MR Signal Amplification for Receptor Imaging

用于受体成像的 MR 信号放大

基本信息

批准号：
7645768
负责人：
Alexei A Bogdanov
金额：
$ 34.85万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7645768
关键词：
Abnormal Cell Achievement Address Adenocarcinoma Animal Model Animals Antibodies Antibody Therapy Binding Biological Markers Brain Cancer Model Cell Adhesion Molecules Cell physiology Cells Clinical Clinical Trials Detection Development Diabetes Mellitus Disease Disease Marker Disease Progression Early Diagnosis Enzymes Epidermal Growth Factor Receptor Fc Receptor Funding Future Genomics Goals Heart Diseases Human Image Imagery Imaging Device Imaging Techniques Immunoglobulin Fragments Immunohistochemistry In Vitro Inflammatory Response Label Laboratory Animals Laccase Lanthanoid Series Elements Lead Life Link Magnetic Resonance Imaging Malignant neoplasm of prostate Mediating Medical Medicine Modeling Molecular Molecular Probes Molecular Target Molecular Weight Monitor Nature Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Organ Organism Oxidoreductase Patients Pattern Peroxidases Pharmaceutical Preparations Phenols Physicians Proteomics Protocols documentation Radioisotopes Research Resolution Safety Scientist Signal Transduction Site Specificity Substrate Specificity System TACSTD2 gene Testing Time Tissues Transgenic Model Translating Xenograft procedure base cancer cell design improved in vivo innovation macromolecule molecular imaging molecular marker monocyte neoplastic cell neutrophil novel novel marker overexpression polymerization public health relevance receptor receptor expression research study response scale up tool tumor

Abnormal Cell Achievement Address Adenocarcinoma Animal Model Animals Antibodies Antibody Therapy Binding Biological Markers Brain Cancer Model Cell Adhesion Molecules Cell physiology Cells Clinical Clinical Trials Detection Development Diabetes Mellitus Disease Disease Marker Disease Progression Early Diagnosis Enzymes Epidermal Growth Factor Receptor Fc Receptor Funding Future Genomics Goals Heart Diseases Human Image Imagery Imaging Device Imaging Techniques Immunoglobulin Fragments Immunohistochemistry In Vitro Inflammatory Response Label Laboratory Animals Laccase Lanthanoid Series Elements Lead Life Link Magnetic Resonance Imaging Malignant neoplasm of prostate Mediating Medical Medicine Modeling Molecular Molecular Probes Molecular Target Molecular Weight Monitor Nature Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Organ Organism Oxidoreductase Patients Pattern Peroxidases Pharmaceutical Preparations Phenols Physicians Proteomics Protocols documentation Radioisotopes Research Resolution Safety Scientist Signal Transduction Site Specificity Substrate Specificity System TACSTD2 gene Testing Time Tissues Transgenic Model Translating Xenograft procedure base cancer cell design improved in vivo innovation macromolecule molecular imaging molecular marker monocyte neoplastic cell neutrophil novel novel marker overexpression polymerization public health relevance receptor receptor expression research study response scale up tool tumor

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项目摘要

DESCRIPTION (provided by applicant): The pressing needs in translating recent achievements of genomic and proteomic screens ex vivo into the visualization of markers in living systems necessitate the development of novel molecular biomarker imaging techniques. The ability to apply molecular imaging to novel markers in vivo would have significant implications for early detection of disease, assessing patient-specific therapies and monitoring dynamic changes in expression patterns during disease progression. This application builds on our recent innovations in designing, testing and applying enzyme-mediated MR signal amplification strategy (MRamp) for imaging molecular targets. The proposed research is based on our observation that paramagnetic phenols in the presence of oxidoreductases give markedly enhanced relaxivity and MR signal. We previously proposed to harness MRamp effect and apply it for the needs of MR molecular imaging. As a result, we accomplished a transition of our research from in vitro level to in vivo experiments. Reaching the following milestones were instrumental in achieving the aims of the research: 1) designing and scaling up synthesis of MRamp substrates; 2) determining that the nature of aromatic reducing group linked to paramagnetic moiety defines substrate specificity and enzyme selectivity; 3) providing evidence that MRamp mechanism includes both polymerization and binding of paramagnetic oligomers to macromolecules; 4) optimizing a complete protocol for small conjugates of anti-receptor antibody and amplification enzymes ( binary amplification system ); 5) performing the testing of the developed system by using MRI in EGFR-expressing tumors; 6) testing alternative amplification enzymes and identifying a candidate for future research. By building on the above key findings we propose to achieve the following specific aims: Specific Aim. 1. Optimize and test in vivo single-enzyme targeted amplification imaging system. We hypothesize that MR signal amplification strategy could be improved by optimizing in vivo delivery. This can be achieved by using a) single, phenol- oxidizing enzyme covalently linked to F(ab')2 fragment of EGFR antibody. This hypothesis will be tested in EGFR-overexpressing tumor models. Specific Aim 2. Develop and test two-enzyme, bi-specific approach for imaging tumor cells co-expressing two different molecular markers. We hypothesize that by using two antibody fragments directed against different targets on the same cells we will image co-expression of adhesion molecule (EpCAM) and EGF receptor on non-small cell lung cancer (NSCLC) cells that are likely to respond to combined antibody therapy. This hypothesis will be tested in a model of NSCLC metastasis to the brain. Specific Aim 3. To use MRamp strategy for imaging inflammatory response and receptor repertoire of tumors in vivo. We hypothesize that monocyte/neutrophil component of inflammatory response can be imaged in tumors separately from receptors by using two MRamp substrates: the first having narrow myeloperoxidase specificity, and the second having laccase specificity. This hypothesis will be tested in transgenic model of prostate cancer. Public health relevance statement: The development of new drugs that can efficiently eliminate tumor cells or slow heart disease and diabetes requires ample testing in laboratory animals to prove safety and efficacy. The use of medical scanners that detect these cellular processes with high accuracy in live animals has the potential to significantly decrease the time between discovery of and subsequent clinical use of new medicines. This decreased time benefits both patients and taxpayers. We are proposing research approaches that will lead to the development of new tools (imaging drugs and compositions) for use with medical scanners. These tools will have applications for tracking the molecules that are linked to the abnormal cells. This research will help scientists and physicians to detect these cells and follow their response to medicines.

