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，转移是原发性肿瘤细胞主要通过穿透血管壁并在血流中循环而扩散到非邻近器官的过程。如果这些循环肿瘤细胞（CTC）可以被灵敏和特异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太罕见而难以检测和定量。已经提出了在循环肿瘤细胞的磁性捕获之后的光声（PA）成像来解决这个问题，但是由于来自血液的强PA信号，该方法在对比度特异性方面受到限制。磁动力光声成像（mmPA）是本课题组开发的一种新的分子成像模式，它将动态操作引入传统的PA成像。与传统PA类似，mmPA保留了超声（US）的高分辨率和穿透力，并可以测量组织中的光吸收。与传统PA不同，磁动操纵与结合磁性纳米颗粒（MNP）的试剂的同时US/PA成像能够直接可视化信号产生对象，并且可以显著减少来自强光学吸收剂（例如血液）的背景信号。我们假设生物靶向的偶联磁性纳米颗粒可用于使用磁捕获和mmPA成像的组合来识别、积累和操纵在脉管系统中循环的CTC。如果成功的话，这种技术可以导致一种非侵入性系统来积累CTC，从而能够使用适合最终临床转化的简单系统进行高度灵敏的CTC检测。为了验证这一假设，制定了一项具有五个具体目标的研究计划。第一个是证明，耦合的MNP靶向模拟循环稀有细胞可以识别，积累，并使用磁捕获和mmPA成像的组合在血管体模中操作。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，适合于在外周血管系统中的潜在临床应用。第三个目标，其中一个高磁性和近红外吸收耦合纳米探针将被合成和表征，重点是开发适当的造影剂，用于此应用。在进行体内测试之前，第四个目标将使用外周血管中的体外流动模型来证明循环中靶细胞的捕获和操纵。最后，通过使用血管系统中转移性细胞运输的鼠模型证明循环中靶细胞的捕获和操纵，将在体内验证整体方法。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。这是发展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.