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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：
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.

摘要酶活性是癌症诊断和评估化疗的重要生物标志物。我们有开发了通过化学交换饱和转移（CEST）检测的MRI造影剂，对酶的活性有反应。我们还开发了CEST MRI方法，可以检测这些代理人在人类癌症小鼠模型的体内肿瘤组织中。重要的是，我们可以选择性地检测在相同组织中的相同研究期间，酶反应剂和无反应“对照”剂位置，这改善了我们对小鼠模型内酶活性的评估。同样多的荧光团在体外和离体研究中彻底改变了酶活性的评价，试剂和CEST MRI具有彻底改变体内酶活性评价的潜力。我们建议在我们最近的研究成功的基础上，将酶反应剂和控制剂联系起来，通过比较顺磁性和反磁性CEST试剂，并通过优化 CEST MRI采集协议的饱和期，以提高CEST的检测灵敏度核磁共振我们还建议开发酶反应CEST试剂，半定量检测尿激酶纤溶酶原激活物（uPA）在胰腺癌小鼠模型中的活性，前列腺特异性前列腺癌小鼠模型中的膜抗原（PSMA）和小鼠中的转氨酶（TG 2）乳腺癌的模型我们建议使用这些CEST试剂和我们的体内CEST MRI方法，研究三个生物医学目的：A）在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，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试剂和CEST MRI来定制为每个患者选择化疗和治疗方案，以支持范例个性化医疗。