Imaging of Tumor-Associated Macrophages with Ferumoxytol

描述(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(“生物医学成像纳米级技术的研究和开发”)和国家癌症研究所(“利用成像技术早期发现疾病”)的使命。乳腺癌间质中的炎性免疫反应已被认为是乳腺癌发生发展的主要促进因素。组织病理学评估表明，乳腺癌间质中肿瘤相关巨噬细胞()的存在和数量与肿瘤的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非侵入性诊断方法，用于乳腺癌的选择性靶向和可视化，基于磁共振(MR)成像和FDA批准的氧化铁纳米化合物阿魏酸甘油(FerahemeTM，流体力学直径28-32 nm)。这一目标的实现将导致开发一种新的非侵入性检测乳腺癌间质中浸润的方法，该方法可以用来预测乳腺癌患者的肿瘤进展和不良预后，并将这些患者分配给个性化的治疗方案。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的开发阶段。Feraheme是FDA批准的用于治疗铁缺乏的药物，原则上将适用于乳腺癌患者的“标签外”翻译应用。其成像途径依赖于肿瘤微血管通透性、间质滞留和静脉注射阿魏酸甘油酯的吞噬功能。体内的吞噬纳米颗粒会引起局部磁场的变化，在静脉注射纳米颗粒24小时后，可以在“延迟的”T2加权磁共振图像上检测到局部磁场强度降低。我们将采用循序渐进的方法，首先在体外比较乳腺癌细胞和不同人群对阿魏醇的摄取和MR信号增强，然后在乳腺癌动物模型中将乳腺癌在MR图像上的阿魏醇增强与肿瘤组织中的数量相关联，最后将乳腺癌阿魏醇摄取和体内MR增强与组织病理学分级相关联。通过开发一种新的成像技术，为乳腺癌的免疫反应和侵袭性提供非侵入性测量，我们预计将显著提高我们在体内表征乳腺癌生物学特征的能力，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结果。 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，与更具侵袭性的肿瘤和更差的长期预后密切相关。目前，肿瘤侵袭性的评估是通过组织学和免疫化学来进行的，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一种基于磁共振成像和FDA批准的纳米阿魏酸缩醇的非侵入性成像方法，以检测乳腺癌中肿瘤相关巨噬细胞的能力。这可以用来为有更多侵袭性肿瘤的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.