Enhancing high intensity focused ultrasound molecule delivery using molecular imaging

海绵吸收水分是因为它们包含数以千计的小孔--扩张毛孔，它们会吸收更多的水分。人体内的组织也可以起到类似的作用。接受化疗的肿瘤会吸收这种药物，摧毁癌细胞。如果有一种方法可以扩大组织毛孔以增加吸收，进而提高有效性，那会怎样？如果这种方法可以帮助穿越血脑屏障等自然障碍会怎么样？*高强度聚焦超声(HIFU)可能就是关键。研究人员目前正在探索使用HIFU改善或诱导分子传递的方法。声空化--一种利用超声波扩张或创造毛孔的过程--及其来自受限和局部力量的相关微流效应被认为是其机制。*这种传递方法仍然缺乏适当的手段来指导和确认直接影响。在这个项目中，我建议开展基础研究，以实现利用分子成像指导HIFU介导的分子递送。这种方法提供了两个明显的好处：它将提供生物特异性的指导，以确保递送到确定的目标，它可以提供有关被修改的分子途径的信息(从而监测反应)。*该计划建立在以前的HIFU成像指导和分子递送经验的基础上，并专注于两个主题：*1)HIFU介导的分子递送，随后进行小动物正电子发射断层扫描(µPET)。我将在HIFU介导的分子递送治疗人类乳头瘤病毒(HPV)感染细胞的结果的基础上再接再厉。我建议验证使用µPET来跟踪动物对以一种转化细胞的蛋白质为靶点的抗体传递的反应。第二个项目将验证uPET在HIFU诱导的血脑屏障开放后作为促进酶替代的工具进行后续交付的有效性。作为一个平行的结果，我们将获得动物分子输送的原型，并与µPET指导配对。*2)用于HIFU介导的前列腺癌肿瘤分子递送的生物特异性成像探针。我将使用我的团队开发的一种标记抗体作为磁共振造影剂，这种抗体已经成功地在细胞和肿瘤的磁共振图像上进行了表征和检测。我们将在这些结果的基础上探索其他标记，并评估该试剂在分子交付后跟踪变化的可行性。*拟议的项目将不同学科联系起来，并将利用已建立的合作。与我过去的项目一样，这项研究还具有强大的培训成分，提供了一个多学科的学习环境，学生将在其中与工程师、物理学家、生物学家和化学家互动。我将以关系和以前的经验为基础，提供跨学科的项目，为参与的学生提供更多的职业机会。**

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.**