Imaging B Cells with Gd-Labeled Dendrimer Nanoclusters

描述(由申请人提供)：近年来，B细胞耗竭治疗作为自身免疫性疾病的一种治疗选择受到越来越多的关注。看来，这些方法的进一步发展将取决于一种方法学，以确定B细胞耗竭与临床反应的关系，以及个体患者应该如何给药。到目前为止，患者一般都会对外周血B细胞进行量化；然而，这种测量显然不能充分反映身体其他部位正在发生的事情。在活体内对多个器官中的B细胞进行重复成像的能力，具有良好的空间分辨率和高灵敏度，将为这一目的提供良好的生物标志物。这项建议的总体目标是开发Gd-偶联树枝状大分子纳米簇作为B细胞靶向T1磁共振(MR)成像对比剂，用于定量淋巴器官中的B细胞。使用单抗去除B细胞，我们将在小鼠身上测试这些技术。提出了三个特定的目标：(1)合成具有不同物理和磁性的B细胞靶向、Gd偶联的树枝状大分子纳米簇(DNCs)；(2)评估各种DNCs在小鼠体内的对比度增强、循环时间、生物分布和消除；(3)评估监测小鼠B细胞耗竭的能力。 公共卫生相关性：我们建议开发Gd-偶联树枝状大分子纳米簇作为B细胞靶向T1磁共振(MR)成像造影剂，用于定量淋巴器官中的B细胞。磁共振成像研究将用于监测接受抗CD20抗体治疗的小鼠脾中B细胞的消耗情况。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We propose 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. MR imaging studies will be used to monitor B cell depletion in the spleen of mice subject to anti-CD20 antibody therapy.