Aim of the PhD Project:
- Targeted radionuclide therapy (TRT) and radiotherapy are effective methods to treat cancer but with side effects.
- The use of radiosensitisers improves their efficacy but they have suboptimal pharmacological properties.
- We will use drug delivery strategies based on nanomedicine combined with imaging to improve and guide TRT and radiotherapy.
Project Description / Background:
Targeted radionuclide therapy (TRT) relies on a radiopharmaceutical to target diseased tissues, such as those containing cancer cells. These radiopharmaceuticals consist of a molecule containing a radionuclide that emits beta or alpha particles, combined with a cell-targeting moiety for specific binding to the target cell (e.g. cancer cell receptor). Recent clinical achievements using TRT include treatment of neuroendocrine tumours with 177Lu-somatostatin analogue peptides and treatment of prostate cancer patients with 225Ac-PSMA (prostate-specific membrane antigen).
Despite their high therapeutic efficacy through targeted radiation damage at the cell level, TRT also induces side effects. These include nephrotoxicity, salivary glands toxicity/xerostomia and myelosupression. In order to improve the therapeutic efficacy of radiation therapies, a group of small-molecule drugs termed radiosensitisers have been developed. The rationale is that by making the target/tumours more radiosensitive using these chemotherapeutics, the radiation dose of TRT and hence their side effects can be minimised. Examples of radiosensitisers include PARP inhibitors such as olaparib and epigenetic modifiers such as vorinostat and 5-aza-2-deoxycytidine. These work by inhibiting key enzymes of the DNA repair (PARP) and DNA acetylation/methylation (epigenetic modifiers) of cells. Unfortunately these radiosensitising drugs – like most chemotherapeutics – are themselves not free from undesirable side effects, which include, among others, increased risk of infection and nephrotoxicity. Most of these are a result of the systemic administration of the drugs, which results in unspecific biodistribution to normal tissues.
Here, we propose to kill two birds with one stone by delivering radiosensitisers using nanomedicine-based drug delivery systems, providing targeted radiosensitisers delivery (thus fewer side effects) to allow targeted radionuclide therapies at lower radiation doses. This approach has previously been clinically proven to preferentially deliver the drugs at the target site (tumours, inflamed tissues) while reducing the side-effects of systemically administered toxic drugs in both cancer and in arthritis.
But, can we identify if the radiosensitisers are reaching its target and what is its local concentration? Being able to do so will allow us to predict the response of each specific target tissue to TRT, thereby influencing the amount of radioactivity that will be used to achieve therapeutic outcomes. In addition, combination of this information with image-based information of the concentration of TRT in the same lesions should be highly predictive of overall response to the combination therapy. Hence, we propose to develop a multi-radionuclide imaging method (multi-isotope PET or SPECT) that will allow us to radiolabel and track independently a nanomedicinal formulation of a radiosensitiser for improved target delivery and lower systemic side-effects, as well as the TRT agents. This will be possible using standard multi-radionuclide SPECT or multi-radionuclide PET imaging, by exploiting the new generation of total-body scanners. We aim to prove that the level of co-localisation of the two imaging signals in the target(s) will show a positive correlation with the response to the treatment. The student should have a background in chemistry, pharmacy or radiopharmacy, or any field related to drug delivery and molecular imaging.