AIMS AND THEMES
We aim to make molecular imaging economic and accessible to patients by developing new, fast and easy-to-use chemistry for synthesis of radiopharmaceuticals in hospitals and centralised radiopharmacies. These innovations will empower emerging scanning technologies (notably Total Body PET and PET-MRI) and new therapeutic radionuclides to achieve the maximum impact on the management of patients with cancer, cardiovascular disease, neurodegenerative disease and other diseases with high socioeconomic impact, in addition to being powerful new tools for biomedical research. These aims will be achieved via a multidisciplinary programme spanning multiple themes with specific aims which all feed into one another.
RADIONUCLIDE PRODUCTION
Whilst a number of radionuclides are produced routinely for clinical use ( C, F, N and O), there are many which show great potential for clinic, yet much research is needed to develop the targetry to produce them. This theme will serve the needs of the programme by ensuring the supply of established radionuclides ( C, F, N, Cu, Cu and O) requires for the other themes, and developing production methodology for new and emerging radionuclides (such as Cl, Zn, Zn, Sc and Mn). Radionuclides will be produced both using the cyclotron facilities at the KCL PET centre and in small scale generators.
This theme is led by Phil Blower and Tony Gee at KCL.
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P.J. Blower, A nuclear chocolate box: the periodic table of nuclear medicine, Dalton Trans., 44, 4819, (2015)
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NANOMEDICINE & CELL TRACKING
Nanomedicine-based drug delivery systems and cell-based therapies represent the next generation of advanced therapies for a number of diseases. Using radionuclide imaging such as PET we can directly answer questions like: where do these cells and nanomedicine go in the body? Do they reach their target? Do the cells survive? Do they adversely affect sensitive off-target sites? Do they replicate?
This theme is led by Dr. Rafael T. M. de Rosales at KCL.
Co-registration of PET and SPECT of representative tumor from the mutimodal PET/SPECT study.
P.J. Gawne, F. Clarke, K. Turjeman, A.P. Cope, N.J. Long, Y. Barenholz, S.Y.A. Terry, R.T.M. de Rosales, PET Imaging of Liposomal Glucocorticoids using Zr-oxine: Theranostic Applications in Inflammatory Arthritis, Theranostics, 10, 3867-3879, (2020).
F. Man, L. Lim, A. Volpe, A. Gabizon, H. Shmeeda, B. Draper, A.C. Parente-Pereira, J. Maher, P.J. Blower, G.O. Fruhwirth, R.T.M. de Rosales, In Vivo PET Tracking of Zr-Labeled Vγ9Vδ2 T Cells to Mouse Xenograft Breast Tumors Activated with Liposomal Alendronate, Molecular Therapy, 27 (2019) 219-229.
F. Man, P. J. Gawne, and R.T.M. De Rosales. Nuclear imaging of liposomal drug delivery systems: A critical review of radiolabelling methods and applications in nanomedicine, Advanced Drug Delivery Reviews, 143, 134-160, (2019)
F. Man, T. Lammers, R.T.M. de Rosales, Imaging Nanomedicine-Based Drug Delivery: a Review of Clinical Studies, Mol Imaging Biol, 20, 683-695, (2018).
S. Edmonds, A. Volpe, H. Shmeeda, A.C. Parente-Pereira, R. Radia, J. Baguña-Torres, I. Szanda, G.W. Severin, L. Livieratos, P.J. Blower, J. Maher, G.O. Fruhwirth, A. Gabizon, R.T.M. de Rosales, Exploiting the Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imaging of Liposomal Nanomedicines, ACS Nano, 10, 10294-10307, (2016).
G.O. Fruhwirth, S. Diocou, P.J. Blower, T. Ng, G.E.D. Mullen, A Whole-Body Dual-Modality Radionuclide Optical Strategy for Preclinical Imaging of Metastasis and Heterogeneous Treatment Response in Different Microenvironments, J Nucl Med, 55, 686-694, (2014).
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In this theme we are designing innovative ligands that are able to rapidly form stable complexes with radiometals for the development of radiopharmaceuticals. The emphasis on new radionuclides, simple radiolabelling with metals and short half life tracers for total body PET, requires development of new chelators for new radiometals and faster acting chelators for established radiometals.
This work is led by Nicholas Long at Imperial College London and Michelle Ma at KCL.
