Engineering Therapeutic Microbubbles

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.

The research proposed here would have a combination of short- and long-term beneficiaries. Most directly, and immediately, affected will be those engaged in translational research, especially that involving the training of new PDRAs and PhDs, within the University of Leeds. For these it will serve to reinforce the benefits of following a multidisciplinary approach to targeting specific medical problems. This project will broaden the base of researchers engaged in therapeutic delivery through a combination of open internal meetings, such as the journal club, and a project seminar programme. Outside the University of Leeds there are other beneficiaries, both academic and industrial who will be users of the research outputs in the medium-term. For example, researchers engaged in the development of ultrasound contrast agents and also those wishing to establish new delivery modes will benefit from having an instrument for the facile and low-cost production of microbubbles (MBs) with improved control over MB size and surface coating. Access to both the microfluidic chips and microbubble instrumentation will be ensured through our commercialisation of this product. In this respect local commerce (private sector) will also be a beneficiary of this research. In the medium-term we will deliver improved understanding in the relationship between the MB coating and ultrasound (US) response and improved mechanisms for US controlled drug release, which will help a number of researchers, develop improved protocols for therapeutic delivery and/or enhance preclinical investigations. Dissemination of our research outputs will be achieved through our organisation of an annual symposium, through publication in high impact journals and via presentations at relevant international meetings. In the longer term this research will lead to new, more effective modes of therapeutic delivery thereby allowing reduced systemic exposure to potent drugs and concomitantly reduced cost and hence will therefore be of interest to big pharma and charitable organisations engaged with improving the treatment of disease. At this early stage we have made contact with a number of large charitable organisations and relevant pharmaceutical companies (from whom we have letters of support) and will keep these companies informed of our progress during the project as well as welcoming them to our annual meetings. The ultimate beneficiaries would be clinicians involved in the deliver of, and the general public as primary recipients of, the technology to be developed. These would benefit from improved efficacy of treatment with reduced side effects and overall improvement in the quality of life, and life expectancy. Finally, the reduced drug content and associated severity of side effects should lead to a reduction in the overall cost of treatment, and, thus could benefit taxpayers.