A Receptor-Targeted Nanoparticle PET Tracer in Human Carotid Atherosclerosis

人颈动脉粥样硬化受体靶向纳米粒子 PET 示踪剂

• 批准号: 10671549
• 负责人: Pamela K Woodard
• 金额: $ 70.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671549
• 关键词: Aftercare; Anatomy; Arterial Fatty Streak; Biology; Blood Platelets; Blood Vessels; C-Type Natriuretic Peptide; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Carotid Endarterectomy; Carotid Stenosis; Cell Lineage; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Complex; Consensus; Data; Detection; Diameter; Disease; Endothelium; Event; Evolution; Funding; G-Protein-Coupled Receptors; Gene Expression; Goals; Grant; Guidelines; Health Care Costs; Human; Hyperplasia; Hypertension; Image; Imaging Techniques; Immunohistochemistry; Individual; Infiltration; Inflammation; Intervention; Interview; Ipsilateral; Ischemia; Ischemic Stroke; Length; Ligands; Macrophage; Magnetic Resonance Imaging; Medical; Molecular; Morphology; Natriuretic Peptides; Observational Study; Operative Surgical Procedures; Outcome Assessment; Outcome Study; Patient-Focused Outcomes; Patients; Peptide Receptor; Perioperative; Physiological; Positron-Emission Tomography; Predictive Value; RNA; Recommendation; Regulation; Research; Risk; Risk Marker; Role; Rupture; Shapes; Signal Transduction; Smooth Muscle Myocytes; Specimen; Surgeon; Symptoms; Telephone; Testing; Tracer; United States; United States National Institutes of Health; Universities; Vascular Smooth Muscle; Vascular remodeling; Washington; Work; X-Ray Computed Tomography; atherosclerosis risk; cell type; cerebrovascular; chelation; cohort; diabetes management; differential expression; first-in-human; fluorodeoxyglucose; high risk; human study; hypertension control; imaging approach; immunoregulation; molecular imaging; nanoparticle; novel; patient stratification; radiotracer; receptor; risk stratification; routine screening; stroke risk; transcriptomics; uptake; vascular smooth muscle cell proliferation

PROJECT SUMMARY Currently no consensus exists in clinical guidelines for management of patients with asymptomatic carotid artery stenosis (ACAS). Some guidelines recommend carotid endarterectomy (CEA) surgery for patients with ACAS of ≥ 60% diameter. However, it is argued that 95% of all surgical interventions for ACAS in the United States may be unnecessary, generating needless healthcare costs of >$2 billion annually. Our goal in this proposal is to study plaque biology in ACAS patients through PET imaging at the molecular level to help identify individuals who are at 'higher-risk’ for ischemic stroke from plaque rupture and may benefit from carotid surgical intervention. We propose a 2-center patient outcomes study that expands upon data and observations from our earlier single center first-in-human study at Washington University using a nanoparticle PET radiotracer that targets the natriuretic peptide receptor C (NPRC) to determine if it can be used to risk stratify patients with ‘higher-risk’ ACAS. We and others have shown that NPRC is expressed at higher levels in complex plaques with features of vulnerability in patients with ACAS. In our most recent NIH R01-funded proof-of-concept study in a cohort of 42 patients with ACAS, we have shown linear correlation between 64Cu-CANF-Comb PET radiotracer uptake and features of high-risk plaque and correlative 64Cu-CANF-Comb PET uptake to the presence of NPRC in CEA specimens of patients who underwent surgery. We propose the following Specific Aims: Aim 1. To determine the ability of 64Cu-CANF-Comb PET to risk stratify ACAS patients treated with optimal medical therapy (OMT) alone with respect to patient outcomes. In this observational study, 80 patients with ACAS ≥ 60% will undergo 64Cu-CANF-Comb PET/MRI. Patients will be maintained on either OMT alone or receive OMT and CEA as determined by their treating vascular surgeon prior to imaging. OMT will consist of antiplatelet, statin, and hypertension and diabetes management when applicable. All patients will be evaluated with phone interviews every 3 months for a minimum of 18 months to assess for ipsilateral ischemic cerebrovascular event. PET signal will be assessed as a marker of risk for event or progression to CEA in comparison to anatomic features of vulnerable plaque on MRI, with the goal of determining a PET signal threshold which suggests higher risk ACAS. Aim 2: To further understand the role of NPRC in the evolution of carotid atherosclerosis. A. Patients treated with OMT alone will undergo repeat PET/MRI at 18 months, or earlier if they develop symptoms. PET/MRI changes over the 18-month interval will be used to further understand the biology of carotid plaque evolution after treatment with OMT. B. In patients who initially undergo CEA, PET signal will be compared to ex vivo plaque vulnerability and NPRC cellular distribution to facilitate understanding of gene expression using immunohistochemistry (IHC) and cell origin through single cell RNA/CITE-seq transcriptomics. Results will provide information on the potential of a new imaging approach, 64Cu-CANF-Comb PET, to risk stratify patients with ACAS and reveal mechanistic information about the role of NPRC in plaque vulnerability and inflammation.

