1st supervisor: Rafael T. M. de Rosales
2nd supervisor: Sam Terry
Targeted radionuclide therapy (TRT) relies on a radiopharmaceutical to specifically target diseased tissues, such as those containing cancer cells. These radiopharmaceuticals typically consist of a molecule containing a radionuclide that emits β- or α 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- and 90Y- labelled 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 small nanomedicines based on PEGylated liposomal drug carriers; this non-invasive strategy will provide more 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 that will allow us to radiolabel and track independently a nanomedicinal formulation of a radiosensitiser for improved target delivery and low side-effects, as well as the TRT agents. 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.