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

弥漫性内在脑桥胶质瘤（DIPG）是一种在儿童中发现的高度侵袭性脑肿瘤。其预后尤其可怕，因为90%的患者在诊断后仅两年内死亡。到目前为止，治疗包括放疗和化疗相结合，尽管这些方法由于肿瘤的位置和治疗效果差而受到限制。自发现顺铂以来，金属抗癌药物得到了相当大的关注。尽管对铂类药物进行了广泛的研究，但目前全球只有三种治疗方法获得批准。该领域已取得实质性进展，探索实现更有针对性的治疗，同时减少副作用的机制。方法包括施用前体，然后从体外（例如用超声波或光）在肿瘤部位激活药物。所谓的点击化学为潜在铂化合物的治疗前和治疗后修饰提供了范围，包括化疗药物，生物活性靶向部分，或用于追踪复合物在细胞中的摄取和分布的荧光标记。作为新化合物的替代品，修饰已批准的抗癌药物为创新铂类药物提供了另一种途径。奥沙利铂的氧化与进一步的生物活性部分已经产生了有希望的结果，关于增强传递和细胞毒性。适应奥沙利铂支架可能改变整个作用模式和诱导细胞死亡的机制。维生素B12（氰钴胺素）及其衍生物已被证明选择性地摄取到肿瘤细胞中。此外，由抗癌剂和钴胺素组成的缀合物在x射线辐射下显示激活。靶向递送抗癌药物与x射线诱导化疗相结合将提高疗效，并对最先进的放射治疗进行重大改进。这项研究将涉及用于治疗DIPG的铂基抗癌剂的合成、表征和评估，特别关注照射激活化合物的潜力。化合物通过x射线的活化将被研究，特别注意波长依赖的影响。x射线源将包括高强度辐射，可在诊所获得，并将通过肿瘤科的Geoffrey Higgins教授获得。与同步加速器产生的能量较低的x射线的相互作用可以在英国国家同步加速器科学设施钻石光源中实现。在这些结果的基础上，这些化合物将被修改，目的是增加x射线的响应性，例如使用敏化剂或x射线可切割的部分。成功的光活化铂配合物将随后评估其在细胞中的毒性。将详细评估可能导致干扰DNA或细胞代谢，从而导致细胞死亡的机制。将通过修饰包括专门针对DIPG的分子来增强化合物的抗癌特性。该项目属于EPSRC医疗保健技术研究领域。

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.