项目摘要 目前，对于无症状颈动脉患者的管理，临床指南尚未达成共识 狭窄（ACAS）。一些指南建议对患有ACAS的患者进行颈动脉内膜切除术（CEA）， ≥ 60%直径。然而，有人认为，在美国，95%的ACAS手术干预可能 不必要的，每年产生不必要的医疗费用> 20亿美元。我们在这个提案中的目标是 通过PET成像在分子水平上研究ACAS患者的斑块生物学，以帮助识别个体 斑块破裂导致缺血性中风的“高风险”患者，颈动脉手术干预可能会受益。 我们提出了一项2中心患者结局研究，该研究扩展了我们早期单中心研究的数据和观察结果。 华盛顿大学的一个中心的第一个人体研究使用了一种纳米粒子PET放射性示踪剂， 利钠肽受体C（NPRC），以确定其是否可用于风险分层患者的“高风险” ACAS。我们和其他人已经表明，NPRC在具有特征的复杂斑块中以较高水平表达， ACAS患者的脆弱性。在我们最近的NIH R 01资助的概念验证研究中， 42例ACAS患者，我们已经显示64 Cu-CANF-Comb PET放射性示踪剂摄取与 CEA中存在NPRC的高危斑块和相关64 Cu-CANF-Comb PET摄取的特征 接受手术的病人的标本。我们提出以下具体目标：目标1。以确定 64 Cu-CANF-Comb PET对接受最佳药物治疗ACAS患者进行风险分层的能力 (OMT)单独考虑患者的结果。在这项观察性研究中，80例ACAS ≥ 60%的患者将 进行64 Cu-CANF-Comb PET/MRI。患者将维持单独OMT或接受OMT和CEA 这由他们的治疗血管外科医生在成像之前确定。OMT将包括抗血小板药物、他汀类药物和 高血压和糖尿病管理（如适用）。所有患者将通过电话访谈进行评估 每3个月一次，至少持续18个月，以评估同侧缺血性脑血管事件。PET信号 将作为事件或进展为CEA的风险标志物进行评估， 在MRI上检测易损斑块，目的是确定提示高风险ACAS的PET信号阈值。 目的2：进一步了解NPRC在颈动脉粥样硬化发生发展中的作用。A.患者 单独接受OMT治疗的患者将在18个月时接受重复PET/MRI检查，如果出现症状，则更早。PET/MRI 18个月间隔的变化将用于进一步了解颈动脉斑块演变的生物学 OMT治疗后。B。在最初接受CEA的患者中，将PET信号与离体斑块进行比较 脆弱性和NPRC细胞分布，以促进使用 通过单细胞RNA/CITE-seq转录组学研究免疫组织化学（IHC）和细胞起源。结果将 提供了关于新成像方法64 Cu-CANF-Comb PET对患者进行风险分层的可能性的信息 与ACAS，并揭示机制信息的作用，NPRC的斑块脆弱性和炎症。