Imaging B Cells with Gd-Labeled Dendrimer Nanoclusters

摘要 近年来，B细胞耗竭治疗作为一种治疗手段受到越来越多的关注。 自身免疫性疾病的治疗选择。看来，这些方法的进一步发展将 依赖于一种方法学来确定B细胞耗竭与临床反应的关系以及个体 应该给病人服药。到目前为止，患者一般都进行了外周血的量化。 B细胞；然而，这一测量显然不能充分反映身体其他部位正在发生的事情。 能够在体内多个器官内重复成像B细胞，具有良好的空间分辨率和高分辨率 敏感性，将为这一目的提供一个极好的生物标志物。这项提案的总体目标是 制备Gd-树枝状大分子纳米团簇作为B细胞靶向T1磁共振成像 淋巴器官中B细胞定量的造影剂。使用单抗(MAb)来 耗尽B细胞，我们将在小鼠身上测试这些技术。提出了三个具体的目标：(1)合成B细胞。 具有各种物理和磁性的靶向、Gd共轭树枝状大分子纳米团簇(DNC)；(2) 评价不同类型DNC的增强、循环时间、生物分布和消除情况 (3)评价监测小鼠B细胞耗竭的能力。

Abstract In recent years, increasing attention has been directed towards the use of B-cell depletion therapy as a treatment option in autoimmune disorders. It appears that the further development of these approaches will depend on a methodology to determine the relation of B-cell depletion to clinical response and how individual patients should be dosed. Thus far, patients have generally been followed by quantification of peripheral blood B cells; however, this measure clearly does not adequately reflect what is happening in the rest of the body. The ability to image B cells in multiple organs in vivo, repeatedly and with good spatial resolution and high sensitivity, would provide an excellent biomarker for this purpose. The overall goal of this proposal is to develop Gd-conjugated dendrimer nanoclusters as B-cell targeted T1 magnetic resonance (MR) imaging contrast agents for the quantification of B cells in lymphoid organs. Using monoclonal antibodies (mAb) to deplete B-cells, we will test these techniques in mice. Three specific aims are proposed: (1) Synthesize B cell- targeted, Gd-conjugated dendrimer nanoclusters (DNCs) with various physical and magnetic properties; (2) Evaluate the contrast enhancement, circulation time, biodistribution, and elimination of the various DNCs in mice; (3) Evaluate the ability to monitor B-cell depletion in mice.