Understanding the Physical Basis of gene/drug delivery with ultrasound and microbubbles

本项目的目的是利用超声结合微泡造影剂提高药物和基因递送的有效性。存在广泛的疾病，包括癌症和心脏病，其将受益于以安全、有效和局部化的方式递送治疗剂的能力。基因疗法作为治疗遗传性和获得性疾病的方法特别具有巨大的潜力。这种治疗面临的主要问题是让足够的药物到达身体的正确位置。目前，使用病毒作为递送剂已经显示出良好的效率，然而，我们身体的免疫应答问题限制了它们在临床应用中的潜力。其他方法目前效率低得多，必须与额外的物理增强相结合，以达到临床相关的效率。我们和其他人最近的研究表明，使用超声结合微泡有可能作为一个安全和位点特异性的基因和药物输送的物理增强剂。微泡本身已经用于诊断超声成像，以提高图像质量并帮助检测疾病。它们实际上是微小的气泡，通常与我们血液中流动的红细胞大小相同。它们含有惰性气体，以免溶解过快，并且通常由与肥皂泡相似的薄层稳定。超声波设备能够检测到它们，因为它们非常强烈地反射声音。在这个项目中，我们将以稍微不同的方式使用这些气泡，增加我们使用的超声波的振幅，我们可以迫使气泡更剧烈地振荡，并导致气泡附近的细胞膜和小血管暂时泄漏。这种泄漏允许上述治疗基因或药物进入需要它们的细胞。世界各地的一些研究小组对这一进程感兴趣，关于这一主题的出版文献越来越多。然而，迄今为止的大多数研究只是为了证明这种方法的可行性，并且在他们调查的参数方面往往非常有限。在这项研究中，我们进行了一系列实验来研究这种方法背后的机制，从声音与微泡的相互作用到气泡振动对培养物和临床前应用中细胞的影响。此外，我们将研究不同的气泡类型（具有不同的外壳和其他化学成分），以找到这种药物和基因递送过程的最佳微泡特性。我们的目标是双重的：i）深入了解使这一过程发挥作用的机制，ii）优化技术以获得最有效的治疗效果。从长远来看，癌症，心脏病和遗传性疾病如肌肉萎缩症的患者总有一天会从这项研究中受益。

The aim of this project is to improve the effectiveness of drug and gene delivery using ultrasound combined with microbubble contrast agents. There are a wide range of diseases, including cancers and heart disease, which would benefit from the ability to deliver therapeutic agents in a safe, efficient, and localized manner. Gene therapy in particular has great potential as a method of treatment for both genetic and acquired diseases. The main problem facing this treatment is getting enough of the medicine to the right place in the body. Currently the use of viruses as delivery agents has shown good efficiency, however problems with the immune response of our bodies is a limit to their potential in clinical use. Other approaches are currently much less efficient and must be combined with additional physical enhancement to work at clinically relevant efficiencies. Recent research by us and others has shown that using ultrasound combined with microbubbles has the potential to act as a safe and site-specific physical enhancer of gene and drug delivery. Microbubbles themselves are already used in diagnostic ultrasound imaging to improve the image quality and aid in the detection of diseases. They are literally tiny bubbles, typical the same size as the red blood cells that flow in our blood. They contain an inert gas so as not to dissolve too quickly, and are usually stabilized by a thin layer not dissimilar to a soap bubble. The ultrasound equipment is able to detect them because they reflect the sound very strongly. In this project we will use these bubbles in a slightly different way, buy increasing the amplitude of the ultrasound that we use we can force the bubbles to oscillate more vigorously and to cause the cell membranes and small vessels near the bubbles to become temporarily leaky. This leakiness allows the therapeutic genes or drugs mentioned above to enter the cells where they are needed. A number of research groups around the world are interested in this process and there is a growing body of published literature on the topic. However, the majority of the studies to date act only to demonstrate the feasibility of this approach and are often very limited in the parameters they investigate. In this research we set out a series of experiments to investigate the mechanisms behind this approach from the interaction of the sound with the microbubbles through to the effect of the bubble vibrations on cells both in cultures and in pre-clinical applications. Additionally we will study different bubble types (with different shells and other chemical compositions) to find the optimum microbubble properties for this drug and gene delivery process. Our aims are twofold: i) to provide insight into the mechanisms that make this process work and ii) to optimise the technique to get the most effective therapeutic effect.In the long term a patients with cancers, heart disease and genetic diseases like muscle dystrophy will one day benefit from this research.