Enhancing high intensity focused ultrasound molecule delivery using molecular imaging

海绵吸水是因为它们有成千上万的小孔--扩大小孔，它们会吸收更多的水。身体中的组织可以以类似的方式起作用。用化学疗法治疗的肿瘤吸收药物，破坏癌细胞。如果有一种方法可以扩大组织孔隙，以增加吸收，从而提高效率？如果这种方法可以帮助通过血脑屏障等自然堵塞呢？*高强度聚焦超声（HIFU）可能是关键。研究人员目前正在探索使用HIFU来改善或诱导分子递送的方法。声空化--一种利用超声波来扩张或产生孔隙的过程--以及与之相关的来自受限和局部力的微流效应被认为是机制。这种交付方法仍然缺乏适当的手段来指导和确认直接效果。在这个项目中，我建议开展基础研究，以实现使用分子成像指导HIFU介导的分子递送。这种方法提供了两个明显的好处：它将提供生物学特异性指导，以确保交付到确定的目标，它可以提供有关被修改的分子途径的信息（从而监测响应）。该计划建立在HIFU成像引导和分子递送的先前经验的基础上，重点关注两个主题：*1）HIFU介导的分子递送，随后是小动物正电子发射断层扫描（µPET）。我将建立在HIFU介导的分子递送治疗人乳头瘤病毒（HPV）感染的细胞的结果。我建议验证使用µPET来跟踪动物对靶向转化细胞的蛋白质的抗体递送的反应。第二个项目将验证µPET在HIFU诱导的血脑屏障开放后作为增强酶替代的工具进行随访。作为一个平行的结果，我们将获得动物分子递送与µPET引导配对的原型。*2）用于HIFU介导的分子递送至前列腺癌肿瘤的生物特异性成像探针。我将使用我的团队开发的标记抗体作为MRI造影剂，该造影剂已成功地在细胞和肿瘤的MR图像上进行表征和检测。我们将在这些结果的基础上探索其他标志物，并评估这种药物在分子递送后跟踪变化的可行性。拟议的项目将不同学科联系起来，并将利用现有的合作关系。与我过去的项目一样，这项研究也具有很强的培训成分，提供了一个多学科的学习环境，学生将与工程师，物理学家，生物学家和化学家互动。我将建立在关系和以往的经验，提供跨学科的项目，提高参与学生的就业机会。**

Sponges absorb water because they contain thousands of small pores - expand the pores, and they'll absorb more water. Tissues in the body can act in a similar way. Tumours treated with chemotherapy absorb the drug, destroying the cancer cells. What if there was a method to expand tissue pores to increase absorption and in turn effectiveness? What if this method could help go through natural blockages such as the blood-brain barrier?***High-intensity focused ultrasound (HIFU) just might be the key. Researchers are currently exploring methods of using HIFU to improve or induce molecular delivery. Acoustic cavitation - a process that uses ultrasound to expand or create pores - and its associated micro-streaming effects from confined and localized forces are believed to be the mechanisms.***This delivery method still lacks the appropriate means to guide and confirm direct effects. In this program, I propose to develop the basic research to achieve guidance for HIFU-mediated molecular delivery using molecular imaging. This approach offers two distinct benefits: it will provide biologically-specific guidance to ensure delivery to identified targets, and it can offer information about the molecular pathways that are modified (thereby monitoring response).***The program builds upon previous experience in HIFU imaging guidance and molecule delivery and focuses in two topics:***1) HIFU-mediated molecule delivery followed up by small animal positron emission tomography (µPET). I will build upon results of HIFU-mediated molecule delivery for the treatment of human papillomavirus (HPV)-infected cells. I propose to validate the use of µPET to follow up response in animals to antibody delivery targeting a protein that transforms cells. A second project will validate µPET to follow up delivery after HIFU-induced blood-brain barrier opening as a tool for enhancing enzyme replacement. As a parallel outcome, we will obtain prototypes for animal molecule delivery paired with µPET guidance. ***2) Biologically-specific imaging probes for HIFU-mediated molecule delivery to prostate cancer tumours. I will work with a labelled antibody developed by my group as an MRI contrast agent, which has been successfully characterized and detected on MR images of cells and tumours. We will build upon these results to explore other markers as well as evaluate the feasibility of this agent to follow up changes after molecule delivery.***The proposed projects link different disciplines and will leverage established collaborations. As with my past projects, the research also features a strong training component, providing with a multidisciplinary learning environment in which students will interact with engineers, physicists, biologists and chemists. I will build upon relationships and previous experience to offer interdisciplinary projects that enhance career opportunities for participating students.**