CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms

项目摘要 腹主动脉瘤(AAA)是一种危及生命的退行性血管疾病。AAAS通常 在破裂前保持无症状，导致高死亡率。AAA在年龄超过50岁的男性中更为普遍 65岁；然而，AAA破裂更多发生在女性。腹主动脉瘤的临床影像主要集中在 AAA直径的测量，这是一个不好的破裂预测标志。有一个未满足的临床 需要一种分子成像策略来对AAA患者进行风险分层。单核细胞趋化 蛋白-1/趋化因子(C-C基序)受体2(MCP-1/CCR2)轴在卵巢癌的发病机制中起重要作用 AAAS通过介导炎性单核细胞的募集和巨噬细胞的浸润，导致 主动脉壁弹性蛋白和胶原的降解。我们已经开发了一种CCR2靶向放射性示踪剂64Cu-DOTA- ECL1i，用于CCR2+促炎单核/巨噬细胞的正电子发射断层扫描(PET)成像 并展示了CCR2+细胞在心血管疾病患者中的特异性检测。在小鼠体内 AAA模型，64Cu-DOTA-ECL1i PET显示AAA壁内有特异性的放射性示踪剂摄取 与CCR2+细胞群体变异的敏感检测相关。放射性示踪剂显著升高 易破裂的AAA的摄取证明了这种放射性示踪剂评估AAA脆弱性的潜力。 此外，给予CCR2抑制剂显著减少了AAA的进展，并抑制了相关的 破裂。我们建议评估与AAA发展和利用相关的CCR2+炎症过程 在啮齿动物AAA模型中，这些过程作为治疗靶点，同时探索靶向CCR2 PET成像 AAA患者，通过实现以下具体目标。目的1.评价~(64)Cu-DOTA-ECL1i正电子发射计算机体层摄影术 临床前模型中腹主动脉发育和破裂过程中CCR2+细胞活性的特征。目标1 A。 易损性AAA患者~(64)Cu-DOTA-ECL1i PET摄取与CCR2+免疫细胞活性的相关性 小鼠腹主动脉破裂模型的组织病理学特征。目标1B。优化CCR2拮抗剂的治疗 方案在小鼠AAA模型中的应用，并评估64CuDOTA-ECL1i PET作为辅助诊断以确定 治疗反应。目的2.确定64Cu-DOTA-ECL1i结合与CCR2+细胞的关系 使用生物库保存的人类AAA样本的成分。目标2 A。测定64Cu-的结合特性 DOTA-ECL1i在体外人类AAA标本中的表达，并与相关的组织病理学特征相关联。 目标2B。确定64Cu-DOTA-ECL1I组织放射自显影与区域CCR2基因的关系 表达、细胞因子谱和局部基质金属蛋白酶活性。目的3.评估64Cu-的性能 DOTA-ECL1i PET/CT检测人主动脉中CCR2+炎症细胞。目标3A。评估64CuDOTA- 开放修复术和对照组AAA患者的ECL1i显像特征 确定示踪剂摄取与预期收集的AAA的分子特征之间的关系 纸巾。Aim3B。评价~(64)Cu-DOTA-ECL1i PET/CT在AAA患者中的成像重复性。

Project Abstract Abdominal aortic aneurysm (AAA) represents a life-threatening degenerative vascular disease. AAAs usually remain asymptomatic until they rupture, leading to high mortality. AAA is more prevalent in men over the age of 65 years-old; however, AAA rupture occurs more often in women. The clinical imaging of AAAs largely centers around measurement of AAA diameter, which is a poor marker for rupture prediction. There is an unmet clinical need for a molecular imaging strategy to phenotype AAA patients for risk stratification. Monocyte chemotactic protein-1/Chemokine (C-C motif) receptor 2 (MCP-1/CCR2) axis plays an important role in the pathogenesis of AAAs by mediating the recruitment of inflammatory monocytes and infiltration of macrophages, resulting in the degradation of aortic wall elastin and collagen. We have developed a CCR2-targeting radiotracer, 64Cu-DOTA- ECL1i, for positron emission tomography (PET) imaging of CCR2+ pro-inflammatory monocytes/macrophages and have demonstrated the specific detection of CCR2+ cells in patients with cardiovascular diseases. In murine AAA models, 64Cu-DOTA-ECL1i PET demonstrated specific radiotracer uptake within the AAA wall that correlated with sensitive detection of variations in CCR2+ cell populations. Marked elevation of radiotracer uptake in rupture-prone AAAs demonstrated the potential of this radiotracer to assess AAA vulnerability. Moreover, administration of a CCR2 inhibitor significantly decreased AAA progression and inhibited associated rupture. We propose to assess CCR2+ inflammatory processes associated with AAA development and exploit these processes as therapeutic targets in rodent AAA models, while exploring targeted CCR2 PET imaging in AAA patients, by achieving the following specific aims. Aim 1. Assess 64Cu-DOTA-ECL1i PET for the characterization of CCR2+ cell activity during AAA development and rupture in pre-clinical models. Aim 1A. Correlate 64Cu-DOTA-ECL1i PET uptake with CCR2+ immune cell activity in vulnerable AAAs and changes in the histopathological properties of murine AAA rupture models. Aim 1B. Optimize CCR2 antagonist treatment regimens in murine AAA models and assess 64Cu-DOTA-ECL1i PET as a companion diagnostic to determine treatment response. Aim 2. Determine the relationship between 64Cu-DOTA-ECL1i binding and CCR2+ cellular composition using bio-banked human AAA specimens. Aim 2A. Determine the binding characteristics of 64Cu- DOTA-ECL1i in ex vivo human AAA specimens and correlate these with associated histopathological features. Aim 2B. Determine the relationship between 64Cu-DOTA-ECL1i tissue autoradiography, regional CCR2 gene expression, cytokine profiles, and local matrix metalloproteinase activity. Aim 3. Assess the performance of 64Cu- DOTA-ECL1i PET/CT to detect CCR2+ inflammatory cells in the human aorta. Aim 3A. Assess 64Cu-DOTA- ECL1i imaging characteristics in AAA patients undergoing open repair and control, healthy volunteers to determine the relationship between tracer uptake and molecular characterization of prospectively collected AAA tissues. Aim3B. Assess the imaging reproducibility of 64Cu-DOTA-ECL1i PET/CT imaging in AAA patients.