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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化疗评估的重要生物标志物。我们有开发了通过化学交换饱和转移(CEST)检测的MRI造影剂，并对酶的活性有反应。我们还开发了CEST MRI方法，可以检测到这些病原体在人类癌症模型的小鼠体内的肿瘤组织中。重要的是，我们可以选择性地检测到在同一组织的同一研究中，酶响应剂和无反应的“对照”剂位置，这改进了我们对小鼠模型中酶活性的评估。就像多个在体外和体外研究中，荧光团已经彻底改变了酶活性的评估试剂和CEST MRI有可能彻底改变活体中酶活性的评估。我们建议在我们最近的研究成果的基础上，将酶反应和控制剂联系起来通过比较顺磁性和抗磁性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检查。我们还建议开发酶响应型CEST试剂，半定量检测前列腺特异性胰腺癌小鼠模型尿激酶型纤溶酶原激活物的活性前列腺癌小鼠模型中的膜抗原(PSMA)和小鼠的转谷氨酰胺酶(TG2) 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方法来研究三个生物医学目标：a)在化疗实施前预测其效果小鼠模型；B)评估化疗的早期反应；C)调查我们的假说在预测和评估疗效方面，活性是比酶表达更准确的生物标志物。总之，这些研究解决了我们最终使用CEST代理和CEST MRI来定制的总体目标为每个患者选择化疗和治疗方案，以支持这一范例个性化的医疗服务。