PARACEST agents for molecular imaging of cancer by MRI

通过 MRI 对癌症进行分子成像的 PARACEST 药物

• 批准号: 7110193
• 负责人: Dean Sherry
• 金额: $ 27.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110193
• 关键词: SCID mouse; antibody; athymic mouse; bioimaging /biomedical imaging; chemical binding; chemical kinetics; chemical synthesis; contrast media; hypoxia; imaging /visualization /scanning; ligands; magnetic resonance imaging; molecular /cellular imaging; molecular probes; neoplastic cell; reduction; small molecule; virus protein

DESCRIPTION (provided by applicant): MRI is the imaging modality of choice for soft tissue imaging but in general lacks sufficient sensitivity for molecular imaging of biological processes associated with cancer. Although Gd-based contrast agents are widely used in clinical MRI as non-specific extracellular agents, new approaches need to be developed to bring MRI into competition with optical and nuclear molecular imaging modalities. Paramagnetic complexes based on chemical exchange saturation transfer (PARACEST) offer a new mechanism for MRI contrast that could potentially improve sensitivity substantially and at the same time offer the unique ability to modulate imaging contrast (on/off) plus reflect specific tissue environments or physiology (pH, redox state, glucose levels). The first aim is to develop bifunctional ligands based on PARACEST for attachment to protein surface residues. These will be attached to model proteins and the water exchange characteristics of the resulting products will be evaluated and the lower detection limit of these systems evaluated by MRI. Two specific targeting systems will be evaluated, a phosphatidyl serine antibody and adenovirus particles with modified knob domain proteins, with the goal of creating activatible PARACEST systems that are completely "off" unless bound to their intended targets in vivo. A PARACEST agent will be developed that is trapped only in hypoxic tumor cells. The overriding goal of this project is to develop a new paradigm of molecular imaging agents for anatomical MR imaging of cancer based upon high sensitivity PARACEST agents.

描述（由申请人提供）：MRI 是软组织成像的首选成像方式，但通常对与癌症相关的生物过程的分子成像缺乏足够的灵敏度。尽管基于 Gd 的造影剂作为非特异性细胞外试剂广泛用于临床 MRI，但仍需要开发新方法以使 MRI 与光学和核分子成像模式竞争。基于化学交换饱和转移 (PARACEST) 的顺磁性复合物提供了一种新的 MRI 对比度机制，可以显着提高灵敏度，同时提供调节成像对比度（开/关）以及反映特定组织环境或生理学的独特能力。 pH、氧化还原状态、葡萄糖水平）。第一个目标是开发基于 PARACEST 的双功能配体，用于附着在蛋白质表面残基上。这些将附着在模型蛋白质上，并评估所得产品的水交换特性，并通过 MRI 评估这些系统的检测下限。将评估两种特定的靶向系统，即磷脂酰丝氨酸抗体和带有修饰的旋钮结构域蛋白的腺病毒颗粒，目的是创建可激活的 PARACEST 系统，除非与体内的预期靶标结合，否则该系统完全“关闭”。将开发一种仅捕获在缺氧肿瘤细胞中的 PARACEST 剂。该项目的首要目标是基于高灵敏度 PARACEST 试剂开发一种新的分子成像剂范例，用于癌症解剖 MR 成像。