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

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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.