in vivo chemistry

Summary: A suite of three highly speculative projects, all involving the application of the tools of chemistry to address significant biological needs and problems, will be explored. All these projects, have exciting longer term translational end-points and practical application. (1). In vivo mediated synthesis of anticancer drugs - a potentially revolutionary approach to chemotherapy in which synthetic chemistry is performed in vivo in the proximity of the cancer to generate the desired cytotoxic active drug, thereby dramatically reducing toxicity and side effects will be explored.(2). MMP-9 (Matrix metalloproteinase-9) has been implicated in tumor metastasis as well as a variety of inflammatory processes (e.g. many lung diseases). We have developed an approach in the group whereby we can identify an ideal substrate for this enzyme (a peptide the enzyme will cleave), but which will not be cleaved by anything else. We will use this information to make a sensor for this enzyme, to allow it be analyzed, localized and followed in vivo (and then inhibited) and in a model system allow cancer cells to be imaged (while monitoring MMP-9 function) as they move through a synthetic sensing gel.(3). A paper in Nature (March 2010) has demonstrated that when patients have been injured (for example in a car accident) cells are damaged and release their contents. One of these (so-called mitochondria - which are make energy for the cell) is the cause of much of the inflammatory responses to injury (thus it is often not the injury that kills but our response to this). Removal of these circulating mitochondria could alleviate a vast medical problem. Polymers are already used to filter blood to remove white blood cells. We will therefore try and discover a new polymer that binds circulating mitochondria and which can then be applied in blood filtration media akin to white blood cell filters to help reduce unwanted inflammatory responses to injury. Key drivers for this proposal are:(i). Application of the tools of synthetic chemistry.(ii). Inherent crossing of traditional disciplinary boundaries. (iii). Pre-clincal translation and longer term improvement in quality of life. (iv). Potential remit changing approach to chemotherapy and revolution in treatment of inflammation.

Impact Summary: The impact of the programme is multi-faceted. This ranges from: Commercial: The possibility of generating drugs in situ and reducing inflammation in poateints following trauma will have critical implications for biotechnology and drug-delivery. This research project thus has a strong prospect of enabling the discovery of a new technology for cancer drug in situ activation/generation (re ADEPT) and this alone has many commercial possibilities. The close relationships the Bradley, Frame & Haslett groups have developed with Edinburgh Research and Innovation (ERI) (which seeks to promote the University of Edinburgh's research and commercialisation activities) will allow successful all commercialisation routes to be explored in a responsive and dynamic manner. This will include for example, Scottish Enterprise Proof of Concept programmes and EPSRC Follow-on-Funds, as well as other licensing or spinout opportunities as appropriate for the specific invention/materials. The biopharma industry will gain access to new technologies as well as insights into new biomedical relevant pathways for drug development. Academic Impact of the Specific Proposal: The traditional immediate beneficiaries are members of the international academic community working in the area of cancer biology who will gain new knowledge, access to new tools, datasets and technologies to enhance their own research impact. Students in the biology, chemistry and medical disciplines will benefit from access to new tools and multi-disciplinary training outputs. Research staff affiliated to the programme will benefit from an advanced and highly multidisciplinary training in cell biology, chemical biology, chemistry and imaging central to the programme. Research Partnership: This is clearly a multi-disciplinary activity, requiring the creation of a team of researchers with the necessary expertise and experience in their individual disciplines to realise the opportunities and address the challenges. The Universities of Edinburgh will greatly benefit from the creation of such a team in terms of their international standing, building of interdisciplinary links, and their ability to attract future funding and industrial support. Broader Academic Impact: One only has to look at the host of collaborators and potential avenues of research already being impacted upon by the chemistry based platforms being developed to appreciate the wide academic impact of the research. We will (resource allowing) make the reagents available to multiple groups across the UK (well beyond the CoI's in this immediate proposal). This will result in numerous academic beneficiaries of this research and will generate significant academic (and commercial) impact. To the General: An important generic skill is the ability to communicate and disseminate information: A multidisciplinary project such as this will provide many opportunities for the involvement in public engagement and dissemination. Research fellows of the group regularly participate in the School of College of Science and Engineering initiative SciFun and at the Edinburgh International Science Festival. The 'Researchers-in-Residence' Programme places postgraduate students in local secondary schools for short periods to interact on projects with 14 - 16 year old pupils.