Magnetic probes for in vivo molecular imaging

描述（由申请人提供）：拟议研究的目的是开发一种实时监测药物传递和作用的体内方法，结合药物对特定细胞类型和细胞内靶点的精确靶向。将开发一种磁性探针，通过双层靶向方法特异性定位淋巴瘤细胞。首先，配体将以共价连接到探针上。这种配体将通过受体介导的内吞作用直接定位到淋巴瘤细胞。由肽组成的第二配体将以共价连接单个探针。这种肽含有一个位点，可以被淋巴瘤细胞中过度表达的细胞内蛋白酶切割。当肽被切割时，探针解离并且它们的磁性改变。活体动物的磁共振成像可以很容易地检测到这种变化。一旦淋巴瘤细胞通过这种方法被准确地靶向和检测到，类似的机制将被用来靶向特定的药物。例如，将蛋白酶抑制剂施用于目标细胞。药物活性的实时反馈是通过共同管理蛋白酶报告探针实现的。最终目标是有效地将该技术从小鼠转化为人类，以无创地表征药物作用。

DESCRIPTION (provided by applicant): The objective of the proposed research is to develop an in vivo method for monitoring drug delivery and action in real time, in combination with precise targeting of drugs to specific cell types and intracellular targets. A magnetic probe will be developed that specifically localizes to lymphoma cells via a two-tiered targeting method. First, a ligand will be covalently attached to the probes. This ligand will direct localization to lymphoma cells via receptor-mediated endocytosis. A second ligand composed of a peptide will covalently link individual probes. This peptide contains a site that can be cleaved by an intracellular protease that is overexpressed in lymphoma cells. When the peptide is cleaved, the probes dissociate and their magnetic properties change. Magnetic resonance imaging in a living animal can easily detect this change. Once the lymphoma cells are faithfully targeted and detected via this method, a similar mechanism will be employed to target a specific drug. For example, protease inhibitors will be administered to the targeted cell. Real-time feedback of drug activity is achieved by co-administering the protease-reporter probes. The ultimate goal is to efficiently translate the technique from mice to humans for noninvasive characterization of drug action.