Investigations into New Chemical Toolkits for Drug Delivery, Sensing and Cellular Imaging Applications using the Fluorescence Labelling of Biomolecule

随着医疗保健和技术进步导致预期寿命延长，不断增加和老龄化的人口面临着越来越大的癌症等非传染性疾病的风险。开发新型的、有针对性的个性化传感和成像药物是非常可取的。这项研究将通过利用廉价的协议和目前正在开发的临床试验药物（例如免疫治疗药物），解决与药物相关的更清洁，快速的合成过程。这项工作将完全嵌入生物传感和成像/医疗保健技术的战略研究方向，这可能对癌症的早期诊断和个性化医疗产生真实的影响。该博士论文将重点关注癌症诊断和治疗的生物传感、想象和治疗创新的一般领域。概述该项目将在很大程度上基于增强对发光探针之间基本相互作用的理解，并在缀合时靶向生物分子（例如合成肽），从而产生生物探针，它可能在受控微环境下靶向活癌细胞。第二个目标是深入了解合成和分析化学，这些化学是抗体标记或小荧光分子标记的化学基础。我们将设计、合成和组装新的金属络合物作为“一体化”成像探针，以癌症临床试验中感兴趣的某些抗体为中心，如阿瓦斯丁或抗EGFR。这些成果将改进用于早期癌症诊断的传感和生物成像探针，包括用于低氧肿瘤，这些肿瘤通常难以进行成像或治疗。这可以推进我们对水性环境中相关缀合化学的基本理解，包括使用生物正交和超分子组装方案，从而允许缀合后抗体行为与其动力学稳定性之间的相关性，与存在于分子附属物中的金属离子以及它们在水介质中的形态形成。Aimsa项目）用于免疫治疗的感兴趣的生物分子的功能化，例如简单的合成肽，B）理解荧光金属络合物如何可以被结合到多模态（PET/光学）探针中，然后将其锚定到抗体上而不破坏脆弱的生物分子结构。c）用与PET/SPECT金属放射性同位素如68 Ga和89 Zr相关的模型物质标记生物分子。锌（II）的“冷”螯合的开发和测试方案，Ga（III）和Zr（IV）离子在水中。Charareh Pourzand博士（20%）将通过提供组织和细胞培养方面的知识和培训来协助该项目。这将允许设计用于细胞内测试的成像探针。Andy Burrows教授（10%）我将作为一个导师，也将支持在更多的化学方面的这个项目

As healthcare and technology advances lead to longer life expectancies, an ever increasing and ageing populationfaces a growing risk from non-communicable diseases such as cancer. The development of novel, targetedpersonalised sensing and imaging drugs is highly desirable. This research would address cleaner, rapid syntheticprocesses with pharmaceutical relevance by the utilisation of inexpensive protocols and drugs currently underdevelopment for clinical trials, e.g. immune-therapeutics. The work would be fully embedded in the strategic researchdirection of biosensing and imaging/healthcare technology, which could have real impact in early diagnosis of cancerand personalised medicine. The PhD thesis will focus on the general area of biosensing, imagining and therapeuticinnovations for cancer diagnosis and therapy.OutlineThe project would largely be based on enhancing the understanding of the fundamental interactions betweenluminescent probes and targeting biomolecules such as synthetic peptides upon conjugation, leading to a biologicalprobe, which could potentially target living cancer cells under controlled microenvironments. A secondary aim wouldbe to gain an in depth understanding of the synthetic and analytical chemistry underpinning the chemistry implicatedin the antibody labelling or tagging with small fluorescent molecules.We would design, synthesise, and characterise new metal complexes as "all-in-one" imaging probes, centred oncertain antibodies of interest for clinical trials of cancer, such as Avastin or anti-EGFR. Outputs would lead toimproved sensing and bioimaging probes for early cancer diagnosis, including for hypoxic tumours, which arecurrently hard to access for imaging or treatment. This could advance our fundamental understanding of theassociated conjugation chemistry in aqueous environments, including using bioorthogonal and supramolecularassembly protocols, thus allowing for correlation between antibody behaviour post conju gation and its kineticstability, with the metal ions present in the molecular appendages and their speciation in aqueous media.Project Aimsa) Functionalisation of biomolecules of interest for immune-therapies such as simple synthetic peptides, onto metalbound imaging probes.b) Understanding how fluorescent metal complexes can be incorporated in multimodality (PET/optical) probes, whichare then anchored onto antibodies without destroying the fragile biomolecular constructs.c) Labelling of biomolecules with model species of relevance to PET/SPECT metallic radio isotopes such as 68Gaand 89Zr. Development and testing protocols for the "cold" chelation of Zn(II), Ga(III) and Zr(IV) ions in water.Dr Charareh Pourzand (20 %) will assist in this project by providing knowledge and training in tissue and cell culture.This will allow for the imaging probes designed to be tested within cells.Professor Andy Burrows (10 %) will act as a mentor and will also support in the more chemical aspects of this project