Non-invasive trapping and imaging of circulating tumor cells in the peripheral va

外周血管循环肿瘤细胞的无创捕获和成像

• 批准号: 8594249
• 负责人: Matthew O'Donnell
• 金额: $ 42.49万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594249
• 关键词: Acoustics; Address; Animals; Biological; Blood; Blood Circulation; Blood Vessels; Cartoons; Cause of Death; Cells; Clinic; Clinical; Contrast Media; Coupled; Detection; Disease; Disease Management; Electromagnetics; Environment; Generations; Goals; Human; Image; Imagery; Imaging technology; Ireland; Journals; LNCaP; Lead; Magnetism; Malignant Neoplasms; Measures; Mechanics; Medical Students; Methods; Modeling; Molecular; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Nude Mice; Optics; Organ; Patients; Penetration; Peripheral; Physiological; Polystyrenes; Primary Neoplasm; Procedures; Process; Prostate; Research; Research Design; Resolution; Sensitivity and Specificity; Signal Transduction; Simulate; Specificity; Surgeon; System; Techniques; Testing; Time; Tissues; Translating; Translations; Ultrasonography; absorption; cell type; clinical application; college; design; imaging modality; improved; in vitro Model; in vitro testing; in vivo; magnetic field; metastatic process; molecular imaging; mouse model; nano; nanoparticle; nanoprobe; neoplastic cell; non-invasive system; performance tests; photoacoustic imaging; prostate cancer cell; prototype; public health relevance; response; trafficking

DESCRIPTION (provided by applicant): Most cancer deaths are caused by metastasis, a process whereby primary tumor cells spread to non-adjacent organs mainly by penetrating the walls of blood vessels and circulating through the bloodstream. Patients would have a much greater opportunity for long-term survival if these circulating tumor cells (CTCs) could be sensitively and specifically detected to guide disease management. However, CTCs are too rare for easy detection and quantification. Photoacoustic (PA) imaging following magnetic capture of circulating tumor cells has been proposed to address this problem, but the method is limited in contrast specificity due to strong PA signals from blood. Magnetomotive photoacoustic imaging (mmPA), a new molecular imaging modality developed in our group, introduced dynamic manipulation into traditional PA imaging. Similar to conventional PA, mmPA retains the high resolution and penetration of ultrasound (US), and can measure optical absorption in tissue. Unlike conventional PA, magnetomotive manipulation with simultaneous US/PA imaging of agents incorporating magnetic nanoparticles (MNPs) enables direct visualization of the signal generating object and can dramatically reduce background signals from strong optical absorbers such as blood. We hypothesize that biologically targeted, coupled magnetic nanoparticles can be used to identify, accumulate, and manipulate CTCs circulating in the vasculature using a combination of magnetic trapping and mmPA imaging. If successful, this technique can lead to a non-invasive system to accumulate CTCs, enabling highly sensitive CTC detection with a simple system appropriate for ultimate clinical translation. To test this hypothesis, a research plan with five specific aims has been developed. The first is to demonstrate that coupled MNPs targeted to mimics of circulating rare cells can be identified, accumulated, and manipulated in a vascular phantom using a combination of magnetic trapping and mmPA imaging. In the second aim, we will develop an effective magnetic trapping approach that can be easily integrated with a real-time US/PA imaging system appropriate for potential clinical applications in the peripheral vasculature. The third aim, in which a highly magnetic and NIR-absorbing coupled nanoprobe will be synthesized and characterized, is focused on developing the appropriate contrast agent for this application. Before performing in vivo tests, the fourth aim will demonstrate trapping and manipulation of targeted cells in circulation using an in vitro model of flow in a peripheral vessel. Finally, the overall approach will be validated i vivo by demonstrating trapping and manipulation of targeted cells in circulation using a murine model of metastatic cell trafficking in the vasculature. The overall goal of the proposed research plan is to help provide the background required to construct a prototype integrated system and to design studies helping translate mmPA technology into the clinic. This is a necessary first step in developing a robust system for metastatic disease management.

描述（由申请人提供）：大多数癌症死亡是由转移引起的，该过程主要通过穿透血管壁并通过血液循环循环，从而将原发性肿瘤细胞扩散到非染色器官。如果这些循环肿瘤细胞（CTC）可以敏感，专门检测到指导疾病管理，则患者将有更大的机会进行长期生存。但是，CTC太罕见了，无法容易检测和定量。已经提出了循环肿瘤细胞磁性捕获后的光声（PA）成像来解决此问题，但是由于血液中强的PA信号，该方法的对比度特异性受到限制。磁极光声成像（MMPA）是我们组中开发的一种新分子成像模态，将动态操作引入了传统的PA成像中。与常规PA相似，MMPA保留了超声（US）的高分辨率和渗透，并且可以测量组织中的光吸收。与常规的PA不同，与磁性纳米颗粒（MNP）同时使用US的磁性操作/PA成像可以直接可视化信号产生对象，并可以大大降低来自强烈的光学吸收剂（如血液）的背景信号。我们假设可以使用具有磁陷阱和MMPA成像的组合在脉管系统中识别，累积和操纵CTCS的CTCS来识别，积累和操纵CTC。如果成功的话，该技术可能会导致非侵入性系统积累CTC，从而使用适合最终临床翻译的简单系统实现高度敏感的CTC检测。为了检验这一假设，已经制定了具有五个特定目标的研究计划。首先是证明可以使用磁陷阱和MMPA成像的组合在血管幻像中鉴定，积累和操纵靶向模拟循环稀有细胞的MNP耦合。在第二个目标中，我们将开发一种有效的磁诱捕方法，该方法可以轻松地与适用于外围脉管系统中潜在临床应用的实时US/PA成像系统集成。第三个目标将合成和表征高度磁性且吸收NIR的耦合纳米探针，重点是为该应用开发适当的对比剂。在进行体内测试之前，第四个目标将证明使用外围血管中流动的体外流量模型对靶细胞的捕获和操纵。最后，通过使用脉管系统中转移性细胞运输的鼠模型证明循环中靶向细胞的捕获和操纵，将验证整体方法。拟议的研究计划的总体目标是帮助提供构建原型集成系统所需的背景，并设计有助于将MMPA技术转化为诊所的研究。这是开发用于转移性疾病管理的强大系统的必要第一步。