权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Detection of in vivo enzyme activities with CEST MRI

使用 CEST MRI 检测体内酶活性

基本信息

批准号：
8495297
负责人：
Mark David Pagel
金额：
$ 49.87万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495297
关键词：
Address Antigens Biological Markers Breast Cadaverine Chelating Agents Chemical Agents Chemicals Chemotherapy-Oncologic Procedure Clinic Clinical Clinical assessments Contrast Media DU145 Detection Development Engineering Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Evaluation Glutamate Carboxypeptidase II Goals Image In Vitro Individual Injection of therapeutic agent Ligands Link Location Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Measurement Measures Medicine Methodology Methods Modeling Monitor Mus Pancreas Patients Performance Physiologic pulse Prostate Proteins Protocols documentation Research Role Signal Transduction Staging Testing Therapeutic Effect Tissues Transglutaminases Translations Treatment Protocols Tumor Tissue Urokinase VCaP Validation cancer diagnosis cancer type chemotherapy design enzyme activity extracellular fluorescence imaging fluorophore human cancer mouse model improved in vivo inhibitor/antagonist innovation malignant breast neoplasm meetings mouse model pinacolyl methylphosphonic acid pre-clinical preclinical study protein expression response success tumor tumor growth tumor microenvironment

项目摘要

ABSTRACT Enzyme activities are important biomarkers for cancer diagnoses and assessing chemotherapies. We have developed MRI contrast agents that are detected via Chemical Exchange Saturation Transfer (CEST) and that are responsive to enzyme activity. We have also developed CEST MRI methods that can detect these agents within in vivo tumor tissues in mouse models of human cancers. Importantly, we can selectively detect an enzyme-responsive agent and an unresponsive "control" agent during the same study in the same tissue location, which improves our evaluation of enzyme activity within the mouse model. Just as multiple fluorophores have revolutionized the evaluation of enzyme activities during in vitro and ex vivo studies, CEST agents and CEST MRI has potential to revolutionize the evaluation of enzyme activities in vivo. We propose to build on our recent research successes by linking enzyme-responsive and control agents to create a dimeric agent, by comparing paramagnetic and diamagnetic CEST agents, and by optimizing the saturation period of the CEST MRI acquisition protocol in order to improve the detection sensitivity of CEST MRI. We also propose to develop enzyme-responsive CEST agents that semi-quantitatively detect the activities of urokinase Plasminogen Activator (uPA) in mouse models of pancreatic cancer, Prostate Specific Membrane Antigen (PSMA) in mouse models of prostate cancer, and transglutaminase (TG2) in mouse models of breast cancer. We propose to use these CEST agents and our in vivo CEST MRI methodology to investigate three biomedical aims: A) to predict the effect of chemotherapies before they are administered to mouse models; B) to evaluate early response to chemotherapies; C) to investigate our hypothesis that enzyme activity is a more accurate biomarker than enzyme expression for predicting and evaluating therapeutic effects. Together, these studies address our overarching goal of eventually using CEST agents and CEST MRI to tailor the choice of chemotherapy and treatment regimen for each individual patient, in order to support the paradigm of personalized medicine.

抽象的酶活性是癌症诊断和评估化疗的重要生物标志物。我们有开发了 MRI 造影剂，可通过化学交换饱和转移 (CEST) 进行检测，并且对酶的活性有反应。我们还开发了可以检测这些物质的 CEST MRI 方法在人类癌症小鼠模型的体内肿瘤组织内。重要的是，我们可以选择性地检测在同一组织的同一研究中使用酶响应剂和无响应“对照”剂位置，这改善了我们对小鼠模型内酶活性的评估。就如同多个荧光团彻底改变了体外和离体研究中酶活性的评估，CEST 试剂和 CEST MRI 有可能彻底改变体内酶活性的评估。我们建议以我们最近的研究成功为基础，将酶响应剂和控制剂与通过比较顺磁性和反磁性 CEST 试剂并优化 CEST MRI 采集协议的饱和期，以提高 CEST 的检测灵敏度核磁共振成像。我们还建议开发酶响应 CEST 试剂，半定量检测尿激酶纤溶酶原激活剂 (uPA) 在小鼠胰腺癌、前列腺特异性模型中的活性前列腺癌小鼠模型中的膜抗原 (PSMA) 和小鼠中的转谷氨酰胺酶 (TG2) 乳腺癌模型。我们建议使用这些 CEST 药物和我们的体内 CEST MRI 方法来研究三个生物医学目标：A）在给予化疗之前预测化疗的效果小鼠模型； B) 评估对化疗的早期反应； C）研究我们的假设，即酶活性是比酶表达更准确的生物标志物，可用于预测和评估治疗效果。这些研究共同解决了我们的总体目标，即最终使用 CEST 制剂和 CEST MRI 来定制为每个患者选择化疗和治疗方案，以支持该范例的个性化医疗。