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)，以提高癌症模型的成像质量，这些模型用于在新药进入临床之前对其进行测试。目前用于测试抗癌药物的模型往往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身上效果良好的药物。我们已经建立了一些更有用的先进癌症模型，这些模型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，这在确定药物反应方面非常重要，使用目前的方法是困难的。标准细胞系可以很容易地在基因上标记为生物发光或荧光(产生光或荧光)，但对于接近患者的细胞很难实现这一点，而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，使用发光需要对动物进行额外的程序，目前使用的荧光探针很容易被动物组织阻挡。我们打算开发的探针将克服这些问题。它们将以比标准荧光探针更高的波长发出荧光，从而使信号能够在体内更深的位置被检测到，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特定群体的细胞摄取，这将使我们能够跟踪例如肿瘤内癌细胞或支持细胞的生长和药物反应。最后，它们将有一个放射性标记，使它们可以用于正电子发射计算机断层扫描和荧光成像，这将进一步提高可以获得的图像的分辨率。因此，这些新的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，并减少在此类模型中使用的动物数量，从而产生重大的3Rs影响。这些新的成像方法的应用将允许从每一种使用的动物中获得更详细的信息，允许随着时间的推移对同一动物进行重复成像，并允许使用先进的模型，这些模型提供了关于药物在临床上可能有多有用的更相关信息。这样的模型被工业界广泛用于药物开发，也被学术界用来理解肿瘤发展的科学基础。因此，我们获得的知识将产生重大的科学影响；它还将产生经济影响，因为它将简化行业筛选药物的过程，并降低抗癌药物的价格。这反过来将通过提供更便宜、更有效的癌症治疗药物而对患者有利。这些探针还可能在非癌症环境中有进一步的应用，包括在其他疾病和正常组织工程方法的开发中。

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.