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

该提案的目的是使用小型荧光探针（纳米探针）来提高癌症模型的成像质量，这些癌症模型用于在新药进入临床之前进行测试。目前用于测试抗癌药物的模型通常不能很好地代表真实的患者肿瘤，因此可能无法正确识别可能在患者中发挥良好作用的药物。我们已经建立了许多先进的癌症模型，这些模型更适用于这一目的，它们使用接近患者的细胞，加入额外的支持细胞，并在肿瘤起源部位生长，而不是在实验动物的皮肤下生长，这为它们提供了更相关的环境。然而，在这些模型中成像癌细胞的生长，并监测肿瘤内不同细胞的行为和相互作用的方式，这对确定药物反应很重要，但目前的方法很困难。标准细胞系可以很容易地进行遗传标记，使它们成为生物发光或荧光（产生光或荧光），但这很难用接近患者的细胞实现，并且以这种方式标记它们的过程也可能导致改变，这意味着它们不再以与患者肿瘤相同的方式表现。此外，发光的使用涉及用于动物的额外程序，并且目前使用的荧光探针容易被动物组织阻断。我们打算开发的探针将克服这些问题。它们将在比标准荧光探针更高的波长下发出荧光，这将允许在体内更深的部位检测到信号，并提高我们可以获得的图像的灵敏度和质量。它们将被设计成易于被肿瘤内的特定细胞群吸收，这将使我们能够跟踪例如肿瘤内的癌细胞或支持细胞的生长和药物反应。最后，它们将具有放射性标记，这将允许它们用于PET以及荧光成像，这将进一步提高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细的临床前癌症模型并减少此类模型中使用的动物数量来产生显著的3R影响。这些新的成像方法的应用将允许从所使用的每只动物获得更详细的信息，允许随着时间的推移对同一动物重复成像，并允许使用先进的模型，这些模型提供有关药物在临床中可能有多有用的更多相关信息。这些模型被工业界广泛用于药物开发，也被学术界广泛用于了解肿瘤发展的科学基础。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，因为它将简化药物筛选过程，并降低抗癌药物的价格。这反过来又会为患者提供更便宜，更有效的癌症治疗药物。这些探针也可能在非癌症环境中有进一步的应用，包括在其他疾病中和在工程正常组织的方法的开发中。

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.