Detection of in vivo protease activities using PARACEST MRI contrast agents

使用 PARACEST MRI 造影剂检测体内蛋白酶活性

• 批准号: 7451742
• 负责人: Mark David Pagel
• 金额: $ 20.39万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7451742
• 关键词: Accounting; Achievement; Address; Animal Model; Animals; Apoptosis; Biochemical; Biological Assay; Biological Markers; Biological Monitoring; Biological Process; Breast Carcinoma; Catalysis; Cathepsin L; Cathepsins B; Cell Death; Cells; Chemicals; Cleaved cell; Clinical; Clinical Pathology; Condition; Contrast Media; Coupled; Cultured Cells; Cytosol; Detection; Development; Diagnostic; Drug Kinetics; Endopeptidases; Enzymes; Evolution; Foundations; Goals; Human; Human Mammary Carcinoma; Hydrogen; In Situ Nick-End Labeling; In Vitro; Incubated; Infusion procedures; Invasive; Kinetics; Lesion; MCF7 cell; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Methods; Monitor; Neoplasm Metastasis; Normal tissue morphology; Pathology; Peptide Hydrolases; Peptides; Protein Overexpression; Proteins; Rate; Relative (related person); Relaxation; Research; Saline; Sampling; Scanning; Signal Transduction; Solutions; Specificity; Staining method; Stains; TNFSF10 gene; Technology; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Urokinase; Water; base; caspase-3; design; extracellular; fluorescence imaging; functional group; improved; in vivo; magnetic field; malignant breast neoplasm; molecular imaging; mouse model; neoplastic cell; preclinical study; response; size; subcutaneous; success; tool; tumor

DESCRIPTION (provided by applicant): Proteases are important biomarkers for many pathologies and biological processes and are often targets of chemotherapeutics. Magnetic Resonance Imaging (MRI) is an outstanding diagnostic tool for identifying suspicious lesions, but suffers from many false-positive results due to a lack of specificity for pathological tissues versus normal tissues. The development of MRI contrast agents that can detect protease biomarkers of metastatic tumors or the response to anti-tumor therapies would greatly improve the specificity of MRI for detecting and evaluating cancer. We have developed a fundamentally new type of protease-responsive MRI contrast agent that is detected through PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST). This mechanism allows each PARACEST contrast agent to be selectively detected, so that multiple PARACEST contrast agents may be simultaneously detected during a single MRI scan session, such as a protease-unresponsive PARACEST contrast agent that can serve as a `control' to account for the pharmacokinetics of the agents. Furthermore, we are the first research team to demonstrate the detection of PARACEST contrast agents within in vivo animal models. We will combine our accomplishments with PARACEST contrast agents to detect multiple enzyme-responsive PARACEST contrast agents within in vivo animal models. More specifically, we will design and apply PARACEST contrast agents to detect caspase-3 during TRAIL-induced tumor cell apoptosis in an in vivo mouse model of MCF-7c3 human mammary carcinoma. We will also design and apply PARACEST contrast agents to simultaneously detect cathepsin B and urokinase Plasminogen Activator in an in vivo mouse model of MCF-7 and MBA-MB-231 mammary carcinoma. The successful achievement of our specific aims will result in new platform technology that can be immediately used during many pre-clinical studies, and that can be used as a foundation for further studies to gain clinical approval for this new type of diagnostic molecular imaging agent to detect protease biomarkers in cancer and other pathological tissues. Narrative: A fundamentally new type of protease-responsive MRI contrast agent has been developed that is detected through PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST). Furthermore, PARACEST contrast agents can be detected within in vivo animal models. This research application will combine these accomplishments with PARACEST contrast agents to detect multiple enzyme-responsive PARACEST contrast agents within in vivo animal models.

描述(申请人提供)：蛋白水解酶是许多病理和生物过程的重要生物标志物，通常是化疗的靶标。磁共振成像(MRI)是一种优秀的诊断工具，用于识别可疑病变，但由于病理组织与正常组织缺乏特异性，导致许多假阳性结果。MRI造影剂的发展将极大地提高MRI对肿瘤的诊断和评价的特异性。我们开发了一种通过顺磁化学交换饱和转移(PARACEST)检测的新型蛋白酶响应型磁共振造影剂。这一机制允许选择性地检测每个PARACEST造影剂，从而可以在单个MRI扫描过程中同时检测多个PARACEST造影剂，例如可以用作解释试剂药代动力学的‘对照’的无酶反应的PARACEST造影剂。此外，我们是第一个在活体动物模型中证明检测到PARACEST造影剂的研究团队。我们将把我们的成果与PARACEST造影剂结合起来，在活体动物模型中检测多种酶反应的PARACEST造影剂。更具体地说，我们将设计和应用PARACEST造影剂来检测TRAIL诱导的人乳腺癌体内模型小鼠模型中caspase-3的凋亡。我们还将设计和应用PARACEST造影剂，在MCF-7和MBA-MB-231乳腺癌的活体小鼠模型中同时检测组织蛋白酶B和尿激酶型纤溶酶原激活剂。我们特定目标的成功实现将带来新的平台技术，可以立即在许多临床前研究中使用，并可以作为进一步研究的基础，以获得这种新型诊断分子显像剂的临床批准，以检测癌症和其他病理组织中的蛋白酶生物标记物。叙述：通过顺磁化学交换饱和转移(PARACEST)检测到的一种全新类型的蛋白酶反应型磁共振造影剂已经被开发出来。此外，可以在活体动物模型中检测到PARACEST造影剂。这一研究应用将把这些成果与PARACEST造影剂结合起来，在活体动物模型中检测多种酶反应的PARACEST造影剂。