Imaging B Cells with Gd-Labeled Dendrimer Nanoclusters

描述（由申请人提供）：近年来，越来越多的人关注使用b细胞消耗疗法作为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取决于确定b细胞消耗与临床反应的关系以及个体患者应该如何给药的方法。到目前为止，通常对患者进行外周血B细胞的定量检测；然而，这一措施显然不能充分反映身体其他部位发生的情况。能够在体内多个器官中重复成像B细胞，具有良好的空间分辨率和高灵敏度，将为这一目的提供一个很好的生物标志物。本提案的总体目标是开发gd共轭树突状纳米簇作为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。使用单克隆抗体（mAb）来消耗b细胞，我们将在小鼠身上测试这些技术。提出了三个具体目标：(1)合成具有多种物理和磁性能的靶向B细胞的gd共轭树状聚合物纳米团簇（dnc）；(2)评价不同dnc在小鼠体内的造影剂增强、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。

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.