PET/CT/MRI多模态多靶点显像用于动脉粥样硬化药物疗效监测的应用基础研究

Atherosclerosis (AS) is a common cardiovascular disease which is seriously harmful to human health. Inflammation and apoptosis plays an important role in the process of the initiation and development of AS. Recently, it takes more attention to the studies with inflammation and apoptosis as the target in diagnosis and treatment of AS. The statins are the most widely used anti-AS drugs for its anti-inflammatory and affecting apoptosis,in this connection, it would be great interest to find an effective method to evaluate this therapy efficiency. Macrophages play an important role in the inflammatory process and active macrophages require more sugar. Therefore, 18F-FDG PET imaging becomes a non-invasive and effective method in detection of inflammation. Additionally, 18F labeled Annexin-5 as an specific apoptosis imaging agent can be sensitive to the detection of apoptosis by PET imaging. This study utilized statins to treat rabbit AS models, the inflammation and apoptosis process will be monitored by PET/CT imaging before and after the intervention, thereafter, impact of statins on atherosclerotic plaque will be evaluated. MRI is a multi-parameters and high resolution imaging equipment, which can be used to measure AS plaque volume and intraluminal stenosis rate. In view of this, MRI imaging of inflammation and apoptosis will be carried out for same animals as well. The aim of this study is to explore the feasibility of monitoring AS plaque activity by virtue of multi-modality and multi-function imaging, eventually providing an effective method in monitoring and evaluation AS drug efficacy.

动脉粥样硬化（AS）是严重危害人类健康的常见心血管疾病，炎症和凋亡在AS发生发展过程中起着重要作用。以炎症及凋亡为靶点进行动脉粥样硬化诊断和治疗的研究近期得到重视。他汀类药物是应用最为广泛的抗AS药物，具有抗炎和影响细胞凋亡作用。巨噬细胞在炎症过程中起着重要作用，活跃的巨噬细胞糖代谢旺盛，因此，18F-FDG作为一种外源性的葡萄糖类似物可用于 PET显像进行炎症的检测。18F标记的Annexin-5是一种特异性的凋亡显像剂，通过PET显像可灵敏地进行细胞凋亡的检测。本研究通过兔AS模型他汀类药物治疗前、后的炎症及凋亡PET/CT和MRI显像，观察他汀类药物对粥样斑块的影响。MRI为多参数、高分辨率成像，可测量AS斑块体积和管腔狭窄率，通过PET/CT与MRI显像在炎症及凋亡监测效果的比较，探讨PET/CT监测AS斑块活性的可行性，通过多模态、多功能显像为AS药物疗效监测和评价提供有效方法。

动脉粥样硬化（AS）是严重危害人类健康的常见心血管疾病，炎症和凋亡在AS 发生发展过程中起着重要作用。以炎症及凋亡为靶点进行动脉粥样硬化诊断和治疗的研究近期得到重视。巨噬细胞在炎症过程中起着重要作用，Annexin-V能高效地识别凋亡巨噬细胞膜上位于胞浆表面的磷脂酰丝氨酸，而AS易损斑块的显像信号就与凋亡巨噬细胞的水平明显相关，因此，Annexin-V是一种特异性的检测AS易损斑块的试剂。本研究通过Annexin-V这种特异性靶向凋亡的蛋白，偶联超小超顺磁性铁纳米颗粒（USPIO）或金纳米颗粒（GNPs）在不改变其对凋亡细胞靶向性的前提下，优化其药代动力学特性，并实现SPECT、CT以及MRI的高灵敏且高分辨率的多模态显像，从而有利于AS易损斑块的精确定位及定量分析。通过小动物SPECT/CT/MRI显像及定量分析，我们发现ApoE-/-基因敲除AS小鼠模型的易损斑块对Tc-99m-DTPA-USPIO-Annexin V和Tc-99m-GNPs-Annexin V在SPECT上的摄取在5小时达到最佳显示时间。与C57小鼠对照，AS易损斑块的大量凋亡巨噬细胞可清晰且特异性的显示。这些凋亡细胞在与Tc-99m-DTPA-USPIO-Annexin V分子探针特异性结合后，在MRI的 T2WI上可见呈较注射前明显减低“完全变暗”的表现，使病变与正常血管明显区分开来而得以清晰显示。而这些凋亡细胞在与Tc-99m-GNPs-Annexin V分子探针特异性结合后，在CT上又相应呈明显强化。这种多模态多功能显像更有助于AS易损斑块的定位、手动勾画、体积测量和诊断。基于类似的分子探针制备方法，我们制备一种新的99mTc-MAG3-bevacizumab分子探针，对ApoE-/-基因敲除AS小鼠模型在阿托伐他汀治疗后进行在体SPECT/CT成像。此外，通过HE染色、免疫组化染色、油红O染色以及体外BSGI成像再次证实了本课题的分子探针通过多模态、多功能显像检测及诊断AS易损斑块的特异性和对AS药物疗效监测和评价的可行性。在本课题的基础上，还延伸了CD11b抗体在AS易损斑块炎症相关性方面的应用，而USPIO偶联其他抗体和蛋白在肝癌等肿瘤方面的应用也有一定突破。