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

使用生物分子荧光标记研究用于药物输送、传感和细胞成像应用的新型化学工具包

• 批准号: 2427593
• 金额: --
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2427593
• 关键词: Investigations; into; New; Chemical; Toolkits

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

随着医疗保健和技术进步导致预期寿命延长，不断增长和老龄化的人口面临着患癌症等非传染性疾病的越来越大的风险。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方案和目前尚未开发的临床试验药物，例如免疫疗法，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学产生真正的影响。这篇博士论文将集中在癌症诊断和治疗的生物传感、成像和治疗创新的一般领域。概要该项目将在很大程度上基于加强对发光探针与靶向生物分子(如偶联合成肽)之间基本相互作用的了解，从而产生一种生物探针，它可能在受控的微环境下靶向活的癌细胞。第二个目标是深入了解抗体标记或标记小荧光分子所涉及的化学基础上的合成和分析化学。我们将设计、合成和表征新的金属络合物，作为“一体化”成像探针，集中在癌症临床试验中感兴趣的某些抗体上，如阿瓦斯丁或抗EGFR。这些成果将改进传感和生物成像探针，用于早期癌症诊断，包括低氧肿瘤，这些肿瘤目前很难进行成像或治疗。这可以促进我们对水环境中相关结合化学的基本理解，包括使用生物正交和超分子组装协议，从而允许抗体结合后的行为与其动力学稳定性之间的关联，分子附件中的金属离子及其在水介质中的形态。AIMSA项目)将免疫治疗中感兴趣的生物分子(如简单的合成肽)功能化到金属结合的成像探针上。b)了解如何将荧光金属络合物结合到多模(PET/光学)探针中，然后在不破坏脆弱的生物分子结构的情况下将其锚定在抗体上。c)标记与PET/SPECT金属放射性同位素相关的生物分子的模式物种，如68和89Zr。开发和测试水中锌(II)、镓(III)和锆(IV)离子的冷络合方案。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这一项目。这将使设计的成像探针能够在细胞内进行测试。Andy Burrow教授(10%)将担任导师，并将在该项目的更多化学方面提供支持