The use of metal complexes in molecular imaging is well established. The availability of technetium-99m from a commercial generator coupled with the properties of this radioisotope (technetium-99m emits 140 keV gamma-ray with 89% abundance) has meant that technetium-99m has become the preferred radioisotope for SPECT imaging. The 6 hour half life is attractive since it allows sufficient time for radiosynthesis and distribution of labelled compounds to imaging centres. The design of chelates and the corresponding metal-complexes plays a significant role in the development of new tracers. The properties of the metal-chelate moiety (e.g. lipophilicity, charge, size) can greatly influence the in vivo characteristics of the final labelled candidate. Another key factor of the design of chelates relates to the radiolabelling conditions utilized - for example, the physiochemical properties of the macromolecule will influence the choice of conditions. For example the pH and temperature can impact on the nature of the macromolecule (aggregation and stability). The labelling conditions (and consequently the design and modification of the chelate) need to be 'tuned' to the properties of the macromolecule. One of the critical properties of the resultant metal-chelate complex is that it is highly stable in vivo. Although, there have been significant developments in the use of chelates in technetium chemistry, recently the requirement to label more complex and larger macromolecules (> 10 kDa) has demonstrated the need to develop alternative chelates. Proposed Programme: (i) Novel chelate synthesis - the IC Chemistry Department and GEHC have considerable experience in this area. The plan is to design chelates which are suited to a broader range of labelling conditions e.g. pH, temperature. Tailored, multifunctional ligands can allow the modification of reactivity and lipophilicity, stablisation of specific oxidation states and investigation of substitution inertness. They can also play an integral role in muting the potential toxicity of a metallodrug to have a positive impact in areas of diagnosis and therapy. To date, ligand coordination to 99mTc has generally utilized N2S2 or N4-donating atoms but within this project, wider and unexplored aspects of Tc coordination chemistry will be investigated in the search for compounds with increased specificity. Chelate motifs to be studied will include P2N2, P4N2, P(=O)2N2, P(=O)4N2, P(=S)2N2 or P(=S)4N2 donor sets, either within a macrocyclic structure or within an open-chained multidentate ligand, such as a functionalised tris(pyrazolyl)borate or similar tripodal species. Another novel facet will involve the incorporation of redox-active groups within the chelate framework i.e. ferrocene, quinolines, dithiolenes, in order to harness and exploit the rich oxidation state chemistry of technetium, focusing on biological and biomedical applications. (ii) Labelling conditions will be developed using Tc-99m. Parameters including reducing agents, pH, temperature, reaction time will be investigated. (iii) Metal-complex stability will be assessed using standard methodology (in vitro & in vivo) and will be compared against existing chelate including bis(amine-oxime), bis-amine-dithiol, tetra-amine and polypyridyl. (iv) Successful chelates will be conjugated onto biomolecules e.g alpha-v-beta-3 inegrin peptide (RGD), Octreotide the somatostatin receptor ligand and other novel macromoles from the GEHC library. Key disease areas for application of these probes will be in oncology, neurology and metabolic disorders. (v) Biological evaluation of the above labelled candidates will be carried out in collaboration with the biology groups. The biological studies will include biodistribution, metabolism and imaging of probe in a suitable animal model. These studies will be carried out at GEHC laboratories.

It is now widely accepted that up to ten years are needed to take a drug from discovery to availability for general healthcare treatment. This means that only a limited time is available where a company is able to recover its very high investment costs in making a drug available via exclusivity in the market and via patents. The next generation drugs will be even more complex and difficult to manufacture. If these are going to be available at affordable costs via commercially viable processes then the speed of drug development has to be increased while ensuring robustness and safety in manufacture. The research in this proposal addresses the challenging transition from bench to large scale where the considerable changes in the way materials are handled can severely affect the properties and ways of manufacture of the drug. The research will combine novel approaches to scale down with automated robotic methods to acquire data at a very early stage of new drug development. Such data will be relatable to production at scale, a major deliverable of this programme. Computer-based bioprocess modelling methods will bring together this data with process design methods to explore rapidly the best options for the manufacture of a new biopharmaceutical. By this means those involved in new drug development will, even at the early discovery stage, be able to define the scale up challenges. The relatively small amounts of precious discovery material needed for such studies means they must be of low cost and that automation of the studies means they will be applicable rapidly to a wide range of drug candidates. Hence even though a substantial number of these candidates may ultimately fail clinical trials it will still be feasible to explore process scale up challenges as safety and efficency studies are proceeding. For those drugs which prove to be effective healthcare treatments it will be possible then to go much faster to full scale operation and hence recoup the high investment costs.As society moves towards posing even greater demands for effective long-term healthcare, such as personalised medicines, these radical solutions are needed to make it possible to provide the new treatments which are going to be increasingly demanding to manufature.

