrane. Using both MRI and near infrared imaging we can track the macrophages with migration of the nanoprobe. With endocytosis by macrophages, the PEI carrier achieved lysosomal escape and release siRNA in cytoplasm, resulted in inhibition of TNF-α. This project will focus on activated macrophages, the key immune cell in IBD, using multi-modality imaging approach to non-invasively evaluate disease activity in IBD, to monitor drug delivery efficiency and therapeautic effect. Hopefully, it will provide new strategies for IBD theranostic management.

炎症性肠病(IBD)是一类慢性非特异性肠道炎症，具有疗效不佳、易复发等临床特点，临床疾病活动度判定困难。研究表明天然免疫在IBD发病机制中起关键性作用。巨噬细胞是天然免疫中的关键作用细胞。巨噬细胞及其特异性分泌的TNF-α细胞因子是IBD诊疗的重要靶点。本项目拟在前期已建立活体巨噬细胞示踪影像技术基础上，构建IBD炎性巨噬细胞免疫趋向的诊疗一体化探针。该探针以标记有多类型影像基团的PEI/siRNA复合物为核心，表层包覆有仿生白细胞膜。磁共振及近红外荧光影像可无创示踪巨噬细胞向IBD相关炎性巨噬细胞的趋向迁移。探针被巨噬细胞内吞后，PEI载体通过质子海绵效应实现溶酶体逃逸，在细胞质释放siRNA并抑制TNF-α炎性因子的生成。本项目聚焦于IBD炎症过程中起关键作用的活化巨噬细胞，通过多模态影像技术无创评价IBD活动度，监测递药效率及基因干扰治疗疗效，为IBD临床诊治一体化提供新的思路。

炎症性肠病（Inflammatory bowel disease, IBD）是一种病因不明确的慢性非特异性肠道炎症性疾病，主要包括克罗恩病（CD），溃疡性结肠炎（UC）。IBD病因及发病机制尚不明确，目前认为IBD由遗传、免疫等因素共同由于导致的病变。IBD临床无法治愈，往往处于急性期缓解期之间周而往复的过程中，给临床治疗带来了极大的困扰。近年的研究及我们以往的研究显示，炎症性肠病（IBD）的炎症微环境是炎症反应得以持续进行的重要场所。炎症微环境中的免疫及非免疫细胞及其分泌的炎症介质等互相作用，充当了炎症联级反应“控制器”的角色。因此通过干预巨噬细胞促炎表型改善炎症微环境是IBD治疗的新手段。本项目通过合成纳米颗粒CENP-PEG，首先发现体内外可以显著降低巨噬细胞的ROS水平，且抑制巨噬细胞促炎表型并降低炎症因子的生成和释放。进一步的活体结果显示CENP-PEG治疗改善了IBD 肠道炎症微环境，包括肠上皮的粘膜屏障恢复、炎症细胞浸润减少，血清及肠道组织的炎症因子水平下降，TH1/TH17比例下降，即CENP-PEG治疗IBD通过抑制巨噬细胞促炎表型使IBD的炎症微环境得以再平衡。同时，本项目获得了一种活体示踪促炎巨噬细胞的PET示踪剂18F-DPA-714。利用PET/CT高分辨率的特点，标记活化的巨噬细胞表面受体TSPO得到该示踪剂。通过PET/CT的无创动态活体成像，在IBD模型小鼠中验证其能够无创、定量评价肠道炎症部位促炎巨噬细胞的浸润，从而评价IBD肠道炎症的活动度，为IBD分子成像的一次有益探索。本项目的开展为IBD临床诊治一体化及免疫介导的疾病治疗模式提供新的思路和理论依据。