近红外二区荧光分子探针用于胰管恶性病变的动态可视化研究

Early diagnosis of pancreatic cancer (PC) is an important health demand in China. Recent studies have shown that macrophage polarization in PC microenvironment predicts the occurrence and poor prognosis of PC. Therefore, dynamic tracing of the process of macrophage polarization is of great importance for early diagnosis of PC. On the basis of the previous works on the indocyanine green (ICG) probe for cancer diagnosis and therapy, and its near-infrared-II (NIR-II) imaging ability (PNAS, 2018, 115, 4465.), in this project, we will develop a small molecule ICG derivative with active targeting mannose receptors on the surface of macrophages, for highly sensitive, high-resolution and deep penetration imaging of the polarization process of macrophages in PA microenvironment. We tend to establishes the correlation between fluorescence signals, pathological features and molecular functions during the development of PC by artificial intelligence, and verifies the method of accurate prediction of early PC in a mouse model. This project focuses on the two key scientific problems: one is how to the design of the probe for effectively crossing the mesenchymal barrier of PC and specifically bind to microenvironment macrophages. Another is how to early diagnosis of PC by NIR-II fluorescence imaging. This project has important scientific significance and clinical value in promoting the development of fluorescent molecular imaging probe and its application in early diagnosis of PC.

胰腺癌早期诊断是我国重大健康需求。最新研究表明：胰腺癌微环境巨噬细胞极化预示着癌症的发生和不良预后。因此，动态示踪巨噬细胞极化过程对胰腺癌早期诊断具有重要意义。项目组在前期吲哚菁绿（ICG）探针研究的基础上，利用新发现的ICG近红外二区荧光成像功能（PNAS, 2018, 115, 4465.），拟发展一种靶向巨噬细胞表面甘露糖受体的ICG小分子荧光探针，通过高灵敏、高分辨、大深度近红外二区成像，动态示踪胰腺癌微环境巨噬细胞的极化过程，利用人工智能建立胰腺癌发生发展过程中巨噬细胞荧光信号-病理特征-分子功能间的相互关联，在小鼠模型上实现胰腺癌早期诊断的方法验证。本项目突出解决如何设计探针高效跨越胰腺癌间质屏障，靶向微环境巨噬细胞；以及如何通过近红外二区分子成像实现胰腺癌早期诊断两个关键科学问题，对推动荧光分子影像探针的发展及其在胰腺癌早期诊断的应用具有重要的科学意义和临床意义。

围绕胰腺癌原位瘤的诊疗一体化动态可视化研究关键科学问题，以葡聚糖和ICG衍生物为原料，通过化学交联和共沉淀技术成功制备了ICG纳米探针。在此基础上，实现了探针特异性靶向识别胰腺癌微环境巨噬细胞，通过低剂量放疗和化疗调控肿瘤组织巨噬细胞数量，ICG纳米探针能动态的示踪巨噬细胞的变化，为胰腺癌巨噬细胞体内示踪和治疗评估提供了成像新工具。本项目突出解决近红外二区成像探针的可控制备和肿瘤的诊疗一体化等关键科学问题，对推动影像引导肿瘤精准手术具有重要意义。目前已发表相关论文19篇，申请相关专利12项。