Microbubble Enhanced Imaging and Therapeutic Delivery

微气泡（mb）是一种微小的气泡，直径约为头发丝宽度的百分之一，周围有一层薄薄的弹性外壳。当与超声（US）成像一起使用时，它们提供了更高的图像对比度。重要的是，有可能将分子附着在MB外壳上，使它们能够特异性地与靶细胞结合，例如在肿瘤中。这使得癌症的直接成像成为可能。此外，还可以将药物有效载荷附加到这些靶向mb上。然后，这些治疗性MBs可以直接靶向肿瘤，使用特定的美国触发器，通过破坏MBs释放其药物载荷，导致局部释放药物。许多抗癌药物都是剧毒的，这限制了它们的使用，并可能导致严重的副作用。治疗性MBs提供了显著减少这些副作用的潜力，同时允许更高剂量的药物输送到肿瘤。我们这个应用程序的重点是结肠直肠癌（CRC），这是英国第三大常见癌症。2010年，英国约有40,700人被诊断出患有肠癌，2008年全球估计有124万新病例被诊断出来。预计随着我国老年人口的增加，结直肠癌的患病率将会增加（www.nice.org.uk），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。我们的目标是提供成本效益高、侵入性小、副作用少、改善患者生活质量的治疗方法。我们的研究项目解决了需要解决的几个关键挑战，以允许MBs作为联合治疗和诊断药物的临床开发。在我们最近的EPSRC项目中，我们成功地构建了用于制造MBs的仪器（具有靶向剂和偶联药物有效载荷）。这使我们能够在临床前模型中测试它们靶向癌细胞和有效治疗肿瘤的能力。为了使我们的MBs能够用于首次人体试验，我们需要让监管机构满意，我们的MBs是安全的，并且具有明确的临床益处。如果提供者最终采用这种治疗方式，我们还需要证明它们具有成本效益。我们已经开发了一种双管齐下的方法来开发基于药物的微泡：1)许多药物未能达到临床试验，因为尽管它们作为药物是有效的，但由于溶解度差或毒性太大而难以进入细胞或组织。为此，我们建议开发一种新的综合筛选平台，该平台将使用MB+超声波的组合，以帮助将此类药物输送到细胞（和肿瘤模型）中。这不仅将允许对许多现有药物进行重新评估，而且还将加快新药的筛选。通过与药物发现弹射器的合作，我们将促进制药公司对这项技术的采用，从而降低识别新候选药物的成本。2)我们将开发我们的专利MB生产仪器，使其可以由外部公司生产，进行首次人体试验。作为其中的一部分，我们需要优化我们制造MBs的方式，修改药物和靶向制剂相互联系的方式，并解决诸如易用性、无菌性等问题。我们还需要证明我们可以用MB+US方法完全消除肿瘤。通过使用根据特定标准（GMP）生产的适合临床试验的材料，以及符合良好实验室规范的工艺，我们将进行必要的体外和体内测试，以将该“研究药物”转移到1期（首次人体）临床试验。

Microbubbles (MBs) are tiny bubbles of gas about 1/100th of a hair's breadth in diameter and surrounded by a thin elastic shell. When used with ultrasound (US) imaging they provide increased image contrast. Importantly, it is possible to attach molecules to the MB shell enabling them to bind specifically to target cells, for example in tumours. This allows direct imaging of cancers. Furthermore, it is also possible to attach drug payloads to these targeted MBs. These therapeutic MBs can then be targeted directly to the tumour and their drug payload released by bursting the MBs, using a specific US trigger, leading to localised release of drug. Many cancer drugs are highly toxic, which limits their use and can cause extreme side effects. Therapeutic MBs offer the potential for significantly reducing these side effects, whilst allowing for higher dose drug delivery to the tumour. Our focus for this application will be on Colorectal Cancer (CRC), the third most common cancer in the UK. Around 40,700 people were diagnosed with bowel cancer in 2010 in the UK with an estimated 1.24 million new cases diagnosed worldwide in 2008. It is anticipated that as our elderly population increases, CRC will increase in prevalence (www.nice.org.uk) raising important issues relating to treatment in elderly patients balanced with quality-of-life and health economics considerations. Our aim is to deliver cost-effective, less invasive treatments with fewer side effects and improved quality of life for patients. Our Programme of research addresses several key challenges that need to be resolved to allow the clinical development of MBs as combined therapy and diagnostic agents. In our recent EPSRC Programme we succeeded in building an instrument for the manufacture of MBs (that have a targeting agent and conjugated drug payload). This enabled us to test their ability to target cancer cells and to effectively treat tumours in pre-clinical models. In order to progress our MBs to the point where they could be used for first-in-man trials we need to satisfy regulatory agencies that our MBs are safe, and have clear clinical benefit. We will also need to demonstrate that they are cost effective, if providers are eventually to take-up this treatment modality.We have developed a two-pronged approach to developing microbubbles for drug based delivery:1) Many drugs fail to reach clinical trials because, whilst they are potent as drugs, they are difficult to deliver into cells, or tissue because of poor solubility or becasue they are too toxic to use. For this we propose to develop a new integrated screening platform, that will use the combination of MB+ultrasound, for aiding the delivery of such drugs into cells (and tumour models). This will not only allow re-assessment of many existing drugs but will also speed up the screening of new drugs. Through partnership with the Medicines Discovery Catapult we will promote uptake of this technology with pharmaceutical companies and thereby reduce cost for the identification of new drug candidates.2) We will develop our, patented, MB production instrument to the point where it could be manufactured by an external company for the first-in-human trials. As part of this we need to optimise how we make the MBs, modify how the drugs and targeting agents are linked to each other and address issues such as ease of use, sterility etc. We also need to show that we can eliminate tumours completely using our MB+US approach. By using materials that have been manufactured according to specific standards (GMP), that are suitable for clinical trials, and processes that are in accord with Good Laboratory Practice we will undertake the necessary in-vitro and in-vivo testing required for moving this "Investigational Medicinal Product" to Phase 1 (First in Human) Clinical trials.