新型靶向OPN多功能纳米微泡对动脉粥样硬化斑块诊治的分子影像学研究

Early precise diagnosis and prompt intervention for vulnerable atherosclerotic plaque are crucial to the prevention of severe cardiovascular events including sudden death. However, early detection is of considerate difficulty using conventional clinical imaging technologies. High-resolution functional molecular imaging may realize precise evaluation of plaque vulnerability by noninvasive in vivo monitoring for the composition and character changes of atherosclerotic plaques. This project is designed to aim at the characteristic pathological proteins in atherosclerotic plaque (OPN), construct multimodel nanoprobe targeting microcalcification and realize noninvasive real-time imaging and quantitative analysis for atherosclerotic plaques basing on high-resolution optical/ultrasound multimodal imaging equipment in atherosclerotic ApoE-/- mice model. An organizational structure constrained large-scale differential homeomorphism registration algorithm is proposed to fuse and three-dimensionally quantify multimodal plaque images. This project may provide a novel strategy to realize early detection of vulnerable plaque and for intervention in the future.

动脉粥样硬化易损斑块是导致严重心血管事件的主要元凶，平滑肌矿化进而形成微钙化灶是易损斑块的重要病理特征之一，但是目前临床常规影像学技术难以对微钙化的形成实现早期预警。高分辨率的功能分子影像能够在体无创监测斑块组织性质变化，有望实现对斑块易损性的精准评估。本研究项目拟针对易损斑块内特征性微钙化的靶点(OPN)，构建以超声微泡为载体、靶向OPN的多模态纳米探针，基于高分辨的光学/超声多模态分子影像平台，对ApoE-/-小鼠颈动脉易损斑块模型中斑块的性质和成份进行在体无创成像和定量分析。以组织学结果为金标准，采用组织结构特异约束的大尺度微分同胚配准算法对斑块的多模态图像配准、融合，实现对动脉粥样硬化斑块易损性的早期预警，为降低心脑血管事件提供新策略。

动脉粥样硬化易损斑块是导致严重心血管事件的主要因素，因此亟需一种能够早期诊断易损斑块的方法。平滑肌细胞的表型转化是易损斑块进展的重要因素，而骨桥蛋白（Osteopontin, OPN）是其特异性的生物标志物。由于精氨酸-甘氨酸-天冬氨酸序列（RGD）及与CD44的相互作用使OPN在泡沫细胞中表达显著增高，同时使巨噬细胞募集能力增强。基于此我们构建了一种OPN靶向的双模态纳米探针(Cy5.5-anti-OPN-PEG-PLA-PFOB, COP-NPs)，即通过超声和光学成像识别易损斑块的分子特征。体外实验结果表明所构建的探针毒性低、生物相容性和靶向性好。此外通过高脂喂养ApoE−/−小鼠20-24周构建动脉粥样硬化模型，尾静脉注射探针，在体实验超声和光学成像结果显示COP-NPs能够靶向聚集在易损斑块内。因此，本课题所构建的COP-NPs探针能够较好的靶向易损斑块内的泡沫细胞，是早期诊断易损斑块较好的工具。