Synthesis and delivery of multi-modal metallodrugs for high-grade gliomas

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive form of brain tumour found in children. Its prognosis is particularly dire as 90% of the patients die from the disease within only two years of diagnosis. As of now, treatment involves radiation combined with chemotherapy, though these approaches are limited due to the location of the tumours and poor response to the therapeutics.
Since the discovery of cisplatin, metallic anti-cancer agents have gained considerable attention. Despite extensive research on platinum-based drugs, only three therapeutics are currently approved worldwide. The field has advanced substantially, exploring mechanisms of accomplishing a more targeted treatment whilst reducing the side-effects. Approaches include administering precursors followed by activation of the drug at the site of the tumour from outside the body, e.g. with ultrasound or light. So-called click chemistry provides scope for pre- and post-treatment modification of prospective platinum compounds, including chemotherapeutics, bioactive targeting moieties, or fluorescent labelling for tracing the uptake and distribution of the complex in the cell.
As an alternative to novel compounds, modifying approved anti-cancer agents provides another approach to innovative platinum drugs. The oxidation of oxaliplatin with further biologically active moieties has yielded promising results regarding enhanced delivery and cytotoxicity. Adapting the oxaliplatin scaffold potentially alters the entire mode of action and mechanism of induced cell death.
Vitamin B12 (cyanocobalamin) and its derivatives have demonstrated selective uptake into tumour cells. Further, conjugates consisting of anti-cancer agents and cobalamins display activation upon radiation with X-rays. The targeted delivery of anti-cancer agents combined with X-ray induced chemotherapy would increase efficacy and pose significant improvements to state-of-the-art radiotherapy.
This research will involve the synthesis, characterisation and evaluation of platinum-based anti-cancer agents for the treatment of DIPG, with a particular focus on the potential for activating the compounds by irradiation. Activation of the compounds via X-rays will be investigated, with particular attention to wavelength-dependent effects. X-ray sources will include high intensity radiation which is available in the clinic and will be accessible through Prof. Geoffrey Higgins in the Department of Oncology. The interaction with less energetic lower X-rays generated by a synchrotron can be realised at the UK's national synchrotron science facility Diamond Light Source. Building on these results, the compounds will be modified with the aim of increasing X-ray responsiveness, for instance with sensitisers, or moieties cleavable by X-rays. Successful photoactivation of the platinum complexes will be followed by evaluation of their toxicity in cells. Mechanisms potentially resulting in interference with DNA or the cell's metabolism, essentially leading to cell death, will be assessed in detail. Enhancing the anti-cancer properties of the compounds will be pursued through modification to include molecules specifically targeting DIPG.
This project falls within the EPSRC healthcare technologies research area.

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.