Student: Joana do Mar Machado
Aim of the PhD Project:
The project will combine new transition metal chemistry with protein engineering to produce and evaluate preclinically (in vitro, in vivo) a theranostic pair of radiopharmaceuticals, that can be labelled quickly and simply with technetium-99m and rhenium-188, for molecular imaging and targeted radionuclide therapy of cancer.
Project Description / Background:
This project will suit a candidate with a first degree in chemistry, with a particular interest in inorganic and biomolecular chemistry as well as medical applications.
From the 1990s to the present time, nuclear medicine has moved from the functional imaging radiopharmaceuticals based on Tc-99m complexes of unknown structure (Tc-99m-bisphosphonates, DMSA, DTPA etc.) and barely understood mechanism of uptake, into a new era of molecular imaging. In particular, the use of biomolecules (mainly peptides and proteins) as molecular targeting vectors has become the mainstay of molecular imaging during this period. Chemistry for radiolabelling such molecules with positron emitting radionuclides such as Ga-68 and F-18 for PET imaging has been a major focus of research and development in the last 20 years (including particularly efficient chelator chemistry developed at King’s, using our proprietary tris(hydroxypyridinone) (THP) chelators). However, the parallel development of Tc-99m-labelling methods for them has been almost entirely neglected since 2000. Yet, despite the growth of PET, Tc-99m radiopharmaceutical development remains a high priority for several reasons. PET scanners, and the provision of radiotracers for PET, are more costly and less widely available than for SPECT with Tc-99m. Both developed countries and low-to-middle income countries are likely to continue to depend on Tc-99m for the foreseeable future. The recent crises in Mo-99 production, leading to shortages of Tc-99m, have galvanised nations and industry into development of new production methods and implementation of new production facilities for Mo-99 and Tc-99m. At the same time, improvements in commercial SPECT scanner design have continued, leading to better quantification, resolution and sensitivity as well as truly dynamic SPECT. There is therefore now an unmet need to develop new chemistry for this new age of molecular imaging with SPECT (Tc-99m)1 and to partner it with chemistry for targeted radionuclide therapy (Re-188)2.
The major unmet need is methodology to make radiolabelling of sensitive biomolecules simple, efficient, and undemanding in terms of infrastructure such as automated synthesis equipment. Without this, clinical application will not progress. To make the new generation of radiotracers readily accessible and economic to the medical community and its patients, including those in lower and middle income countries, the ideal radiolabelling would employ a procedure similar to the well-established kit-based Tc-99m chemistry developed in the 1970s, involving operations as simple as adding Tc-99m generator eluate to a kit vial containing the required reducing agents and other ingredients. Purification and other additional steps should be avoided. These requirements are not met by current chemistry for biomolecular 99mTc/188Re labelling. The same principles apply to the development of methods for radiolabelling biomolecules with radionuclides for targeted radionuclide therapy.
Meeting this unmet need will enable us to meet the more directly clinical unmet need for widely available labelled proteins for imaging cancer and other diseases in the clinic.
- Blower PJ. A nuclear chocolate box: the periodic table of nuclear medicine. Dalton Trans 2015;44:4819-4844.
- Blower PJ. Rhenium-188 radionuclide therapy: challenges and prospects. Int J Nucl Med Res 2017; July special issue 39-53.