Aim of the PhD Project:
- Generate 18F-PSMA-bioharmonophore peptide conjugates as smart imaging agents for prostate diagnosis.
- Validate the PSMA-PET/nonlinear optics tracer in the detection and localisation of prostate cancer with human tumour tissue.
Prostate cancer (PCa) is the second most common diagnosed tumour in males worldwide, with over one million new patients diagnosed every year(1). Prostate-specific membrane antigen receptor (PSMA) is highly enriched in the majority of PCa cells and is positively correlated to belligerence of the tumour(2). PSMA-positron-emission tomography (PET) uses this feature by visualising PSMA expressing prostate tumours(2). PSMA-PET using 18F-labeled PSMA agents is increasingly used to identify recurrences, with higher detection rates compared to other imaging modalities(3). However, there is an increasing interest for PSMA-PET scans in patients with a primary diagnosis of intermediate- or high-risk PCa for staging purposes. Yet PSMA-PET imaging is not as sensitive as optical imaging. Very small lesions that might be picked up by a microscope may not be seen on PSMA-PET, with negative predictive values of as low as 40% as opposed to positive predictive values of >90%. Hence, there is a need to advance 18F-PSMA-PET that will allow for more accurate diagnosis, staging and treatment follow-up in patients with PCa.
The Pantazis lab recently reported bioharmonophores(4), which are polymer-encapsulated, self-assembling peptides that are biodegradable. They display a strong second harmonic generating (SHG) signal upon two-photon excitation, a non-linear optical process in which two photons directed at a non-centrosymmetrical media (e.g. peptide assemblies lacking a generalised mirror symmetry) combine to form a new photon with twice the energy and half the wavelength. Unlike fluorescence, the SHG signal of bioharmonophores neither bleaches nor saturates with increasing illumination intensity, resulting in exceptional sensitivity in diagnostic applications. The Stasiuk lab has recently reported a PSMA-SPECT tracer(5) and a 18F-PET tracer aimed at prostate cancer(6).
In this project, we will establish a smart diagnostic probe that utilises the well-known advantages of PSMA-PET tracers with the self-assembly properties of tripeptides that form the core of bioharmonophores. Specifically, we propose to generate 18F-PSMA-bioharmonophore peptide conjugates as smart imaging agents for prostate diagnosis. Successful targeting of our PET tracer conjugate to cancer cells will lead to their specific accumulation within cells. The proximity of these conjugates in vesicles will facilitate the self-assembly of the bioharmonophore tripeptides generating a high contrast, pH-resistant, non-toxic nonlinear signal.
The combination of PET imaging and cancer cell-inducible optical imaging of our multimodal smart imaging probe will improve the specificity and the predictive value when compared with conventional PET tracer imaging for (metastatic) prostate cancer. As 18F-based radiotracers are readily available in most UK trusts, our PSMA-PET tracer conjugate can be easily translated into the clinic.
The project requires a student with a background in chemical engineering/medical physics. Knowledge of optics will be beneficial.
- F. Brayet al.,CA Cancer J Clin 68, 394-424 (2018).
- A. Ghosh, W. D. Heston,J Cell Biochem91, 528-539 (2004).
- S. Fantiet al.,The Lancet Oncology 19, e696-e708 (2018).
- A. Y. Sonayet al.,ACS Nano 10.1021/acsnano.0c10634 (2021).
- S. Y. Yap, et. al. , Chem. Commun., 56, 11090-11093 (2020).
- G. Firth et al., Probe, Chem. