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

描述(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。如果能够灵敏和特异地检测到这些循环中的肿瘤细胞(CTCs)来指导疾病治疗，患者将有更大的长期生存机会。然而，四氯化碳太稀少，不容易检测和定量。光声成像(PA)后，循环的肿瘤细胞磁捕获已被提出解决这个问题，但该方法的对比特异性受到限制，因为强烈的PA信号来自血液。磁动型光声成像是本课题组开发的一种新的分子成像方式，它将动态操作引入到传统的PA成像中。与传统PA类似，MMPA保留了超声(US)的高分辨率和穿透性，并可以测量组织中的光吸收。与传统的PA不同，磁动势操纵通过同时对含有磁性纳米颗粒(MNP)的试剂进行US/PA成像，可以直接看到信号产生对象，并可以显著减少来自血液等强光吸收物质的背景信号。我们假设，生物靶向的、耦合的磁性纳米颗粒可以用于识别、积累和操纵在血管中循环的CTCs，方法是结合磁性捕获和MMPA成像。如果成功，这项技术可以导致一个非侵入性的系统来积累CTC，使高灵敏度的CTC检测能够通过适合最终临床翻译的简单系统来实现。为了验证这一假设，制定了一个有五个具体目标的研究计划。第一个是证明结合磁性捕获和MMPA成像技术，可以在血管模体中识别、积累和操纵针对循环稀有细胞的偶联MNPs。在第二个目标中，我们将开发一种有效的磁捕获方法，该方法可以很容易地与实时US/PA成像系统集成，适合于外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近红外吸收的耦合纳米探针，重点是开发适合这一应用的造影剂。在进行体内测试之前，第四个目标将使用外周血管流动的体外模型来演示捕获和操纵循环中的靶细胞。最后，整个方法将通过体内验证，通过使用血管系统转移细胞转移的小鼠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.