Detection of micrometastasis using a dual-ligand nanoparticle

使用双配体纳米粒子检测微转移

• 批准号: 9068039
• 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/9068039
• 关键词: 4T1; Affect; Animals; Avidity; Blinded; Blood Vessels; Breast Cancer Model; Breast cancer metastasis; 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; Gold; Health; Image; Immunohistochemistry; In Vitro; Integrin Binding; Integrins; Label; Length; Ligands; Link; Liver; Lung; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Metastatic to; Microcirculation; Micrometastasis; Modeling; 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 subtypes; cancer type; density; design; diagnostic accuracy; effective intervention; fluorescence imaging; fluorescence molecular tomography; human disease; improved; in vivo; iron oxide; nanoparticle; overexpression; radiologist; receptor; 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）：绝大多数癌症死亡是由于转移性疾病。虽然有效的干预措施（如手术、放疗）在很大程度上取决于我们在早期发现弥散性疾病的能力，但对隐藏在大量正常细胞中的微转移进行成像是一项独特的挑战。我们试图设计一种双配体纳米颗粒，能够“感知”与转移相关的内皮细胞。通过选择两种合适的化学特异性，双配体策略既可以协同扩增纳米颗粒靶向表达两种受体的微转移瘤，又可以检测仅表达一种受体的转移瘤，否则使用单配体策略将无法检测到这种转移瘤。我们的中心假设是，双配体纳米颗粒与血管靶向策略相结合，增加了对微转移的高度敏感和特异性识别的可能性。纳米颗粒由氧化铁纳米球组成，通过化学方式连接成线性纳米链。我们假设双配体策略不仅可以增强对表达两种受体区域的靶向特异性，还可以“捕获”两种受体中只有一种主要表达的转移区域。由于纳米颗粒的形状和大小决定了它们的边缘和与血管床的附着，我们还假设可以优化纳米链的长宽比和总体尺寸，从而早期准确地检测转移性疾病。我们将通过以下具体目标来验证我们的假设：具体目标1：优化双配体纳米链的设计，在体外微循环流动条件下进行血管靶向。我们试图从两个靶向肽的长度、宽度和密度方面优化纳米链的设计。纳米链的边缘和靶向性将在不同流速的内皮细胞和癌细胞微通道网络中进行评估。特异性目的2：在小鼠4T1乳腺肿瘤模型中检测双配体纳米链对微转移微环境的识别能力。我们试图通过荧光分子断层扫描定量评估体内转移瘤中荧光标记纳米链的积累来优化成像的剂量和时间框架。特异性目的3：利用MRI检测双配体纳米链检测转移的准确性。纳米链增强MRI将通过分析医生对转移的感知来评估。在这项盲法研究中，放射科医生将阅读健康和肿瘤动物的MR图像，以估计诊断的准确性。作为本研究的一个案例，我们选择检测三阴性乳腺癌在肝脏和肺部的转移，因为这种癌症亚型具有高度转移性和致死率。然而，这项技术可以用于许多类型的癌症，因为肝脏和肺部是常见的转移部位。