Engineering Therapeutic Microbubbles

结直肠癌（CRC）是英国第三大常见癌症，英格兰和威尔士每年约有32，300例新诊断病例和14，000例死亡。结直肠癌的发生与年龄密切相关，83%的病例发生在60岁以上的人群中。预计随着我国老年人口的增加，CRC的患病率将增加（National Institute for Clinical Excellence，www.nice.org.uk）。这就提出了与老年患者的治疗有关的重要问题，这些问题与生活质量和卫生经济学考虑相平衡。纳米技术和工程所面临的挑战是提供具有成本效益的，侵入性较小的治疗方法，副作用较少，对患者的生活质量有潜在的好处。这是特别重要的CRC在目前的NHS肠道筛查计划推出的所有个人年龄在60至69岁。这提出了快速，准确，可接受的，安全和具有成本效益的调查和治疗老年症状患者的重要问题。超声在现代医学中具有明确且不断增长的作用，并且对引入超声造影剂（诸如微泡（MB））的需求不断增加。这些MB的尺寸通常小于百分之一毫米，使得它们可以穿过脉管系统，并且通过超声信号的散射导致成像增强。所谓的第三代MB不仅将以大大增强的灵敏度和特异性进行功能成像，而且还将携带用于治疗或基因治疗的治疗有效载荷。这些将最有可能通过破坏目标部位的气泡而释放，并且它们的效果通过声孔作用（声音诱导细胞壁破裂以允许药物进入）进一步增强。虽然我们的建议的重点是为癌症治疗提供治疗，但甲基溴开发的基本技术和超声波技术同样适用于其他疾病，例如心血管和肌肉骨骼疾病，这些疾病的临床需求尚未得到满足，特别是在老龄人口中。因此，这是一项与不同疾病相关的通用技术开发。我们的研究计划解决了这些第三代MB成功开发的几个关键问题。首先，我们建议开发一种基于微流体的机器，用于创建均匀大小的MB（人类应用所必需的）。该仪器还允许我们在MB上涂上合适的涂层，以使它们特异性地靶向癌细胞。其次，我们将开发新的涂层，以控制气泡对超声信号的响应方式。然后，我们将添加所需药物的有效载荷以递送到微泡表面上。与此同时，我们将开发产生超声信号的新方法，这些信号可用于选择性地破坏MB，同时在药物应被递送的细胞中产生孔。这种研究计划的一个必要部分是使用组合模型对开发用于CRC靶向治疗的MB进行全面测试和评估。首先，针对试管中生长的癌细胞，其次，针对感染相关癌症的小鼠。在我们的研究项目结束时，我们将提高我们对MB和超声技术如何结合以产生治疗递送/基因治疗的新途径的理解。这将为启动下一阶段的研究提供一个平台，这是在这种方法可以用于临床之前所需的。

Colorectal Cancer (CRC) is the third most common cancer in the UK, with approximately 32,300 new cases diagnosed and 14,000 deaths in England and Wales each year. Occurrence of colorectal cancer is strongly related to age, with 83% of cases arising in people older than 60 years. It is anticipated that as our elderly population increases, CRC will increase in prevalence (National Institute for Clinical Excellence, www.nice.org.uk). This raises important questions relating to treatment in elderly patients balanced with quality-of-life and health economics considerations. The challenge to nanotechnology and engineering is to deliver cost-effective, less invasive treatments with fewer side-effects and potential benefits for quality of life in patients. This is particularly important in CRC at the present time as the NHS bowel-screening programme is rolled out for all individuals aged 60 to 69. This raises important issues for rapid, accurate, and acceptable, safe and cost-effective investigation and treatment of older symptomatic patients. Ultrasound has a clear and growing role in modern medicine and there is increasing demand for the introduction of ultrasound contrast agents such as microbubbles (MBs). These MBs are typically less than one hundredth of a millimetre in size, so that they can pass through the vasculature, and lead to imaging enhancements by scattering of the ultrasound signal. So-called third generation MBs will not only perform functional imaging with greatly enhanced sensitivity and specificity but will also carry therapeutic payloads for treatment or gene therapy. These will most likely be released by destroying the bubbles at the targeted site and their effect enhanced further by sonoporation (sound induced rupture of the cell walls to allow drugs in). Although the focus of our proposal is therapeutic delivery for cancer treatment, the basic technologies for MB development and ultrasound technology are equally applicable to other conditions e.g. cardiovascular and musculoskeletal disease where there is an unmet clinical need, particularly in ageing populations. As such this is a generic technology development relevant to different diseases.Our programme of research addresses several key issues central for the successful development of these 3rd Generation MBs. Firstly, we propose to develop a machine, based on microfluidics, for the creation of MBs of uniform size (necessary for human application). This instrument will also allow us to put suitable coatings on the MBs to target them specifically at cancerous cells. Secondly, we will develop novel coatings to allow control over the way bubbles respond to ultrasound signals. We will then add payloads of the required drug to be delivered onto the micro-bubble surface. At the same time we will develop novel methods of generating ultrasound signals which can be used to selectively destroy the MBs and simultaneously create holes in the cells to which the drugs should be delivered. A necessary part of such a programme of research is the full testing and evaluation of the MBs developed for targeted therapy of CRC using a combination models. Firstly, against cancer cells grown in test tubes and secondly, against mice infected with the relevant cancer. At the conclusion of our research project we will have enhanced our understanding of how MB and ultrasound technologies can be combined to yield new routes for therapeutic delivery/gene therapy. This will provide a platform to launch the next stage of research, required before such an approach could be used clinically.