Clinical translation of targeted intracoronary imaging for inflammatory activity

炎症活动在冠状动脉疾病(CAD)的发生和发展中起着重要作用， 这是美国和世界各地死亡的主要原因。到目前为止，还没有办法想象和 以影响患者管理所需的精确度量化冠脉炎症。有一个 作为一种新的临床近红外荧光(NIRF)显像剂，这种能力差距有可能改变 名为LUM015的药物最近已被引入癌症应用领域。活动后的LUM015荧光 组织蛋白酶裂解，因此似乎是一种高度特异的靶向因子，在炎症活动中 动脉粥样硬化，因为组织蛋白酶是斑块进展和冠状动脉血栓形成风险的关键介质。 在这项拨款中，我们建议研究人类首次使用LUM015 NIRF进行冠状动脉内冠状动脉内评估。 我们将通过开发和临床验证多模式成像系统来实现这一目标 同时获得共同定位的冠状动脉内光学相干断层扫描(OCT)图像的导管 皮损显微解剖和LUM015 NIRF评估组织蛋白酶介导的斑块炎症活性。这 通过研究LUM015的靶向分布和给药参数，技术将被临床转化 在动脉粥样硬化的动物模型和接受颈动脉内膜切除术的人类中(目标1)。技术将会 被开发用于将LUM015近红外自发荧光(NIRAF)从流行于 高级计算机辅助设计(目标2.1)。我们还将通过创造一种创新的双光纤来推进NIRF-OCT技术 导管/旋转接头，去除纤维自发荧光背景。由此导致的LUM015的增加 NIRF灵敏度将允许将注射和成像之间的时间降至最低，这对捕获非常重要 许多患者接受心导管术(目标2.2)。新的导管还将改善OCT图像 质量，这在当前的多模式系统中是次要的。在完成目标1和目标2后，血管内 LUM015 NIRF-OCT技术将在接受心导管术的患者中进行测试，以显示NIRF- OCT可以预测冠心病的严重程度(目标3)。通过建立一种新的临床影像方法来评估 冠状动脉微结构和活体炎症活动，这项工作将对冠心病的研究产生重大影响， 药物开发，以及旨在改善临床结果的个性化CAD管理。

Inflammatory activity plays a major role in the development and progression of coronary artery disease (CAD), the major cause of mortality in the US and around the world. Until now, there has been no way to visualize and quantify coronary inflammation with the precision required to impact patient management. There is an opportunity for this capability gap to change, as a new clinical near-infrared fluorescence (NIRF) imaging agent called LUM015 has recently been introduced for cancer applications. LUM015 fluoresces following active cathepsin cleavage and thus appears promising as a highly specific targeted agent for inflammatory activity in atherosclerosis, as cathepsins are key mediators of plaque progression and coronary thrombosis risk. In this grant, we propose to investigate a first-in-human use of LUM015 NIRF for intracoronary CAD assessment. We will accomplish this objective by developing and clinically validating a multimodality imaging system and catheter that simultaneously obtains co-localized, intracoronary optical coherence tomography (OCT) images of lesional microanatomy and LUM015 NIRF to evaluate cathepsin-mediated plaque inflammatory activity. This technology will be clinically translated by investigating the targeting profile and dosing parameters for LUM015 in animal models of atherosclerosis and in humans undergoing carotid endarterectomy (Aim 1). Technology will be developed to spectrally unmix LUM015 NIRF from NIR autofluorescence (NIRAF) that is prevalent in advanced CAD (Aim 2.1). We also will advance NIRF-OCT technology by creating an innovative two-fiber catheter/rotary junction that removes fiber autofluorescence background. The resultant increase in LUM015 NIRF sensitivity will allow the time between injection and imaging to be minimized, which is important to capture many patients undergoing cardiac catheterization (Aim 2.2). The new catheter will also improve OCT image quality, which is inferior in current multimodality systems. After completion of Aims 1 and 2, the intravascular LUM015 NIRF-OCT technology will be tested in patients undergoing cardiac catheterization to show that NIRF- OCT can predict CAD severity (Aim 3). By establishing a new clinical imaging methodology for evaluating coronary microstructure and inflammatory activity in vivo, this work will have a major impact on CAD research, drug development, and personalized CAD management aimed at improving clinical outcomes.