Imaging of Tumor-Associated Macrophages with Ferumoxytol

使用 Ferumoxytol 对肿瘤相关巨噬细胞进行成像

• 批准号: 8018215
• 负责人: Heike Elizabeth Daldrup-Link
• 金额: $ 21.67万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-03 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018215
• 关键词: Adjuvant Chemotherapy; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Award; Axillary lymph node group; Biological Assay; Biopsy; Breast Cancer Cell; Caliber; Cancer Biology; Cancer Etiology; Cancer Patient; Cell Proliferation; Cells; Cessation of life; Clinical; Collaborations; Contrast Media; Development; Diagnostic; Disease; ERBB2 gene; Early Diagnosis; Equipment; Evaluation; FDA approved; Goals; Histologic; Histology; Histopathology; Hormone Receptor; Hour; Human; Image; Imagery; Imaging Techniques; Immune response; Immune system; Immunochemistry; Immunohistochemistry; In Vitro; Infiltration; Inflammatory; Intravenous; Iron; Label; Lead; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Menopausal Status; Microvascular Permeability; Mission; Mitogens; Monitor; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering; Neoplasms; Nodal; Operative Surgical Procedures; Outcome; Patients; Peptide Hydrolases; Phagocytosis; Pharmaceutical Preparations; Phenotype; Population; Prognostic Marker; Research; Research Personnel; Role; Signal Transduction; Staging; Technology; Therapeutic; Tissues; Transgenic Animals; Tumor Pathology; Tumor Tissue; United States; Universities; Weight; Woman; Xenograft procedure; angiogenesis; base; bioimaging; carcinogenesis; cytokine; ferumoxytol; imaging modality; improved; in vivo; insight; interstitial; iron oxide; macrophage; magnetic field; malignant breast neoplasm; molecular imaging; nanoparticle; nanoscale; neoplastic cell; novel; novel diagnostics; outcome forecast; prognostic; radiologist; research and development; response; tool; tumor; tumor progression; uptake

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.

描述（由申请人提供）：这项研究是针对国家生物医学成像与生物工程研究所的使命（“生物医学成像的纳米级技术的研究与开发”）和国家癌症研究所（“使用成像的疾病早期发现”）。乳腺癌基质中的炎症免疫反应已被确定为乳腺癌致癌和进展的主要促进因子。组织病理学评估表明，乳腺癌基质中与肿瘤相关的巨噬细胞（TAM）的存在和数量与肿瘤侵袭性和预后不良密切相关。我们项目的主要目的是基于磁共振成像（MR）成像和FDA批准的氧化铁纳米粒子化合物化合物铁氧基酚（Ferahemetm，Ferahemetm，FerahemetM，流体动力学28-32 Nm），开发了一种新的且非侵入性的诊断测定，用于乳腺癌中TAM的选择性靶向和可视化TAM。实现这一目标将导致乳腺癌基质中TAM浸润的新颖和非侵入性测定的发展，该测定法可以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选择。值得注意的是，只有少量的基于纳米颗粒的药物处于开发阶段，可以在临床环境中应用它们。 Feraheme已通过FDA批准用于治疗铁缺乏症，原则上适用于乳腺癌患者的“关闭标签”翻译应用。成像方法依赖于肿瘤微血管通透性，间质保留和TAM吞噬作用的静脉内吞噬乳腺癌的吞噬作用。 TAM中的吞噬细胞纳米颗粒会导致局部磁场的改变，这可以检测为静脉内纳米粒子给药后24小时，在“延迟” T2加权MR图像上降低了信号强度的区域。在逐步的方法中，我们首先将比较乳腺癌细胞和MR信号增强的乳腺癌细胞和不同人群的TAM体外人群，然后将乳腺癌对乳腺癌增强的MR图像上的乳腺癌增强与MR图像的乳腺癌与乳腺癌的肿瘤模型中的TAM量相关，并与乳腺癌的肿瘤模型相关联。组织病理学肿瘤等级。通过利用一种新型的成像技术，该技术为乳腺癌免疫反应和侵略性提供了非侵入性措施，我们预计将显着提高我们表征体内乳腺癌生物学的能力，将患者分配到个性化的治疗选择，发展和监测新的抗炎疗法，并最终改善患有乳腺癌患者的长期患者。 公共卫生相关性：肿瘤相关的巨噬细胞是乳腺癌组织中的免疫系统细胞，它们与更具侵略性的肿瘤密切相关，长期预后较差。目前，通过组织学和免疫化学评估肿瘤侵袭性，这两者都需要活检或手术的肿瘤组织。该项目的目的是基于磁共振成像和FDA认可的纳米颗粒铁氧毒醇，研究非侵入性成像方法的能力，检测乳腺癌中肿瘤相关的巨噬细胞。这可以用来将具有更侵略性肿瘤的患者分配给个性化的治疗选择，开发和监测新的抗炎疗法，并最终改善长期结局。