The aim of this project is to reduce the number of mice used in preclinical anti-cancer drug development by developing and applying novel near infrared quantum dots (NIR-QDs) to improve the sensitivity and resolution of preclinical imaging. This will increase the amount of information generated in each animal, reducing the overall number of animals required per study.
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 the clinic. Imaging the growth of cancer cells in animal 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. This project will develop novel NIR-QDs which fluoresce at a higher wavelength than currently available standard fluorescent probes. This will provide a more sensitive imaging approach, allowing signals to be detected at deeper sites within the body and improving the quality of the images obtained.
The application of these new probes will allow (i) more detailed information to be gained from each animal used, (ii) repeat imaging of the same animal over time, and (ii) the use of advanced models which provide more relevant information about how useful a drug is likely to be in the clinic.
Research details and methods
The NIR-QDs developed during the course of this project will be designed so that they do not photo-bleach, will be water-soluble, and optically active in the NIR wavelength, providing improved tissue penetration and sensitivity. They will incorporate targeting ligands for uptake by specific populations of cells within the tumour which will allow the growth and drug response of cancer cells or supporting cells within the tumours to be followed. They will also include a positron-emitting radionuclide label which will allow them to be used for positron emission tomography (PET) imaging as well as fluorescence imaging, which will provide a further improvement in the resolution of the images that can be obtained, and will facilitate dual imaging in the same animal.
- Further Funding: NC3Rs PhD Studentship, Application of a 3D hydrogel-based model to replace use of animals for passaging patient-derived xenografts, April 2017, £90,000
- Further Funding: NC3Rs Project Grant, The human tumour micro-environment modelled in in vitro biomatrices and applied to cancer drug discovery, October 2009, £407,235
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 focused 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.
Kuruppu AI, Zhang L, Collins H, Turyanska L, Thomas NR, Bradshaw TD (2015). An apoferritin-based drug delivery system for the tyrosine kinase inhibitor Gefitinib. Adv Healthc Mater. 4(18): 2816-21. doi: 10.1002/adhm.201500389.
Principal investigatorDr Anna Grabowska
InstitutionUniversity of Nottingham
Co-InvestigatorProfessor David Bates
Professor Neil Thomas
Professor Amalia Patane
Dr Lyudmila Turyanska
Professor Stephen Morgan
Professor Alan Perkins
Dr Jeni Luckett
Dr Philip Clarke