MR AGENTS SENSITIVE TO BIOLOGICAL INDICATORS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目的主要目标是开发顺磁性化学交换饱和转移（PARACEST）成像剂结合到抗体表面时的应用，并作为缺氧的小分子传感器。MRI是软组织成像的首选成像模式，但通常缺乏足够的灵敏度，用于与癌症相关的生物过程的分子成像。虽然钆基造影剂作为非特异性细胞外试剂广泛用于临床MRI，但需要开发新的方法来使MRI与光学和核分子成像模式竞争。 基于化学交换饱和转移（PARACEST）的顺磁性复合物为MRI对比度提供了一种新的机制，其可以潜在地显著提高灵敏度，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（pH、氧化还原状态、葡萄糖水平）的独特能力。 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。 这些将附着于模型蛋白质，并将评价所得产物的水交换特性，并通过MRI评价这些系统的检测下限。 将评估两种特异性靶向系统，磷脂酰丝氨酸抗体和具有修饰的结结构域蛋白的腺病毒颗粒，其目标是创建可活化的PARACEST系统，该系统完全“关闭”，除非在体内与其预期靶标结合。 将开发仅在缺氧肿瘤细胞中捕获的PARACEST试剂。 该项目的首要目标是开发一种新的分子成像剂的范例，用于基于高灵敏度PARACEST剂的癌症解剖MR成像。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.