Molecular Imaging of Macrophage Infiltration in Solid Cancers

描述（由申请人提供）：尽管患者发病率和死亡率仍然相对较高，但癌症治疗占医疗保健费用水平的增加。目前用于评估免疫细胞浸润到癌症中的程度的方法需要侵入性活检程序，该程序不能随着时间的推移在同一肿瘤上进行，因此排除了对患者免疫应答的纵向跟踪。在目前的项目中，我们建议开发一种新的分子成像探针，用于可视化巨噬细胞浸润到肿瘤中。具体而言，我们的目标是开发一种针对MHCII阳性巨噬细胞的分子标记物的微泡造影剂，该分子标记物被认为是肿瘤排斥反应的指示。在这个I期计划中，我们将使用抗小鼠MHC II类抗体作为靶向配体。抗体将使用经证实的生物相容性偶联化学偶联到超声分子成像剂的表面。我们将验证配体缀合和微泡稳定性，并评估所得微泡制剂在体外和肿瘤进展的小鼠模型中的靶向功效。我们将使用这种显像剂来定量跟踪肿瘤排斥和生长的配对小鼠模型中巨噬细胞的流入。这些目标的成功完成将导致分子成像探针，可用于准确和快速地鉴定肿瘤浸润巨噬细胞的质量和数量，其应用既可作为科学研究试剂，也可作为临床诊断试剂。

DESCRIPTION (provided by applicant): Treatment of cancer accounts for an increasing level of healthcare expense although patient morbidity and mortality remain relatively high. Current methods for assessing the extent of immune cell infiltration into cancers require invasive biopsy procedures that cannot be done on the same tumor over time, thus precluding longitudinal tracking of immune responses in patients. In the current project, we propose to develop a novel molecular imaging probe for visualization of macrophage infiltration into tumors. Specifically, we aim to develop a microbubble contrast agent targeted to a molecular marker of MHCII positive macrophages, thought to be indicative of a tumor rejection response. In this Phase I proposal, we will use an anti-mouse MHC class II antibody as a targeting ligand. Antibodies will be conjugated to the surface of an ultrasound molecular imaging agent using proven biocompatible coupling chemistry. We will validate ligand conjugation and microbubble stability, and assess the targeting efficacy of the resultant microbubble formulations in vitro and in a mouse model of tumor progression. We will use this imaging agent to quantitatively track the influx of macrophages in paired mouse models of tumor rejection and growth. Successful completion of these aims will result in a molecular imaging probe that may be used to accurately and rapidly identify the quality and quantity of tumor infiltrating macrophages, with applications as both a lie science research reagent and as a clinical diagnostic.