The goal of the proposed Oxford Industrial Doctorate in Systems Approaches to Biomedical Science is to ensure that the UK has a strong pipeline of future innovators and research leaders in the pharmaceutical, biomedical, biotechnology, and biomedically-related IT sectors. It will build on the track record and model of inter-disciplinary scientific training of the two existing DTCs in Oxford (at the Life Sciences Interface and in Systems Biology), and of our existing Industrial Doctorate pilot scheme, to provide a comprehensive industrial research training programme, tailored to the needs of each individual student, and will engage with internationally leading industrial partners and academic groups drawn from across the spectrum of EPSRC's healthcare-related programmes. Graduates from the IDC programme will receive extensive exposure to the industrial context of their research in both the taught programme and in their industry-based research projects. This will allow them to develop the skills in project management, strategic planning, leadership, team working, commercial awareness, and problem solving that will be required to translate innovations in basic and medical science into commercial product development.The proposal has very strong support from across the relevant industry sectors (pharmaceutical, biomedical and imaging, health-related IT and biotechnology). The 13 companies supporting this proposal are: GE Healthcare (Dr Jonathan Allis, Vice President for Technology); GSK (Professor Paul Matthews, Vice President, Imaging and Head, GSK Clinical Imaging Centre); AstraZeneca (Dr Andy Hargreaves, Director, Advanced Science and Technology Lab); Roche (Dr Bryn Roberts, Global Head of Group Research); Novartis (Dr Ulrich Hummel, Unit Head, Structural Sciences); Pfizer (Ian Machin, Director Pain Discovery Biology); Siemens Molecular Imaging (Dr. Jrme Declerck, Head of Science and Technology), Microsoft Research (Prof Stephen Emmott , Director of External Research), Philips (Dr Lothar Spies, Head of Digital Imaging); Fujitsu European Laboratory (Dr Ross Nobes, Head of Computational Biology), UCB Celltech (Dr Jiye Shi); Inhibox (Dr Paul Finn); and Summit (Richard Vickers, Drug Discovery). Full details of the levels of support to be provided to the IDC by each of these companies are given in the attached letters of support from each of the representatives listed above. Several of these companies will be directly involved in the teaching programme of the proposed IDC.Producing these industrial scientists is of paramount importance if the UK is to remain at the forefront of the biotechnology, biomedical and pharmaceutical sectors. Current economic conditions are resulting in financial pressures across these sectors, but future innovation and product development requires that the training of these future generations of scientists commences now. EPSRC support is therefore vital. Similarly, the interdisciplinary nature of the proposed training and research programmes necessitate a critical mass of students within the training programme who can support and learn from one another, and the overall goals of the IDC simply could not be met by the standard PhD training route.

The rise of artificial intelligence (AI) has given us unprecedented opportunities to analyse big data sets and to derive insights from them. One such area is healthcare; the UK NHS have internationally unique quantity and quality of patient data by way of digital medical records. The retrospective analysis of those records in specific clinical settings gives us the potential to develop clinical decision support tools that significantly change the way in which patients will be diagnosed and managed in the future. However, there are significant challenges to realising this vision: Data are mostly stored in NHS-based systems that are not accessible to industry. Businesses may have the skills and resources to develop new products but are not connected to real-world patient care. Meaningful innovation will therefore require close partnership between NHS, academia and industry. This innovation scholar secondment will enable a joint programme by GE Healthcare, the University of Sheffield and the Sheffield Teaching Hospitals NHS Foundation Trust by allowing Dr Jan Wolber from GE Healthcare to be seconded to the University of Sheffield part-time for a duration of three years to be strategically involved in joint research and development in several disease areas. The expected outcome of this secondment is the delivery of several proof-of-concept analytics applications that can assist clinical decision making in the areas of cardiology, respiratory medicine and neurology. These applications would then be formally developed into products by GE Healthcare for deployment into clinical practice in the UK, hence benefitting patients across the nation and beyond. The applications may deliver benefits in the quality and consistency of care delivery across the NHS as well as enabling early diagnosis and stratification of patients into appropriate care pathways, which in turn can improve outcomes and quality of life, as well as possibly contributing to the reduction of healthcare costs over the life of a patient by making the right treatment decisions at the right time.

The broad theme of the research training addresses the most rapidly developing parts of the bio-centred pharmaceutical and healthcare biotech industry. It meets specific training needs defined by the industry-led bioProcessUK and the Association of British Pharmaceutical Industry. The Centre proposal aligns with the EPSRC Delivery Plan 2008/9 to 2010/11, which notes pharmaceuticals as one of the UK's most dynamic industries. The EPSRC Next-Generation Healthcare theme is to link appropriate engineering and physical science research to the work of healthcare partners for improved translation of research output into clinical products and services. We address this directly. The bio-centred pharmaceutical sector is composed of three parts which the Centre will address:- More selective small molecule drugs produced using biocatalysis integrated with chemistry;- Biopharmaceutical therapeutic proteins and vaccines;- Human cell-based therapies.In each case new bioprocessing challenges are now being posed by the use of extensive molecular engineering to enhance the clinical outcome and the training proposed addresses the new challenges. Though one of the UK's most research intensive industries, pharmaceuticals is under intense strain due to:- Increasing global competition from lower cost countries;- The greater difficulty of bringing through increasingly complex medicines, for many of which the process of production is more difficult; - Pressure by governments to reduce the price paid by easing entry of generic copies and reducing drug reimbursement levels. These developments demand constant innovation and the Industrial Doctorate Training Centre will address the intellectual development and rigorous training of those who will lead on bioprocessing aspects. The activity will be conducted alongside the EPSRC Innovative Manufacturing Research Centre for Bioprocessing which an international review concluded leads the world in its approach to an increasingly important area .