基于上转换纳米材料的动脉粥样硬化巨噬细胞CD36受体多模态分子成像

Macrophage CD36 receptor plays a significant role in atherosclerotic inflammation damage and can be regarded as an important molecule in the progression of atherosclerosis. It is an evident and challenging job of molecular imaging to assess the level of inflammation damage and the vulnerability of the plaque at molecular level in a noninvasive way. Based on the preliminary work, our project team intends to do MR(7T), CT(micro type) and conversion fluorescence imaging (UCL) tri-modal imaging and fusion quantitative analysis on ApoE - / - mice atherosclerosis model, by using the CD36 targeted molecular contrast agent (CD36mAb-PEG-NaYbF4@NaGdF4 compound) which is synthesized from the new up-conversion nanoparticles and has high sensitivity, high specificity and low biological toxicity. We plan to observe the CD36 targeted molecular imaging features of the inflammation damage and the vulnerability of plaque at different stages of atherosclerosis in vivo. Afterwards, the aortas will be carefully isolated by using microscopic dissection and fixed for pathological analysis of the macrophage content and the expression level of CD36. Quantitatively analyze the macrophage gathering stages and expression level of CD36 of atherosclerotic process, then make the comparison and correlation between the results and the plaque vulnerability. It is our aim to establish a multimodal molecular imaging and fusion quantitative analysis evaluation criteria of the atherosclerotic inflammation damage level and the vulnerability of the plaque at molecular level. The ability to sensitively, accurately and noninvasively evaluate atherosclerosis from a molecular, cellular, and compositional perspective may give clinicians powerful tools for unprecedented in vivo identification and assessment of atherosclerosis , vulnerable plaque and risk at earlier stages, thereby contributing to personalized approaches to disease management and to improve the prognosis of cardiovascular and cerebrovascular diseases effectively.

巨噬细胞CD36受体在动脉粥样硬化炎性损伤及斑块进展中发挥关键作用，如何在细胞分子水平无创定量评估斑块易损性是分子影像学的巨大挑战。本项目基于前期工作基础，拟以ApoE-/-小鼠动脉粥样硬化模型为研究对象，基于新型上转换纳米材料合成具有高灵敏度、高特异性及生物安全性好的CD36靶向对比剂（CD36mAb-PEG-NaYbF4 @NaGdF4复合物），采用7T MRI、microCT及荧光显像（UCL）定量分析，活体观察斑块不同阶段炎性损伤程度及CD36靶向分子成像特征，并与组织病理学巨噬细胞含量及CD36表达水平对比研究，定量分析巨噬细胞富集及CD36表达水平与斑块易损性的关系，在分子水平建立炎性损伤程度及斑块易损性的多模态分子影像学融合定量评价标准。本项目的完成将为病变早期检测、易损斑块早期识别及风险评估提供灵敏、准确、无创的量化影像学依据，对指导临床决策及改善预后具有重要意义。

炎性损伤是动脉粥样硬化易损性的重要原因，而巨噬细胞CD36受体在炎性损伤发挥关键作用，因此，如何在细胞分子水平无创定量评估斑块易损性是分子影像学的巨大挑战。本项目立足于斑块易损性，从基础实验和临床两方面进行研究。基础实验中，制备出具有循环时间长、生物毒性低的新型上转换纳米材料CD36 受体靶向对比剂（CD36mAb-PEG-NaYbF4@NaGdF4 复合物），在动脉粥样硬化模型大鼠中研究了多种功能序列在早期检测及卒中后微结构改变，并在病理水平验证了斑块炎性组织与影像学的对应关系。临床研究上将多模态血管成像（高分辨MRA、4D-FLOW、HRMRI等）技术应用于临床动脉粥样硬化斑块病人，筛选鉴定临床上易损斑块评价的敏感影像学标志物，并建立临床动脉粥样硬化斑块易损性评价的多模态影像学评估标准，为易损斑块早期识别、风险评估及早期预警提供影像学依据。