Microbubble Enhanced Imaging and Therapeutic Delivery

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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.