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

Lead Research Organisation: University of Nottingham
Department Name: School of Medicine

Abstract

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.

Technical Summary

This proposal will use near infrared quantum dots (NIR-QDs), to improve sensitivity and resolution of imaging in advanced pre-clinical cancer models. Successful development of NIR-QDs will have 3Rs impact, enabling use of more refined, patient-relevant cancer models and reducing numbers of animals used. Academia and Pharma are focussed on developing new cancer drugs resulting in the use of >430,000 mice/year. We estimate that since more advanced patient-relevant cancer models will predict drug failure earlier in preclinical testing, numbers of animals used for continued evaluation of such failing drugs would be reduced by half (~170,000 animals/year).
Bioluminescent/fluorescent imaging despite advantages has drawbacks, especially for use in advanced cancer models. Bioluminescent imaging requires administration of substrate (an additional in vivo procedure); organic fluorophores photo-bleach and have limited sensitivity due to light absorption by tissues. For application in advanced models using close-to-patient tissues, standard labelling methods cause loss of cellular heterogeneity resulting in models unrepresentative of the original tumour.
The NIR-QDs we will develop do not photo-bleach, will be water-soluble and optically active in the NIR wavelength, providing improved tissue penetration and sensitivity, and will incorporate targeting ligands for uptake by specific populations of cells within complex xenografts, and a positron-emitting radionuclide for translation into the PET/CT imaging platform.
The knowledge gained will have scientific as well as 3Rs impact, leading to development of probes that can be more broadly applied to imaging complex tissues in diseases other than cancer, and in a non-disease context e.g. bioengineered tissues. The probes also have potential for economic impact, through improving the drug discovery cascade by refinement of patient-relevant pre-clinical cancer models that are better able to predict clinical outcomes.

Publications

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