Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (USA).
Veterans Affairs Connecticut Healthcare System, West Haven, CT (USA).
Theranostics. 2021 Apr 3;11(12):5876-5888. doi: 10.7150/thno.55106. eCollection 2021.
Inflammation plays a major role in the pathogenesis of several vascular pathologies, including abdominal aortic aneurysm (AAA). Evaluating the role of inflammation in AAA pathobiology and potentially outcome requires non-invasive tools for high-resolution imaging. We investigated the feasibility of X-ray computed tomography (CT) imaging of phagocytic activity using nanoparticle contrast agents to predict AAA outcome. Uptake of several nanoparticle CT contrast agents was evaluated in a macrophage cell line. The most promising agent, Exitron nano 12000, was further characterized and used for subsequent testing. AAA was induced in mice through angiotensin II (Ang II) infusion for up to 4 weeks. Nanoparticle biodistribution and uptake in AAA were evaluated by CT imaging in Ang II-infused mice. After imaging, the aortic tissue was harvested and used from morphometry, transmission electron microscopy and gene expression analysis. A group of Ang II-infused mice underwent nanoparticle-enhanced CT imaging within the first week of Ang II infusion, and their survival and aortic external diameter were evaluated at 4 weeks to address the value of vessel wall CT enhancement in predicting AAA outcome. Exitron nano 12000 showed specific uptake in macrophages . Nanoparticle accumulation was observed by CT imaging in tissues rich in mononuclear phagocytes. Aortic wall enhancement was detectable on delayed CT images following nanoparticle administration and correlated with vessel wall CD68 expression. Transmission electron microscopy ascertained the presence of nanoparticles in AAA adventitial macrophages. Nanoparticle-induced CT enhancement on images obtained within one week of AAA induction was predictive of AAA outcome at 4 weeks. By establishing the feasibility of CT-based molecular imaging of phagocytic activity in AAA, this study links the inflammatory signal on early time point images to AAA evolution. This readily available technology overcomes an important barrier to cross-sectional, longitudinal and outcome studies, not only in AAA, but also in other cardiovascular pathologies and facilitates the evaluation of modulatory interventions, and ultimately upon clinical translation, patient management.
炎症在几种血管病变的发病机制中起主要作用，包括腹主动脉瘤（AAA）。评估炎症在 AAA 病理生物学和潜在结果中的作用需要用于高分辨率成像的非侵入性工具。我们研究了使用纳米颗粒造影剂进行吞噬活性的 X 射线计算机断层扫描（CT）成像以预测 AAA 结果的可行性。在巨噬细胞细胞系中评估了几种纳米颗粒 CT 造影剂的摄取。最有前途的试剂 Exitron nano 12000 进一步进行了表征，并用于随后的测试。通过血管紧张素 II（Ang II）输注在小鼠中诱导 AAA 长达 4 周。通过 CT 成像评估 Ang II 输注小鼠中的纳米颗粒生物分布和摄取。成像后，收获主动脉组织并用于形态测量，透射电子显微镜和基因表达分析。一组 Ang II 输注小鼠在 Ang II 输注的第一周内接受了纳米颗粒增强的 CT 成像，并在 4 周时评估了它们的存活和主动脉外径，以解决血管壁 CT 增强在预测 AAA 结果中的价值。Exitron nano 12000 显示在巨噬细胞中具有特异性摄取。在富含单核吞噬细胞的组织中通过 CT 成像观察到纳米颗粒的积累。在给予纳米颗粒后，在延迟 CT 图像上可以检测到主动脉壁增强，并且与血管壁 CD68 表达相关。透射电子显微镜证实了 AAA 外膜巨噬细胞中存在纳米颗粒。在 AAA 诱导后一周内获得的图像上进行的纳米颗粒诱导 CT 增强可预测 4 周时的 AAA 结果。通过建立 AAA 中吞噬活性的基于 CT 的分子成像的可行性，本研究将早期时间点图像上的炎症信号与 AAA 的演变联系起来。这种现成的技术克服了横断面，纵向和结果研究中的一个重要障碍，不仅在 AAA 中，而且在其他心血管疾病中，并且促进了调节干预措施的评估，最终在临床转化后，患者管理。
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