MRI with Protease-Sensing Contrast Agents

使用蛋白酶感应造影剂进行 MRI

• 批准号: 6880482
• 负责人: LYNN M MATRISIAN
• 金额: $ 25.83万
• 依托单位: ALERION BIOMEDICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880482
• 关键词: bioassay; bioimaging /biomedical imaging; biomarker; breast neoplasms; chelating agents; chemical structure function; chemical synthesis; colon neoplasms; contrast media; diagnosis design /evaluation; disease /disorder model; enzyme activity; gadolinium; genetically modified animals; laboratory mouse; magnetic resonance imaging; metalloendopeptidases; neoplasm /cancer; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; noninvasive diagnosis; pharmacokinetics; solubility; technology /technique development; water

DESCRIPTION (provided by applicant): The goal of this Phase I STTR project is to design, synthesize, and test a new class of biochemically activated magnetic resonance imaging (MRI) contrast agents to detect and monitor enzymatic activity in vivo. The proposal responds to the Program Announcement entitled "Systems and methods for small animal imaging". We base this work on the hypothesis that activation of MRI contrast agents by extracellular proteases represents a particularly promising strategy to detect and image biochemical processes relevant to cancer. This represents a multi-disciplinary effort that brings together expertise in cancer biology, chemistry, enzymology, and physics at industrial and academic institutions to achieve the stated goals; specifically, we propose to determine if tumor-associated matrix metalloproteinase (MMP) activity can be non-invasively imaged by MRI in preclinical models of human cancer. We will approach the generation and testing of reagents useful for MRI detection of protease targets in Phase I of the project with the following specific aims: 1) Design and produce a gadolinium-chelate MRI contrast agent (Proteolytic Contrast Agent, PCA) that has decreased aqueous solubility following MMP cleavage of the agent; 2) Characterize the pharmacodynamic properties of both uncleaved and protease-cleaved PCAs in the context of in vivo mouse models of cancer. The success of the Phase I project will be judged by the completion of two well-defined milestones: 1) Preparation of one or more Gd-based MRI contrast agents that exhibit in vitro at least a 10-fold decrease in aqueous solubility in response to proteolytic cleavage by MMP; and 2) Collection of MRI data in vivo demonstrating a statistical difference in the value of k(out), the efflux transfer rate from the tumor, between MMP-positive and MMP-negative tumors and/or relative to that measured with an uncleavable analog in at least one of two mouse models of human cancer, i.e., by demonstrating a measured difference in the temporal response of the MRI contrast referable to proteolytic cleavage of the PCA. The success of this project has the potential for improved non-invasive detection and evaluation of cancer in small animals and eventually in patients. It provides the basis for Phase II of the project, with the overall goal of developing a commercial PCA product or products to provide for non-invasive clinical assessment to benefit patients with cancer, as well as to advance the use of MRI for functional imaging in clinical practice.

描述（由申请人提供）： 该阶段ISTTR项目的目的是设计，合成和测试一类新的生化磁共振成像（MRI）对比剂，以检测和监测体内的酶活性。该提案回应了题为“小动物成像的系统和方法”的计划公告。我们基于以下假设，即通过细胞外蛋白酶激活MRI对比剂是一种与癌症相关的生化过程的特别有希望的策略。这代表了一项多学科的工作，该努力将工业和学术机构的癌症生物学，化学，酶学和物理学方面的专业知识融合在一起，以实现既定目标；具体而言，我们建议确定与肿瘤相关的基质金属蛋白酶（MMP）活性是否可以由MRI在人类癌的临床前模型中无创地成像。我们将采用以下特定目的在项目I期中的MRI检测蛋白酶靶标有用的试剂的生成和测试：1）设计和生成降低的Gadolinium-Chelate MRI对比剂（蛋白水解对比剂，PCA）已减少MMP裂解后的水溶性； 2）在体内癌症模型的背景下，未裂解和蛋白酶切割的PCA的药效学特性均表征。第一阶段项目的成功将根据两个定义明确的里程碑的完成来判断：1）制备一种或多种基于GD的MRI对比剂，在体外表现出至少降低了10倍的水溶性，而水溶性则响应于MMP蛋白水解裂解； 2）在体内收集MRI数据，证明了K（OUT）的统计差异，MMP阳性和MMP阴性肿瘤之间的肿瘤的外排转移速率和/或相对于用无法解决的模拟测量的统计差异在两个小鼠人类癌症模型中的至少一种中，即通过证明MRI对比度的时间响应的测得差异可引用于PCA的蛋白水解裂解。该项目的成功有可能改善小动物和患者最终对癌症的非侵入性检测和评估。它为项目的第二阶段提供了基础，其总体目标是开发商业PCA产品或产品，以提供非侵入性临床评估以使患者受益，并促进在MRI中使用MRI进行功能成像临床实践。