Magnetic probes for in vivo molecular imaging

描述（由申请人提供）：拟定研究的目的是开发一种体内方法，用于真实的实时监测药物递送和作用，并将药物精确靶向至特定细胞类型和细胞内靶标。将开发一种磁性探针，通过两层靶向方法特异性定位于淋巴瘤细胞。首先，配体将共价连接到探针。该配体将通过受体介导的内吞作用直接定位于淋巴瘤细胞。由肽组成的第二配体将共价连接各个探针。该肽含有可被在淋巴瘤细胞中过表达的细胞内蛋白酶切割的位点。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。一旦通过这种方法忠实地靶向和检测淋巴瘤细胞，将采用类似的机制来靶向特定药物。例如，将蛋白酶抑制剂施用至靶细胞。药物活性的实时反馈通过共同施用蛋白酶-报告探针来实现。最终目标是将该技术从小鼠有效地转化为人类，用于药物作用的非侵入性表征。

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.