基于纳米技术PET/MRI分子成像对易损斑块MMPs活体监测的研究

Cardiovascular and cerebrovascular diseases become the leading cause of mobidity and mortality worldwide with the changes of human life styles. Prevailing researches showed that thrombosis formation and vascular occlusion induced by rupture of vulnerable plaque frequently leads to major adverse cardiovascular event. Although experts already reach to an agreement in prevention and therapy of atherosclerosis, the cardiovascular and cerebrovascular diseases are still in a high level due to onset and sudden rupture of vulnerable plaque. Therefore, how to achieve the goal of early diagnosis and effective intervention for vulnerable plaque is still an essential clinical issue. Matrix metalloproteinases (MMPs) are closely associated with the formation and stability of vulnerable plaques. Different from current medical imaging, molecular imaging aims to unravel biological and physiological information of diseases from molecular and cellular levels in living subjects, which can be applied to observe vulnerable plaque characteristics real-timely and dynamically as well as evaluate efficacy of preventive and therapeutic approaches. It is imperative to construct suitable molecular imaging probe, which can improve specificity and sensitivity of imaging. To select potential specific molecular target for the vulnerable plaque is the first key step. Magnetic resonance imaging (MRI) is technically advantageous in discriminating among tissues with high resolution, which can be used to characterize the morphology and composition of atherosclerotic plaques. Screening and assessing vulnerable plaques with MRI technique has become a focus of clinical research lately. In the present study, we aim to utilize MMP-2 and MMP-9 as molecular targets. To render ultrasmall superparamagnetic iron oxide (USPIO) particles specific for the extracellular MMPs, the magnetic nanoparticle base material has been derivatized with NOTA for the nuclear tracer 64Cu and the MMPs-cleavable peptide modified with polyethylene glycol, yielding a multi- modality reporter (64Cu-MMPsCNPs) for PET/MR imaging, which can be used for assessing vulnerable plaque characteristics and therapeutic efficacy. In addition, we use the miR-29a to directly repress MMPs in vulnerable plaque and evaluate therapeutic effect of miR-29a by our novel probe.

动脉粥样硬化(AS)是心脑血管疾病最主要病因，其中易损斑块突然破裂所诱发的血小板聚集和血栓形成是引起脑卒中和急性心肌梗死的重要发病机制。如何更有效地早期诊断AS易损斑块是目前研究热点之一。MMPs与易损斑块的形成及稳定性密切相关。本项目拟MMP2和MMP-9为分子成像靶点，将聚乙二醇修饰的USPIO和PEG链接的MMPs可剪切肽段(MMPsC-PEG)桥连成MMPs可控的纳米颗粒，并通过NOTA藕联放射性同位素64Cu，构建新型多功能PET/MR成像智能纳米探针64Cu-NOTA-Fe3O4-MMPsC-PEG。本项目组将联合PET/MRI双模态成像与病理分析，评价此新型纳米探针在小鼠AS易损斑块早期检测中的应用价值。此外，我们将miR-29a作为一种新型AS基因疗法，融入我们拟制备的新型多模态纳米智能探针中，开发一种新型的靶向MMPs的AS易损斑块诊治一体化评价体系，从而实现个体化医疗。

动脉粥样硬化(AS)是心脑血管疾病最主要病因，其中易损斑块突然破裂所诱发的血小板聚集和血栓形成是引起脑卒中和急性心肌梗死的重要发病机制。如何更有效地早期诊断AS易损斑块是目前研究热点之一。MMPs与易损斑块的形成及稳定性密切相关。本项目拟MMP2和MMP-9为分子成像靶点，将聚乙二醇修饰的USPIO和PEG链接的MMPs可剪切肽段(MMPsC-PEG)桥连成MMPs可控的纳米颗粒，并通过NOTA藕联放射性同位素64Cu，构建新型多功能PET/MR成像智能纳米探针64Cu-NOTA-Fe3O4-MMPsC-PEG。本项目组将联合PET/MRI双模态成像与病理分析，评价此新型纳米探针在小鼠AS易损斑块早期检测中的应用价值。此外，我们将miR-29a作为一种新型AS基因疗法，融入我们拟制备的新型多模态纳米智能探针中，开发一种新型的靶向MMPs的AS易损斑块诊治一体化评价体系，从而实现个体化医疗。