Student: Aisleen Whelan
1st supervisor: Graeme Stasiuk, King’s College London
2nd supervisor: Samantha Terry, King’s College London
Clinical Supervisor: Mark Green, King’s College London
Industry Supervisor: Howard Greenwood, NNL
Project aims:
- 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
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.
The PhD candidate will be expected to have a degree in chemical sciences, biochemistry or cancer biology with a willingness to undertake nanoparticle synthesis organic chemistry, inorganic radiochemistry, tissue culture and preclinical animal studies.
Scheme showing a RaS QDs radiotherapeutics at tumours.