Engineering Therapeutic Microbubbles

结直肠癌(CRC)是英国第三大常见癌症，在英格兰和威尔士每年约有32,300例新确诊病例和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。预计随着老年人口的增加，结直肠癌的患病率将会增加(国家临床卓越研究所，www.nice.org.uk)。这提出了与老年患者的治疗有关的重要问题，平衡了生活质量和卫生经济学方面的考虑。纳米技术和工程面临的挑战是提供具有成本效益、侵入性更小、副作用更少、对患者生活质量有潜在好处的治疗方法。目前，这一点在儿童权利委员会中尤为重要，因为NHS的肠道筛查方案是为所有60岁至69岁的人开展的。这对快速、准确、可接受、安全和具有成本效益的老年有症状患者的调查和治疗提出了重要问题。超声在现代医学中的作用越来越明显，对微泡(MBS)等超声造影剂的需求也越来越大。这些MB的大小通常小于百分之一毫米，因此它们可以穿过血管系统，并通过散射超声信号而导致成像增强。所谓的第三代MBS不仅将进行灵敏度和特异度大大提高的功能成像，还将携带治疗有效载荷，用于治疗或基因治疗。这些药物最有可能通过破坏目标部位的气泡来释放，它们的效果通过声波作用(声音诱导细胞壁破裂以允许药物进入)进一步增强。尽管我们建议的重点是癌症治疗的治疗交付，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，如心血管和肌肉骨骼疾病，这些疾病的临床需求没有得到满足，特别是在老龄化人口中。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MBS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，用于创建统一大小的MBS(人类应用所必需的)。该仪器还将使我们能够在MBS上涂上适当的涂层，以特别针对癌细胞。其次，我们将开发新型涂层，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将其输送到微泡表面。与此同时，我们将开发产生超声信号的新方法，这种方法可以用来选择性地破坏MBS，同时在应该向其输送药物的细胞上制造洞。这种研究方案的一个必要部分是使用组合模型对为针对CRC的靶向治疗而开发的MBS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，我们将加强我们对MB和超声波技术如何相结合的理解，以产生治疗输送/基因治疗的新途径。这将提供一个平台来启动下一阶段的研究，这是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.