Targeted, radiolabelled near-infrared quantum dots for high sensitivity and resolution, dual modality imaging of human tumours in mice

靶向放射性标记近红外量子点，用于小鼠人类肿瘤的高灵敏度和分辨率双模态成像

• 批准号: NC/L001861/1
• 负责人: Anna Maria Grabowska
• 金额: $ 47.13万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FL001861%2F1
• 关键词: Targeted; radiolabelled; near; infrared; quantum

The aim of the proposal is to use small fluorescent probes (nanoprobes), to improve the quality of imaging of cancer models that are used to test new drugs before they are moved forward into the clinic. Current models used for testing anti-cancer drugs are often not very representative of real patient tumours and so may not correctly identify drugs likely to work well in a patient. We have established a number of advanced models of cancer which are more useful for this purpose which use close-to-patient cells, incorporate additional supporting cells and are grown at site of origin of the tumour, rather than below the skin of the experimental animal, which provides them with a more relevant environment. However, imaging the growth of cancer cells in these models, and monitoring the way that the different cells within the tumours behave and interact with each other, which are important in determining drug response, is difficult with current methods. Standard cell-lines can be readily labelled genetically so that they are bioluminescent or fluorescent (produce light or fluoresce), but this is difficult to achieve with the close-to-patient cells, and the process of labelling them in this way can also result in alterations that mean that they no longer behave in the same way as patient tumours. In addition, use of luminescence involves additional procedures for the animals and the fluorescent probes currently used are easily blocked by the animal tissues. The probes we intend to develop will overcome these problems.They will fluoresce at a higher wavelength than standard fluorescent probes which will allow the signal to be detected at deeper sites within the body and improve the sensitivity and quality of the images we can obtain. They will be designed so that they are readily taken up by specific populations of cells within the tumour which will allow us to follow the growth and drug response of e.g. cancer cells or supporting cells within the tumours. Lastly, they will have a radiolabel which will allow them to be used for PET as well as fluorescence imaging, which will provide a further improvement in the resolution of the images that can be obtained. Thus, the successful development of these new nanoprobes will have significant 3Rs impact, by providing more refined pre-clinical cancer models, and reducing numbers of animals used in such models. Application of these new methods of imaging will allow more detailed information to be gained from each animal used, allow repeat imaging of the same animal over time, and allow the use of advanced models which provide more relevant information about how useful a drug is likely to be in the clinic. Such models are widely used by industry for drug development, as well as by academics for understanding the science underlying tumour development. Thus, the knowledge we will gain will have significant scientific impact; it will also have economic impact because it will streamline the process by which drugs are screened by industry, and reduce the price of anti-cancer drugs. This in turn will be good for patients by providing cheaper, more effective drugs for treatment of cancer. The probes are likely to also have further applications in non-cancer settings including in other diseases and in the development of methods for engineering normal tissues.

该提案的目的是使用小型荧光探针（纳米探针），以提高癌症模型的成像质量，这些癌症模型在新药被转移到诊所之前用于测试新药。用于测试抗癌药物的当前模型通常不太代表真正的患者肿瘤，因此可能无法正确识别可能在患者中工作得很好的药物。我们已经建立了许多先进的癌症模型，这些模型对此目的更有用，这些目的是使用接近患者的细胞，结合了额外的支撑细胞，并在肿瘤起源部位生长，而不是在实验动物的皮肤以下，从而为它们提供了更相关的环境。但是，在这些模型中成像癌细胞的生长，并监测肿瘤中不同细胞行为和相互作用的方式，这对于确定药物反应很重要，这对于当前方法很困难。标准细胞系可以很容易地在遗传上标记，以使它们具有生物发光或荧光（产生光或荧光），但这很难在接近到患者的细胞中实现，并且以这种方式对其进行标记的过程也会导致变化，这意味着它们不再像患者肿瘤一样行事。此外，发光的使用涉及动物的其他程序，并且当前使用的荧光探针很容易被动物组织阻塞。我们打算开发的探针将克服这些问题。它们的波长比标准荧光探针更高，这将使信号在体内更深的位点检测到信号，并提高我们可以获得的图像的灵敏度和质量。它们的设计将使它们容易被肿瘤内的特定细胞种群吸收，这将使我们能够遵循例如癌细胞或支持肿瘤内的细胞。最后，它们将具有放射性标记，该标标将允许它们用于PET以及荧光成像，这将进一步改善可以获得的图像的分辨率。因此，这些新纳米探针的成功开发将通过提供更精致的临床前癌症模型，并减少此类模型中使用的动物数量，从而产生显着的3RS影响。这些新成像方法的应用将允许从所用动物中获得更多详细的信息，允许随着时间的推移重复对同一动物进行反复成像，并允许使用高级模型，这些模型提供了有关药物在诊所中可能有用的有用信息的更相关信息。这种模型被行业广泛用于药物开发，以及学者，以了解肿瘤发展的科学。因此，我们将获得的知识将产生重大的科学影响。它也将产生经济影响，因为它将简化由行业筛选药物的过程，并降低抗癌药物的价格。反过来，这将通过提供更便宜，更有效的癌症药物来对患者有好处。这些探针也可能在包括其他疾病的非癌症环境和工程正常组织的方法中进一步应用。