Clinical translation of targeted intracoronary imaging for inflammatory activity

炎症活动在冠状动脉疾病（CAD）的发展和进展中起主要作用， 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度量化冠状动脉炎症。有一个 作为一种新的临床近红外荧光（NIRF）成像剂， LUM 015最近被引入用于癌症应用。LUM 015在激活后发出荧光 组织蛋白酶切割，因此似乎有希望作为高度特异性的炎症活性靶向剂， 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。 在这项资助中，我们计划研究首次在人体中使用LUM 015 NIRF进行冠状动脉内CAD评估。 我们将通过开发和临床验证多模态成像系统来实现这一目标， 导管，同时获得共定位的冠状动脉内光学相干断层扫描（OCT）图像， 病变显微解剖和LUM 015 NIRF，以评价组织蛋白酶介导的斑块炎症活性。这 将通过研究LUM 015的靶向特征和给药参数，将该技术转化为临床应用 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中（目的1）。技术将 开发用于从NIR自发荧光（NIRAF）中光谱分离LUM 015 NIRF， 高级CAD（目标2.1）。我们还将通过创建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。LUM 015的增加 NIRF灵敏度将使注射和成像之间的时间最小化，这对于捕获 许多患者接受心导管插入术（目标2.2）。新导管还将改善OCT图像 质量，这在当前的多模态系统中是低劣的。在完成目标1和2后， LUM 015 NIRF-OCT技术将在接受心导管插入术的患者中进行测试，以显示NIRF- OCT可以预测CAD严重程度（目的3）。通过建立一种新的临床成像方法来评估 冠状动脉微观结构和体内炎症活动，这项工作将对CAD研究产生重大影响， 药物开发和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.