描述（由申请人提供）：将基因组和蛋白质组学筛选最新成就转换为生命系统中标记的最新成就的紧迫需求需要开发新型分子生物标志物成像技术。在体内将分子成像应用于新标记的能力将对疾病的早期发现，评估患者特异性疗法并监测疾病进展过程中表达模式的动态变化具有重要意义。该应用基于我们最近在设计，测试和应用酶介导的MR信号扩增策略（MRAMP）成像分子靶标方面的创新。拟议的研究是基于我们的观察结果，即存在氧化还原酶的顺磁酚可显着增强的松弛性和MR信号。我们先前提出要利用MRAMP效应，并将其应用于MR分子成像的需求。结果，我们完成了从体外水平到体内实验的研究过渡。达到以下里程碑有助于实现研究的目的：1）设计和扩大MRAMP底物的合成； 2）确定与顺磁部分相关的芳族还原组的性质定义了底物特异性和酶选择性； 3）提供证据表明MRAMP机制既包括聚合和顺磁性低聚物与大分子的结合； 4）优化针对抗受体抗体和扩增酶（二元扩增系统）的小偶联物的完整方案； 5）通过在表达EGFR的肿瘤中使用MRI对开发系统进行测试； 6）测试替代性放大酶并确定未来研究的候选者。通过在上述关键发现上构建，我们建议实现以下特定目标：特定目标。 1。在体内单酶靶向扩增成像系统中进行优化和测试。我们假设可以通过优化体内递送来改善MR信号放大策略。这可以通过使用a）与f（ab'）2 egfr抗体的f（ab'）2片段共价链接的单一的酚氧化酶来实现。该假设将在EGFR过表达的肿瘤模型中进行检验。具体目标2。开发和测试两酶，双特异性方法，用于成像共表达两个不同分子标记的肿瘤细胞。我们假设，通过在相同细胞上使用针对不同靶标的两个抗体片段，我们将在非小细胞肺癌（NSCLC）细胞上对粘附分子（EPCAM）和EGF受体进行图像表达，这些细胞可能会响应合并的抗体治疗。该假设将在NSCLC转移对大脑的模型中进行检验。具体目的3。使用MRAMP策略对体内肿瘤的炎症反应和受体库进行成像。我们假设可以使用两种MRAMP底物分别在肿瘤中成像炎症反应的单核细胞/中性粒细胞成分：第一种具有狭窄的髓过氧化物酶特异性，第二种具有漆酶特异性。该假设将在前列腺癌的转基因模型中进行检验。公共卫生相关性声明：开发可以有效消除肿瘤细胞或慢速心脏病和糖尿病的新药需要进行实验动物的大量测试，以证明安全性和有效性。在活动物中检测这些细胞过程的医疗扫描仪的使用可能会显着减少发现新药物和随后的临床使用之间的时间。这种时间减少的时间使患者和纳税人都受益。我们提出的研究方法将导致与医疗扫描仪一起使用的新工具（成像药物和成分）的开发。这些工具将具有跟踪与异常细胞相关的分子的应用。这项研究将帮助科学家和医生检测这些细胞并遵循它们对药物的反应。