Microbubbles for Hydrophobic Drug Delivery and Enhanced Diagnostics; Towards Personalised Healthcare for the Treatment of Colorectal Cancer

结直肠癌（CRC）是全球第三大常见癌症，每年有超过80万例新诊断病例，其中约4万例在英国。一旦超过可以通过手术切除的程度，预后就很差，尽管有新的国家筛查方案，但在英格兰和威尔士，每年约有16,000人死亡。从历史上看，化疗在晚期疾病中相对无效。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。预计随着老年人口的增加，结直肠癌的患病率将会增加（National Institute for Clinical Excellence, www.nice.org.uk）。这就提出了与老年患者的治疗与生活质量和健康经济学考虑相平衡的重要问题。纳米技术和工程学面临的挑战是为老年患者提供具有成本效益的微创治疗，同时提高疗效、减少副作用和提高生活质量。结合成像与靶向给药（治疗诊断）的方法预计将变得越来越普遍。这是因为“分层医学”的发展和实施需要确定对特定患者群体有效的治疗方法，并共同开发诊断方法，以确保正确的患者在正确的时间得到正确的治疗。向肿瘤细胞输送药物是有效治疗癌症的基本要求。即使化合物在体外与生化靶点发生强烈的相互作用，它们也不能在体内以足够的浓度到达肿瘤以选择性地杀死肿瘤细胞，从而影响临床应用。有许多药物，如果它们能到达它们想要的靶点，就有很大的潜力。事实上，有一类潜在的药物本质上是疏水的（这意味着它们不容易溶于水），这使得它们很难通过血液输送。鉴于全球药物开发生产力的下降，很明显，提供疏水药物的新方法将是非常重要和有价值的。这里提出的研究旨在开发一种先进的药物输送系统，该系统有望比传统治疗方法具有几个优势。理想情况下，它的靶向性和触发性将提高药物效力，控制药物释放以获得持续的治疗效果，提供更大的安全性，减少所需的药物总剂量，减少毒副作用。显然，这种药物输送系统将同样适用于各种疾病领域以及癌症。我们的系统将由一个运载工具组成，它将穿过身体的血管系统，直到到达目标部位——癌细胞。运载工具将携带疏水药物（或其他治疗剂）的有效载荷。车辆与肿瘤的附着将通过增强型超声技术进行监测（目前在专家中心临床使用）。一旦附着在癌细胞上，一种特殊的超声波脉冲将触发药物的释放，以提供高剂量的局部剂量。我们将建造的交通工具由微小的气泡组成，这些气泡太小而无法用肉眼看到，直径约为1微米。这些“微气泡”将携带着包裹在更小的油滴（直径约200纳米）中的疏水药物。有几种运载工具的潜在设计，我们将建造和测试。一旦确定了最佳的递送载体，我们将评估这些载体是否可以用于改善许多疏水药物的递送，这些药物目前还不能有效地用于治疗。与我们的合作者一起，我们正在研究一些此类药物，这些药物有望有效治疗CRC及其转移，并将在该项目中与MB递送载体一起开发。

Colorectal cancer (CRC) is the third most common cancer worldwide with over 800,000 new cases diagnosed each year, approximately 40,000 of these being in the UK. Once beyond the point at which it can be surgically removed the prognosis is poor and despite the new National Screening Programme there are ~16,000 deaths in England and Wales each year. Historically, chemotherapy has been relatively ineffective in advanced disease.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 facing nanotechnology and engineering is to deliver cost-effective, minimally invasive treatments with an improved efficacy, fewer side effects and enhanced quality-of-life in older patients. The approach of combining imaging with targeted drug delivery (theragnostics) is expected to become increasingly common. This is because the development and implementation of "stratified medicine" requires identification of treatments effective for particular groups of patients, with co-development of diagnostics to ensure the right patient gets the right treatment at the right time. Drug delivery to tumour cells is a fundamental requirement for the effective treatment of cancer. Even if compounds interact strongly with a biochemical target in vitro, their failure to reach tumours in vivo in sufficient concentrations to selectively kill tumour cells compromises clinical use. There are numerous drugs which have excellent potential if they could reach their desired target site. Indeed a whole class of potential drugs exists that are hydrophobic in nature (meaning they don't dissolve easily in water) making them difficult to deliver via the blood stream. Given the declining productivity of drug development worldwide it is clear that new methods of delivering hydrophobic drugs will be of great importance and value.The research proposed here is aimed at developing an advanced drug delivery system that is expected to possess several advantages over conventional treatments. Ideally, its properties of being both targeted and triggered will improve drug potency, control drug release to give a sustained therapeutic effect, provide greater safety, reduce the total drug dose required and decrease toxic side effects. Clearly such drug delivery systems would be equally applicable in a variety of disease areas as well as cancer.Our system will consist of a delivery vehicle that will pass through the body's vasculature until it reaches its target site - a cancer cell. The vehicles will carry a payload of hydrophobic drugs (or other therapeutic agent). Attachment of the vehicles to the tumour will be monitored by enhanced ultrasound techniques (as currently used clinically in expert centres). Once attached to the cancer cells, a special ultrasound pulse will trigger the release of the drugs to provide a high local dosage. The vehicles we will construct consist of tiny bubbles that are too small to see by eye, ~1 micron in diameter. These "microbubbles" will carry a cargo of hydrophobic drugs packaged in even smaller oil droplets (~200 nm diameter). There are several potential designs of delivery vehicles, which we will construct and test. Once the optimal delivery vehicle is identified we will evaluate whether these can be used to improve the delivery of numerous hydrophobic drugs, which cannot currently be effectively formulated for use as treatments. With our collaborators we are investigating a number of such drugs, which promise to be effective for the treatment of CRC and its metastases and which will be developed with MB delivery vehicles during this project.