CHEMOKINE RECEPTORS BASED NANOAGENTS IMAGING ATHEROSCLEROSIS

基于趋化因子受体的动脉粥样硬化成像纳米制剂

• 批准号: 9188466
• 负责人: Yongjian Liu
• 金额: $ 37.08万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188466
• 关键词: Address; Affinity; Amides; Apolipoprotein E; Area; Arterial Fatty Streak; Atherosclerosis; Binding; Biodistribution; Biological; Biological Markers; Blood Circulation; Blood Vessels; CCR1 gene; CCR5 gene; CCR8 gene; CXCR3 gene; CXCR4 gene; Cell Line; Cells; Cholesterol; Clinical; Comb animal structure; Data; Detection; Diagnostic; Diet; Disease; Disease Progression; Drug Kinetics; Environment; Event; Growth; Image; In Vitro; Individual; Inflammation; Inflammatory; Injury; Knowledge; Label; Lesion; Leukocytes; Link; Macrophage Inflammatory Proteins; Measures; Mediating; Methods; Modeling; Molecular Probes; Molecular Weight; Mus; Nanostructures; Nature; Pathologic; Peptides; Polymers; Positron-Emission Tomography; Proteins; Radiolabeled; Recruitment Activity; Research; Role; Sensitivity and Specificity; Severities; Signal Transduction; Site; Specificity; Stimulus; Structure; Testing; Therapeutic; Tracer; Up-Regulation; Variant; Viral; XCR1 gene; advanced disease; aortic arch; base; burden of illness; cell type; chemokine; chemokine receptor; clinical development; clinically relevant; design; experimental study; flexibility; functional group; improved; in vivo; injured; interest; macrophage; molecular imaging; monocyte; nanoparticle; nanoprobe; nanoscale; novel; personalized management; public health relevance; response; screening; small molecule; targeted imaging; tool; uptake; vMIP-II; vascular inflammation; vector

DESCRIPTION (provided by applicant): Remarkable progress has been made over the past decade in the molecular imaging of atherosclerotic lesion. The majority of studies have focused on the peptide based probes, which is monovalent and rapidly cleared from systemic circulation, leading to low targeting efficiency and contrast ratio. Thus, more and more efforts are toward using nanoparticle based molecular probe for targeted plaque imaging due to the tunable pharmacokinetics and multivalency. Of various nanoplatforms, core-shell polymeric nanoparticles are of particular interest owing to the flexible design of structures with accurate control of functional groups for multi- applications. Among an array of biomarkers upregulated on atherosclerotic lesion, chemokine receptors are promising targets owing to their critical roles in the initialization and progression of disease. Recently, we have developed chemokine receptors targeted Comb nanoparticles conjugated with novel peptides and labeled with 64Cu for atherosclerosis PET imaging. These targeted nanoagents demonstrated the sensitivity and targeting specificity in experimental mouse ApoE-/- model. In the proposed project, we will optimize the construction of viral macrophage protein-II (vMIP-II) conjugated Comb nanoparticles targeting a group of chemokine receptors and D-ala-peptide T-amide (DAPTA) conjugated Comb nanoparticles specifically targeting CCR5. Our preliminary PET imaging showed specific accumulation of 64Cu-vMIP-Comb and 64Cu-DAPTA-Comb at the aortic arch in ApoE-/- mice. However, the targeting efficiency and target-to-background ratio need further improvement. Thus, we will increase the number of vMIP-II peptide conjugated on each Comb nanoparticle and optimize the pegylation for enhanced targeting efficiency and reduce the blood circulation for minimized non-specific binding. The preferred vMIP-Comb will be used to determine the sensitivity and specificity in early stage of atherosclerosis. For DAPTA-Comb, we will follow the same strategy to optimize the nanostructure for in vitro screening in CCR5+ cell line. The candidate DAPTA-Com will be evaluated in ApoE-/- mice with significant lesion (Specific Aim 1). Then we will use the candidate vMIP-Comb and DAPTA-Comb to determine whether they can detect variation in atherosclerosis burden or progression. We will further analyze the specific cell type associated with radiolabeled nanoparticles in atherosclerotic lesion and correlate the PET signals obtained with the two nanoagents to the pathological examination including plaque area and macrophage area (Specific Aim 2). We anticipate that the targeted nanoparticles will provide sensitive and specific detection of chemokine receptors at plaque and serve as useful tools to detect the burden and progression of atherosclerotic plaque.

描述（申请人提供）：在过去的十年中，动脉粥样硬化病变的分子成像取得了显著进展。大多数研究集中在基于肽的探针上，其是单价的并且从体循环中快速清除，导致低靶向效率和对比率。因此，越来越多的研究致力于使用基于纳米颗粒的分子探针用于靶向斑块成像，这是由于可调的药代动力学和多价性。在各种纳米平台中，核-壳聚合物纳米颗粒由于其结构的灵活设计以及用于多种应用的官能团的精确控制而特别令人感兴趣。在动脉粥样硬化病变中上调的一系列生物标志物中，趋化因子受体是有希望的靶点，因为它们在疾病的起始和进展中起关键作用。最近，我们已经开发了趋化因子受体靶向梳状纳米颗粒共轭与新的肽和64铜标记的动脉粥样硬化PET成像。这些靶向纳米药物在实验小鼠ApoE-/-模型中表现出敏感性和靶向特异性。在拟议的项目中，我们将优化构建病毒巨噬细胞蛋白-II（vMIP-II）缀合的梳状纳米颗粒，靶向一组趋化因子受体和D-ala-肽T-酰胺（DAPTA）缀合的梳状纳米颗粒，特异性靶向CCR 5。我们的初步PET成像显示64 Cu-vMIP-Comb和64 Cu-DAPTA-Comb在ApoE-/-小鼠的主动脉弓处特异性积聚。但是，靶向效率和靶背景比需要进一步提高。因此，我们将增加每个Comb纳米颗粒上缀合的vMIP-II肽的数量，并优化聚乙二醇化以增强靶向效率，并减少血液循环以最小化非特异性结合。优选的vMIP-Comb将用于确定动脉粥样硬化早期的灵敏度和特异性。对于DAPTA-Comb，我们将遵循相同的策略来优化纳米结构，用于在CCR 5+细胞系中进行体外筛选。将在具有显著病变的ApoE-/-小鼠中评价候选DAPTA-Com（特定目标1）。然后，我们将使用候选vMIP-Comb和DAPTA-Comb来确定它们是否可以检测动脉粥样硬化负荷或进展的变化。我们将进一步分析动脉粥样硬化病变中与放射性标记纳米颗粒相关的特定细胞类型 并将用两种纳米剂获得的PET信号与包括斑块面积和巨噬细胞面积的病理学检查相关联（具体目标2）。我们预期靶向纳米颗粒将提供斑块处趋化因子受体的敏感和特异性检测，并作为检测动脉粥样硬化斑块的负担和进展的有用工具。