Imaging of Tumor-Associated Macrophages with Ferumoxytol

描述（由申请人提供）：本研究是对国家生物医学成像和生物工程研究所（“生物医学成像纳米级技术的研究和开发”）和国家癌症研究所（“使用成像早期检测疾病”）的使命的响应。乳腺癌间质中的炎性免疫反应已被确定为乳腺癌发生和进展的主要促进因素。组织学评价显示，乳腺癌间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结局密切相关。我们项目的主要目标是开发一种新的非侵入性诊断检测方法，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ferumoxytol（Feraheme TM，流体动力学直径28-32 nm）。这一目标的实现将导致开发一种用于乳腺癌间质中TAM浸润的新型非侵入性测定法，其可用于预测乳腺癌患者的肿瘤进展和不良结局，并将这些患者分配给个体化治疗选择。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被FDA批准用于治疗铁缺乏症，并且原则上适用于乳腺癌患者的“标签外”转化应用。成像方法依赖于乳腺癌中静脉内施用的ferumoxytol的肿瘤微血管渗透性、间质滞留和TAM吞噬作用。TAM中吞噬的纳米颗粒引起局部磁场的改变，这可以在静脉内纳米颗粒给药后24小时在“延迟”T2加权MR图像上检测到信号强度降低的区域。在逐步的方法中，我们将首先比较乳腺癌细胞和TAM的不同群体在体外的定量ferumoxytol摄取和MR信号增强，然后将乳腺癌在MR图像上的ferumoxytol增强与乳腺癌动物模型中肿瘤组织中TAM的量相关联，最后将乳腺癌ferumoxytol摄取和体内MR增强与组织病理学上的肿瘤分级相关联。通过利用一种新的成像技术，为乳腺癌免疫反应和侵袭性提供非侵入性测量，我们预计将显着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，并最终改善乳腺癌患者的长期预后。 公共卫生相关性： 肿瘤相关巨噬细胞是乳腺癌组织中的免疫系统细胞，其与更侵袭性的肿瘤和更差的长期预后密切相关。目前，肿瘤的侵袭性是通过组织学和免疫化学来评估的，这两种方法都需要来自活检或手术的肿瘤组织。该项目的目标是研究基于磁共振成像和FDA批准的纳米颗粒ferumoxytol的非侵入性成像方法检测乳腺癌中肿瘤相关巨噬细胞的能力。这可用于将更具侵袭性的肿瘤患者分配给个性化的治疗方案，开发和监测新的抗炎疗法，并最终改善长期结果。

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.