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

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.

The research proposed here would have a combination of short- and long-term beneficiaries and will offer long-term socio- and economic- benefit.

Academic Impact.
Most directly and immediately affected will be those engaged in translational research, especially 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 and diagnostics through a combination of open internal meetings such as our regular Journal Club, our project-associated seminar programme and other specialized workshops in Colorectal Cancer (CRC), and surgical oncology. It will impact through our Annual Leeds International Microbubble Symposium.

Outside the University of Leeds researchers engaged in the development of drugs for cancer treatment will gain access to a simple route for formulation of hydrophobic drugs for targeted, triggered, delivery. Through a mutually beneficial collaboration with YICT and UCL we will have access to new drugs with excellent prospects for application in CRC. They will gain alternative delivery routes to overcome their existing pharmacokinetic problems. A wide range of researchers engaged in MB research (not just for medical application) will have a platform for the simple formulation of microbubbles with complex architectures. Our long term aim is to develop an instrument for the facile and low-cost production of microbubbles (MBs) with improved control over MB size and surface coating and to commercialize this in collaboration with our partners. In addition, researchers engaged in the use of fluorescent probes will benefit from the development of cadmium-free quantum dots. Whilst Qdots have been demonstrated to be excellent probes in biology, their progress in the clinic has been hindered by their potential toxicity. The development of Cd-free Qdots will benefit researchers working in not only biological applications, but also those working on solar cells.

Socio-Economic Impact.
Approximately 40,000 cases of CRC are diagnosed each year, and there are ~16,000 deaths in England and Wales per annum. The prognosis, if diagnosed with locally progressive disease is poor. Further, this is an illness most prevalent in the over 60s and is thus of increasing concern, both in terms of quality of life as well as economically, as life expectancy increases. The development of more effective modes of therapeutic delivery, thereby allowing reduced systemic exposure to potent drugs and concomitantly reduced cost will therefore have significant long term implications for the NHS directly and indirectly for tax-payers.

New, improved modes of delivery will obviously be of interest to major Pharma and charitable organisations engaged in improving the treatment of diseases. At this early stage we have made contact with a number of large charitable organisations and relevant pharmaceutical companies and have letters of support as part of our "Engineering Therapeutic Microbubbles" Programme from Astra Zeneca, Roche, CRUK and Arthritis Research UK. In the shorter term the Nottingham-based SME "Pharminox" who make and hold the patents for GW610, would potentially accelerate the process of registration of this drug if improved efficacy were demonstrated. Further, Epigem plc, Redcar, will benefit from the commercialization of relevant MB instruments and subsequent sales of microfluidic chips.

The ultimate beneficiaries would be the general public as primary recipients of, the technology to be developed and clinicians involved in its delivery. They would benefit from the development of more personalised plans of care, with improved efficacy of treatments, with reduced side effects and overall improvement in the quality of life, and life expectancy.