Detection of micrometastasis using a dual-ligand nanoparticle

使用双配体纳米颗粒检测微转移

• 批准号: 8557669
• 负责人: Efstathios Karathanasis
• 金额: $ 32.2万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8557669
• 关键词: Affect; Animals; Avidity; Blinded; Blood Vessels; Breast Cancer Model; Case Study; Cessation of life; Chemicals; Clinical; Contrast Media; Coupled; Data; Detection; Development; Diagnostic; Dimensions; Disease; Disseminated Malignant Neoplasm; Dose; Endothelial Cells; Endothelium; Epidermal Growth Factor Receptor; Exhibits; Fluorescence; Gold; Image; Immunohistochemistry; In Vitro; Integrin Binding; Integrins; Label; Length; Ligands; Link; Liver; Lung; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Mammary Neoplasms; Metastatic Lesion; Metastatic to; Microcirculation; Micrometastasis; Modeling; Molecular; Mus; Nanosphere; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Peptides; Perception; Physicians; Population; Probability; Radiosurgery; Reading; Shapes; Signal Transduction; Site; Specificity; Staging; System; Technology; Testing; Treatment outcome; Variant; Width; Work; bioluminescence imaging; cancer cell; cancer type; density; design; diagnostic accuracy; effective intervention; fluorescence imaging; human disease; improved; in vivo; iron oxide; malignant breast neoplasm; nanoparticle; overexpression; public health relevance; radiologist; receptor; tomography; triple-negative invasive breast carcinoma; tumor; vascular bed

DESCRIPTION (provided by applicant): The vast majority of cancer deaths are due to metastatic disease. While effective interventions (e.g. surgery, radiation) strongly depend on our ability to detect disseminated disease at an early stage, imaging micrometastases hidden in a large population of normal cells presents a unique challenge. We seek to design a dual-ligand nanoparticle capable of 'sensing' the endothelium associated with a metastasis. By selecting two appropriate chemical specificities, a dual-ligand strategy can provide both synergistic amplification of nanoparticle targeting to micrometastases expressing both receptors but also detection of metastatic tumors expressing only one receptor that would be otherwise missed using a single-ligand strategy. Our central hypothesis is that a dual-ligand nanoparticle coupled with a vascular targeting strategy offer an increased likelihood of highly sensitive and specific recognition of micrometastasis. The nanoparticle is comprised of iron oxide nanospheres chemically linked into a linear nanochain. We hypothesize that the dual- ligand strategy will not only enhance the targeting specificity towards regions that express both receptors, but also 'capture' metastatic regions in which only one of the two receptors is predominantly expressed. Since the shape and size of nanoparticles govern their margination and attachment to the vascular bed, we also hypothesize that the aspect ratio and overall dimensions of the nanochain can be optimized, resulting in early and accurate detection of metastatic disease. We will test our hypotheses with the following Specific Aims: Specific Aim 1: Optimize the design of dual-ligand nanochains to perform vascular targeting under flow conditions of the microcirculation in vitro. We seek to optimize the design of nanochains in terms of their length, width and density of the two targeting peptides. The margination and targeting avidity of the nanochains will be evaluated in microchannel networks seeded with endothelial and cancer cells at different flow rates. Specific Aim 2: Test the ability of the dual-ligand nanochains to recognize the microenvironment of micrometastasis in the 4T1 mammary tumor model in mice. We seek to optimize the dose and timeframe for imaging by quantitatively assessing the accumulation of fluorescently labeled nanochains in metastases in vivo using fluorescence molecular tomography. Specific Aim 3: Test the accuracy of the dual-ligand nanochains to detect metastases using MRI. Nanochain- enhanced MRI will be assessed using an analysis of physician perception of metastases. In this blinded study, radiologists will read MR images of healthy and tumor-bearing animals to estimate the diagnostic accuracy. As a case study for the proposed work, detection of triple-negative breast cancer metastases in the liver and lungs was selected, because this cancer subtype is highly metastatic and deadly. However, this technology can be used for many types of cancer, since liver and lungs are common metastatic sites.

描述（由申请人提供）：绝大多数癌症死亡都是由于转移性疾病。尽管有效的干预措施（例如，手术，辐射）在很大程度上取决于我们在早期检测传播疾病的能力，但对大量正常细胞中隐藏的微转移成像带来了独特的挑战。我们试图设计一种能够“传感”与转移相关的内皮的双 - 配体纳米颗粒。通过选择两个合适的化学特异性，双指定策略可以同时提供对表达这两种受体的微型转移酶的纳米颗粒靶向的协同扩增，并且还检测出一种仅表达一种受体的转移性肿瘤，这些受体否则就会使用单配体策略遗漏。我们的中心假设是，与血管靶向策略相结合的双 - 配体纳米颗粒提供了高度敏感和比较特定的微含量识别的可能性。纳米颗粒由化学连接到线性纳米方蛋白的氧化铁纳米球组成。我们假设双重策略不仅会增强对表达这两种受体的区域的靶向特异性，而且还将“捕获”转移区域，其中两个受体中只有一个主要表达了两个受体。由于纳米颗粒的形状和大小控制着其在血管床上的边缘和附着，因此我们还假设可以优化纳米方蛋白的纵横比和整体维度，从而提高转移性​​疾病的早期和准确检测。我们将以以下特定目的测试我们的假设：特定目标1：优化双 - 配体纳米句的设计以在体外的微循环流动条件下执行血管靶向。我们试图根据纳米座的设计优化两种靶肽的长度，宽度和密度。将在以不同流速的内皮和癌细胞播种的微通道网络中评估纳米句的边缘和靶向性。具体目标2：测试双 - 配体纳米句的能力，识别小鼠4T1乳腺肿瘤模型中微量量的微环境。我们试图通过定量评估使用荧光分子断层扫描的荧光标记的纳米偶体在转移中标记的纳米ch的积累来优化成像的剂量和时间范围。特定目标3：测试双 - 配体纳米句的准确性，使用MRI检测转移。纳米链增强的MRI将通过对转移酶的医师感知分析进行评估。在这项盲目的研究中，放射科医生将阅读健康和肿瘤动物的MR图像，以估计诊断准确性。作为拟议工作的案例研究，选择了肝脏和肺中三阴性乳腺癌转移的检测，因为该癌症亚型是高度转移和致命的。但是，由于肝脏和肺是常见的转移性部位，因此该技术可用于多种类型的癌症。