One-step, site-specific labelling of His-tagged proteins with technetium-99m and rhenium-188 for cancer imaging and therapy

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:
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.

Strains on the healthcare system in the UK create an acute need for finding more effective, efficient, safe, and accurate non-invasive imaging solutions for clinical decision-making, both in terms of diagnosis and prognosis, and to reduce unnecessary treatment procedures and associated costs. Medical imaging is currently undergoing a step-change facilitated through the advent of artificial intelligence (AI) techniques, in particular deep learning and statistical machine learning, the development of targeted molecular imaging probes and novel "push-button" imaging techniques. There is also the availability of low-cost imaging solutions, creating unique opportunities to improve sensitivity and specificity of treatment options leading to better patient outcome, improved clinical workflow and healthcare economics. However, a skills gap exists between these disciplines which this CDT is aiming to fill.

Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.

- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.

- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.

- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.

We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.