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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：
8353415
负责人：
Mark David Pagel
金额：
$ 53.28万
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/8353415
关键词：
Address Antigens Biological Markers Breast Cadaverine Chelating Agents Chemical Agents Chemicals Chemotherapy-Oncologic Procedure Clinic Clinical Clinical assessments Contrast Media 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

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We propose to continue to develop CEST agents and CEST MRI methods that detect enzyme activities within in vivo mouse models of cancer. We propose to use our CEST agents and CEST MRI methods to evaluate chemotherapies and to assess whether enzyme activity is a better biomarker than enzyme expression.

描述（由申请人提供）：酶活性是癌症诊断和评估化疗的重要生物标志物。我们已经开发了通过化学交换饱和转移（CEST）检测的MRI造影剂，并且对酶活性有反应。我们还开发了CEST MRI方法，可以在人类癌症小鼠模型的体内肿瘤组织中检测这些药物。重要的是，我们可以在相同的研究中在相同的组织位置选择性地检测酶反应剂和无反应的“对照”剂，这改善了我们对小鼠模型中酶活性的评估。正如多种荧光团在体外和离体研究中彻底改变了酶活性的评价一样，CEST试剂和CEST MRI有可能彻底改变体内酶活性的评价。我们建议建立在我们最近的研究成功，通过连接酶响应和控制剂，以创建一个二聚体的代理，通过比较顺磁性和抗磁性CEST代理，并通过优化饱和期的CEST MRI采集协议，以提高CEST MRI的检测灵敏度。我们还建议开发酶响应CEST试剂，半定量检测胰腺癌小鼠模型中尿激酶纤溶酶原激活物（uPA）、前列腺癌小鼠模型中前列腺特异性膜抗原（PSMA）和乳腺癌小鼠模型中转氨酶（TG 2）的活性。我们建议使用这些CEST试剂和我们的体内CEST MRI方法来研究三个生物医学目的：A）在给予小鼠模型之前预测化疗的效果; 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，用于预测和评估治疗效果。总之，这些研究解决了我们的总体目标，即最终使用CEST药物和CEST MRI为每位患者量身定制化疗和治疗方案的选择，以支持个性化医学的范式。公共卫生关系：我们建议继续开发CEST试剂和CEST MRI方法，以检测体内小鼠癌症模型中的酶活性。我们建议使用我们的CEST试剂和CEST MRI方法来评估化疗，并评估酶活性是否是比酶表达更好的生物标志物。