Imaging of Tumor-Associated Macrophages with Ferumoxytol

描述（由申请人提供）：本研究是为了响应国家生物医学成像和生物工程研究所（“生物医学成像纳米技术的研究和开发”）和国家癌症研究所（“利用成像早期发现疾病”）的使命。乳腺癌基质中的炎症免疫反应已被确定为乳腺癌发生和发展的主要促进因素。组织病理学评估显示，乳腺癌基质中肿瘤相关巨噬细胞（TAM）的存在和数量与肿瘤侵袭性和不良预后密切相关。我们项目的主要目标是开发一种新的无创诊断方法，用于选择性靶向和可视化乳腺癌中的TAM，基于磁共振（MR）成像和fda批准的氧化铁纳米颗粒化合物阿鲁莫木醇（FerahemeTM，水动力直径28- 32nm）。实现这一目标将导致开发一种新的无创检测乳腺癌基质中TAM浸润的方法，该方法可用于预测乳腺癌患者的肿瘤进展和不良预后，并为这些患者分配个性化的治疗方案。值得注意的是，只有少数基于纳米颗粒的药物处于可以应用于临床环境的开发阶段。Feraheme已获fda批准用于治疗缺铁，原则上可用于乳腺癌患者的“标签外”转化应用。该成像方法依赖于静脉给药阿魏木糖醇在乳腺癌中的肿瘤微血管通透性、间质保留和TAM吞噬。TAM中被吞噬的纳米颗粒引起局部磁场的改变，在静脉注射纳米颗粒24小时后，可以在“延迟”t2加权MR图像上检测到信号强度下降的区域。在一个循序渐进的方法中，我们将首先在体外比较乳腺癌细胞和不同TAM群体的定量阿魏木糖醇摄取和MR信号增强，然后将乳腺癌在MR图像上的阿魏木糖醇增强与乳腺癌动物模型中肿瘤组织中TAM的数量联系起来，最后将乳腺癌阿魏木糖醇摄取和MR增强与组织病理学上的肿瘤分级联系起来。通过开发一种新的成像技术，为乳腺癌免疫反应和侵袭性提供了一种非侵入性的测量方法，我们期望显著提高我们在体内表征乳腺癌生物学的能力，为患者分配个性化的治疗方案，开发和监测新的抗炎疗法，最终改善乳腺癌患者的长期预后。

DESCRIPTION (provided by applicant): This study is in response to the mission of the National Institute of Biomedical Imaging and Bioengineering ("Research and development of nano-scale technologies for biomedical imaging") and the National Cancer Institute ("Early detection of disease using imaging"). The inflammatory immune response in breast cancer stroma has been identified as a major promoting factor for breast cancer carcinogenesis and progression. Histopathologic evaluations showed that the presence and quantity of tumor-associated macrophages (TAM) in breast cancer stroma correlates strongly with tumor aggressiveness and poor outcome. The major goal of our project is to develop a new and non-invasive diagnostic assay for selective targeting and visualization of TAM in breast cancer, based on magnetic resonance (MR) imaging and the FDA-approved iron oxide nanoparticle compound ferumoxytol (FerahemeTM, hydrodynamic diameter 28-32 nm). Realization of this goal will lead to the development of a novel and non- invasive assay for TAM infiltration in breast cancer stroma, which could be utilized to predict tumor progression and poor outcome in breast cancer patients and assign these patients to individualized therapeutic options. Of note, only few nanoparticle-based drugs are in a stage of development where they can be applied in a clinical setting. Feraheme is FDA-approved for the treatment of iron deficiency and would be in principle applicable for "off label" translational applications in patients with breast cancer. The imaging approach relies on the tumor microvascular permeability, interstitial retention and TAM phagocytosis of intravenously administered ferumoxytol in breast cancers. The phagocytosed nanoparticles in TAM cause alterations of local magnetic fields, which can be detected as areas of decreased signal intensity on "delayed" T2-weighted MR images, 24 hours after intravenous nanoparticle administration. In a step-by-step approach, we will first compare the quantitative ferumoxytol uptake and MR signal enhancement of breast cancer cells and different populations of TAM in vitro, then correlate the ferumoxytol-enhancement of breast cancers on MR images with the quantity of TAM in the tumor tissue in animal models of breast cancer and finally correlate breast cancer ferumoxytol uptake and MR enhancement in vivo with tumor grade on histopathology. By exploiting a novel imaging technique that provides a non-invasive measure for breast cancer immune response and aggressiveness, we anticipate to significantly improving our ability to characterize breast cancer biology in vivo, to assign patients to individualized therapeutic options, develop and monitor new anti-inflammatory therapies and ultimately, improve long term outcomes of patients with breast cancer. PUBLIC HEALTH RELEVANCE: Tumor associated macrophages are immune-system cells in breast cancer tissue, which correlate strongly with more aggressive tumors and worse long term prognosis. Currently, tumor aggressiveness is evaluated by histology and immunochemistry, both of which require tumor tissue either from a biopsy or surgery. The goal of this project is to investigate the ability of a non-invasive imaging method, based on magnetic resonance imaging and the FDA approved nanoparticle ferumoxytol, to detect tumor associated macrophages in breast cancer. This could be used to assign patients with more aggressive tumors to individualized therapeutic options, develop and monitor new anti-inflammatory therapies and ultimately improve long term outcomes.