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

用于高级别胶质瘤的多模式金属药物的合成和递送

• 批准号: 2329459
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2329459
• 关键词: Synthesis; delivery; multi; modal; metallodrugs

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.

弥漫性内在脑桥胶质瘤（DIPG）是一种高度侵袭性的脑肿瘤，见于儿童。其预后特别可怕，因为90%的患者在诊断后两年内死于该病。到目前为止，治疗涉及放射与化疗相结合，尽管这些方法由于肿瘤的位置和对治疗剂的不良反应而受到限制。自顺铂发现以来，金属抗癌药物受到了广泛的关注。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药物获得批准。该领域取得了实质性进展，探索了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，然后在肿瘤部位从体外激活药物，例如用超声或光。所谓的点击化学为预期的铂化合物的治疗前和治疗后修饰提供了范围，包括化学治疗剂、生物活性靶向部分或用于追踪细胞中复合物的摄取和分布的荧光标记。作为新型化合物的替代品，修饰已批准的抗癌药物为创新铂类药物提供了另一种方法。奥沙利铂与其他生物活性部分的氧化在增强递送和细胞毒性方面产生了有前景的结果。调整奥沙利铂支架可能会改变诱导细胞死亡的整个作用模式和机制。维生素B12（氰钴胺）及其衍生物已被证明可被肿瘤细胞选择性摄取。此外，由抗癌剂和钴酸盐组成的缀合物在用X射线辐射时显示活化。抗癌药物的靶向递送与X射线诱导的化疗相结合将提高疗效，并对最先进的放射治疗提出显著改进。该研究将涉及用于治疗DIPG的铂基抗癌剂的合成，表征和评估，特别关注通过辐射激活化合物的潜力。将研究通过X射线的化合物的活化，特别注意波长依赖性效应。X射线源将包括诊所提供的高强度辐射，并可通过肿瘤科的Geoffrey Higgins教授获得。与同步加速器产生的低能量低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，将对化合物进行修饰，目的是增加X射线响应性，例如使用敏化剂或可被X射线裂解的部分。铂络合物的成功光活化之后将评价其在细胞中的毒性。将详细评估可能导致干扰DNA或细胞代谢（基本上导致细胞死亡）的机制。将通过修饰以包括特异性靶向DIPG的分子来增强化合物的抗癌性质。该项目属于EPSRC医疗保健技术研究领域的福尔斯。