Imaging B Cells with Gd-Labeled Dendrimer Nanoclusters

描述（由申请人提供）：近年来，越来越多的注意力集中在使用B细胞耗竭疗法作为自身免疫性疾病的治疗选择上。这些方法的进一步发展似乎将取决于确定B细胞耗竭与临床应答的关系以及个体患者应如何给药的方法。到目前为止，患者通常通过外周血B细胞的定量进行随访;然而，这种测量显然不能充分反映身体其他部位发生的情况。在体内以良好的空间分辨率和高灵敏度对多个器官中的B细胞重复成像的能力将为此目的提供优异的生物标志物。该提案的总体目标是开发Gd缀合的树枝状聚合物纳米簇作为B细胞靶向的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，我们将在小鼠中测试这些技术。提出了三个具体目标：（1）合成具有各种物理和磁性的靶向B细胞的Gd缀合的树枝状聚合物纳米簇（DNC）;（2）评价小鼠中各种DNC的对比度增强、循环时间、生物分布和消除;（3）评价监测小鼠中B细胞消耗的能力。 公共卫生相关性：我们建议开发Gd-共轭树枝状聚合物纳米簇作为B细胞靶向的T1磁共振（MR）成像造影剂，用于淋巴器官中B细胞的定量。MR成像研究将用于监测接受抗CD 20抗体治疗的小鼠脾脏中的B细胞耗竭。

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.