MR AGENTS SENSITIVE TO BIOLOGICAL INDICATORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的主要目标是开发顺磁化学交换饱和转移(PARACEST)显像剂在抗体表面结合和作为低氧小分子传感器的应用。MRI是软组织成像的首选成像方式，但通常缺乏足够的灵敏度来对与癌症相关的生物过程进行分子成像。尽管基于Gd的造影剂作为非特异性细胞外造影剂被广泛应用于临床MRI，但需要开发新的方法来使MRI与光学和核分子成像方式竞争。基于化学交换饱和转移的顺磁复合物(PARACEST)提供了一种新的磁共振成像对比度的机制，可以显著提高灵敏度，同时提供独特的能力来调节成像对比度(开/关)以及反映特定的组织环境或生理(pH、氧化还原状态、血糖水平)。第一个目标是开发基于PARACEST的双功能配体，用于连接到蛋白质表面残基。这些将被附着在模型蛋白质上，并将评估结果产物的水交换特性，以及通过核磁共振对这些系统的检测下限进行评估。将对两种特定的靶向系统进行评估，一种是磷脂酰丝氨酸抗体，另一种是带有修饰的结节结构域蛋白的腺病毒颗粒，目标是创建可激活的PARACEST系统，除非与体内预期的目标结合，否则它们是完全“关闭”的。将开发一种仅捕获在缺氧肿瘤细胞中的PARACEST试剂。该项目的首要目标是开发一种基于高灵敏度PARACEST试剂的用于癌症解剖磁共振成像的新的分子成像试剂范例。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major goals of this project are to develop applications of paramagnetic chemical exchange saturation transfer (PARACEST) imaging agents when bound to antibody surfaces and as small molecule sensors of hypoxia. 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.