Reductive activation of azido compounds for imaging and therapy

This project will involve the activation of organic azide compounds (containing the N3 group, which can be reduced to the amine NH2 group) within cells to produce compounds which are useful for cancer imaging, diagnosis or treatment. Azides have been chosen due to their high stability and resistance to reaction under cell conditions by hydrolysis or oxidation.
Two methods of targeted activation for the production of cancer-relevant molecules will be explored: 1) the use of high energy X-rays which can penetrate into tissues (radiotherapy) and 2) the use of hypoxic conditions found within cancerous tumours. Hypoxia (a marker of many cancers) is defined as low oxygen concentration (typically <2%), compared to normoxia (21% oxygen, atmospheric oxygen pressure, used for preclinical testing) or physoxia (tissue normoxia, which varies depending on the tissue). Activation under hypoxic conditions is an effective way to target cancerous tissues over normal tissues, as low oxygen concentrations are common in tumours, particularly solid tumours. X-rays are commonly used in cancer treatment currently (for radiotherapy) due to their ability to penetrate into the body and are also a targeted method. These two activation methods will be explored independently and in combination to determine their mechanisms of action, whether different products are produced following activation, and how much activation is caused by each pathway.

The conditions described above will be used to activate prodrugs, defined as molecules which can be converted to active drugs within the body. These prodrugs will either be organic or metal-containing, such platinum or lanthanide complexes. The organic prodrugs will have structures which include the azide group connected to drugs which are currently approved for cancer treatment, or connected to systems which fluoresce (for use in cancer imaging). Platinum complexes are extensively used in chemotherapy (due to their ability to react with DNA to cause cell death) - in this project, platinum-based azide prodrugs will be activated to give complexes previously reported to have anticancer properties. Lanthanide complexes (containing elements from lanthanum to lutetium) are known to be luminescent and can be used in cancer imaging for diagnostic purposes.

Overall, this project aims to synthesis novel organic, platinum- or lanthanide-containing complexes containing azide groups which can be activated by X-rays or under hypoxic conditions to release active drugs or provide diagnostic information on cancer. This project falls within the EPSRC research areas of chemical biology, clinical technology and medical imaging.

The primary impact of the OxICFM CDT will be the highly-trained world-class scientists that it delivers. This impact will encompass both the short term (during their doctoral studies), the medium term (subsequent employment) and ultimately the longer timescale defined by their future careers and consequent impact on science, engineering and policy in the UK.

The impact of OxICFM students during their doctoral studies will be measured by the culture change in graduate training that the Centre brings about - in working at the interface between inorganic synthesis and manufacturing, and fostering cross-sector industry/academia working practices. By embedding not only from larger companies, but also SMEs, we have developed a training regime that has broader relevance across the sector, and the potential for building bridges by fostering new collaborations spanning enormous diversity in scientific focus and scale. Moreover, at a broader level, OxICFM offers to play a unique role as a major focus (and advocate) for manufacturing engagement with academic inorganic synthetic science in the UK.

From a scientific perspective, OxICFM will be uniquely able to offer a broad training programme incorporating innovative and challenging collaborative projects spanning all aspects of fundamental and applied inorganic synthesis, both molecular and materials based (40+ faculty). These will address key challenges in areas such as energy provision/storage, catalysis, and resource provision/renewal necessary to enhance the capability and durability of UK plc in the medium term. To give some idea of perspective, the output from previous CDTs in Oxford's MPLS Division include two start-up companies and in excess of 30 patents.

It is not only in the industrial and scientific realms that students will have impact during their timeframe of their doctorate. Part of the training programme will be in public engagement: team-based challenges in resource development/training and outreach exercises/implementation will form part of the annual summer school. These in turn will constitute a key part of the impact derived from the CDT by its engagement with the public - both face-to-face and through electronic/web-based media. As the centre matures, our aspiration is that our students - from diverse backgrounds - will act as ambassadors for the programme and promote even higher levels of inclusion from all parts of society.

For our partners, and businesses both large and small in the manufacturing sector, it will be our students who are considered the ultimate output of the OxICFM CDT. Our programme has been shaped by the need of such companies (frequently expressed in preliminary discussions) to recruit doctoral graduates who can apply themselves to a broad spectrum of multi-disciplinary challenges in manufacturing-related synthesis. OxICFM's cohort-based training programme integrates significant industry-led training components and has been designed to deliver a much broader skill set than standard PhD schemes. The current lack of CDT training at the interface of inorganic chemistry and manufacturing (and the relevance of inorganic molecules/materials to numerous industrial sectors) heightens the need for - and the potential impact of - the OxICFM CDT. Our students will represent a tangible and valuable asset to meet the long-term skills demand for scientists to develop new materials and nanotechnology identified in the UK Government's 2013 Foresight report.

In the longer term, the broad and relevant training delivered by OxICFM, and the uniquely wide perspective of the manufacturing sector it will deliver, will allow our graduates to obtain (and thrive in) positions of significant responsibility in industry and in research facilities/institutes. Ultimately we believe that many will go on to be future research leaders, driving innovation and changing research culture, and thereby making a lasting contribution to the UK economy.