CHELATOR CHEMISTRY
J.A. Jackson, I.N. Hungnes, M.T. Ma* and C. Rivas* Bioconjugates of Chelators with Peptides and Proteins in Nuclear Medicine: Historical Importance, Current Innovations, and Future Challenges, Bioconjugate Chem. articles asap, (2020)
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Fluorine-18 remains the workhorse radionuclide of PET and this theme will focus on biomolecules such as proteins, using novel approaches such as using chelated metal ions as a binding site for the fluoride ion.
This theme is led by Gill Reid at the University of Southampton.
FLUORINE-18 CHEMISTRY
P.J. Blower, W. Levason, S.K. Luthra, G. McRobbie, F.M. Monzittu, T.O. Mules, G. Reid and M.N. Subhan, Exploring transition metal fluoride chelates - synthesis, properties and prospects towards potential PET probes, Dalton Transactions, 48, 6767, (2019)
W. Levason, F.M. Monzittu and G. Reid, Coordination chemistry and applications of medium/high oxidation state metal and non-metal fluoride and oxide-fluoride complexes with neutral donor ligands, Coordination Chemistry Reviews, 391, 90-130 (2019)
F.M. Monzittu, I. Khan, W. Levason, S.K. Luthra, G. McRobbie and G. Reid, Rapid Aqueous Late-Stage Radiolabelling of [GaF (BnMe -tacn)] by F/ F Isotopic Exchange: Towards New PET Imaging Probes, Angew. Chem. Int. Ed., 57, 6658-6661, (2018)
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ORGANIC RADIOCHEMISTRY
The aims of this work pack are to improve fast-labelling methodology to incorporate short-lived radionuclides C, N and the novel Cl into radiopharmaceuticals. it will focus on both new chemical reactions and technologies for automation such as microfluidics.
This theme will be led by Tony Gee at KCL.
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S. Bongarzone, N. Raucci, I. C. Fontana, F. Luzi, A. D. Gee, Carbon-11 carboxylation of trialkoxysilane and trimethylsilane derivatives using [ C]CO , Chem. Commun., advanced article, (2020)
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R. Southworth, R. T. M. De Rosales, L. K. Meszaros, M. Ma., G. E. D. Mullen, G. O. Fruhwirth, J. D. Young, C. Imberti, J. Bagunya Torres, E. Andreozzi and P. J. Blower, Opportunities and challenges for metal chemistry in molecular imaging: from gamma camera imaging to PET and multimodality imaging, Advances in Inorganic Chemistry, 68, 1-41, (2016)
The aims of this work pack are to validate molecular mechanisms of new diagnostic and therapeutic radiopharmaceuticals emerging from the other work packages, and to develop preclinical multiplexed PET methodology in which several tracers can be used to study a single subject. These methods and tracers can then be translated to human scanning applications. Biological validation will be led by theme lead Rick Southworth in cardiovascular applications and Tony Ng in cancer applications, while addressing the physics and image reconstruction issues associated with tandem multiplexed scanning will be led by Paul Marsden and Andrew Reader. Gilbert Fruhwirth and Samantha Terry will also be leading primary research within this theme, studying the biological effects of radiotherapeutics.
BIOLOGICAL VALIDATION
This picture represents how radioactivity can be used for good in medical sciences. It shows DNA damage in breast cancer cells that have been exposed to radioactive Tc-99m for a considerable length of time, here, 24 hours, Tc-99m is used worldwide for non-invasive radionuclide imaging. Our team is studying how Tc-99m might also be used as a novel cancer therapeutic when used in the appropriate manner. The ability to cause damage to the DNA is one key step for any cancer therapeutic. Theoretically, it could become a potent form of radiotherapy with minimal side effects or damage to healthy tissues, due to it Auger electron emissions. The red stain represents DNA damage in the form of double-strand breaks. In blue, is the nucleus of the cells themselves and the cell membrane is in green. This picture beautifully summarises, in a snapshot, the radiobiological research we carry out with the aim of assessing the safety of different radionuclides currently used in clinical practice, like Tc99m, while also developing new targeted radionuclide therapies that will allow tailoring of the therapy to each unique patient.
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CLINICAL TRANSLATION
The role of this work pack is to liaise closely with the theme leads and with potential clinical users (particular in cardiovascular disease, cancer and other diseases of high socioeconomic impact) to identify new opportunities for new radiopharmaceuticals to be clinically translated, and to identify clinical problems to be addressed by new chemistry developments in the other theme. This will ensure that benefit to patients is maximised and accelerated.
This workpackage will be led by Sally Barrington at KCL.
S. Barrington, P. Blower and G. Cook, New horizons in multimodality molecular imaging and novel radiotracers, Clinical medicine (London), 17, 444-448, (2017)
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