Inorganic nanoparticles for radiolabelling with 223Ra / 212Pb, for multimodal imaging and therapy in cancer.

Aim of the PhD Project:
To develop methodology to produce 223RaS Quantum dot (QD) nanoparticles and 212PbS QDs for dual modal therapeutic and optical imaging probe.
Develop ligands specifically tuned for 223Ra and 212Pb that allow for nucleation of QDs at different temperatures using microwave synthesis techniques.
Incorporate targeting for surface receptors expressed in cancer such as PSMA for prostate cancer and uPAR in high grade glioma (HGG)
Validation of therapeutic efficacy in vitro and in vivo of alpha and beta-emitting QDs.
Project description:
This project sets out to develop new methods of targeting alpha (and beta) particle-emitting radionuclide therapies to cancer cells utilising nanoparticle platforms. Quantum dots will be the nanoparticle of choice as they can be synthesised in a facile manner using microwave synthesis and functionalised with targeting peptides/antibodies in a simple one-pot manner. The alpha-emitting-nanoparticles will then also be fluorescent giving the option of imaging where the therapeutic particle is by near-infrared imaging. This project will focus on radium-223 and lead-212, as they are promising radionuclide therapeutics and can be made into 223RaS or 212PbS quantum dots.
Drugs containing alpha-particle-emitting radionuclides have been identified as promising treatments for late-stage metastatic cancer and there is significant research and commercial interest in this area. The first alpha-emitting pharmaceutical developed for clinical use, with proven patient benefit was radium-223 dichloride. Radium-223 dichloride is a licenced product for patients with late-stage prostate cancer which has spread to their bones and has been in use in the NHS since 2016. Developments since then now enable the use of alpha-particle-emitting radionuclides to treat primary types of cancer. In these drugs, the radionuclide must be attached to a targeting molecule so it can be specifically delivered to the cancer cells. This requires the radionuclide to be strongly and stably bound to the targeting molecule. As radium has unique chemical properties (low charge-to-ionic radius ratio causing weak electrostatic metal-ligand interactions) the use of chelation chemistry is limited. To overcome this, we will produce nanoparticles from simple source elements/molecules that are tuned to bind to radium-223 preferentially and then functionalise the surface of the nanoparticle with a targeting group in a facile one-pot manner.
212Pb, the radionuclide studied here, is gaining attention as an alternative a-emitter due to its increasing availability, suitable half-life, and several options with which to attach it to tumour-targeting compounds. Also, it holds promise to treat both large primary tumours and small metastases through its release of b and a particles. 212Pb is also generator-produced, making on-demand elution possible. Initial (pre)clinical work has shown the potential of 212Pb-labeled radiopharmaceuticals in treating cancers, however other methods with which to enhance 212Pb uptake in cancer cells are an interesting avenue to explore.
We will validate the targeting of these 223RaS/212PbS therapeutic QDs in 2 cancer models. Firstly, prostate cancer models will be used to compare the QDs to the therapeutic alpha/beta counterparts that are in the clinic. Secondly high-grade glioma (HGG) models, where the use of radiotherapy is limited to less targeted radiotherapy such as gamma knife or proton beam, will also be explored.

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.