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

描述（由申请人提供）：大多数癌症死亡是由转移引起的，这是一个原发肿瘤细胞主要通过穿透血管壁并通过血液循环扩散到非邻近器官的过程。如果这些循环肿瘤细胞（CTCs）能够被敏感和特异性地检测到，以指导疾病管理，患者将有更大的长期生存机会。然而，ctc太罕见，难以检测和量化。为了解决这个问题，已经提出了循环肿瘤细胞磁捕获后的光声成像（PA），但由于血液中强烈的PA信号，该方法在对比度特异性方面受到限制。磁动机光声成像（mmPA）是本课组开发的一种新型分子成像技术，将动态操作引入传统的光声成像中。与传统的PA类似，mmPA保留了超声的高分辨率和穿透性（US），并且可以测量组织中的光吸收。与传统的PA不同，磁动机操作与结合磁性纳米颗粒（MNPs）的试剂同时进行US/PA成像，可以直接可视化信号产生对象，并可以显着减少来自强光吸收剂（如血液）的背景信号。我们假设，通过结合磁捕获和mmPA成像，生物靶向、耦合磁性纳米颗粒可用于识别、积累和操纵循环在脉管系统中的ctc。如果成功，该技术可以形成一个非侵入性的CTC积累系统，使CTC检测具有高灵敏度，适合最终临床转化的简单系统。为了验证这一假设，已经制定了一个有五个具体目标的研究计划。首先，研究人员证明，利用磁捕获和mmPA成像的结合，可以在血管幻影中识别、积累和操纵针对循环稀有细胞模拟物的耦合MNPs。在第二个目标中，我们将开发一种有效的磁捕获方法，可以很容易地与实时US/PA成像系统集成，适用于周围血管系统的潜在临床应用。第三个目标是合成和表征高磁性和nir吸收的耦合纳米探针，重点是开发适合该应用的造影剂。在进行体内试验之前，第四个目标将演示利用外周血管流动的体外模型在循环中捕获和操纵目标细胞。最后，整个方法将在体内进行验证，通过使用小鼠血管转移细胞运输模型来演示捕获和操纵循环中的靶细胞。拟议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技术转化为临床的研究。这是开发一个强大的转移性疾病管理系统的必要的第一步。

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.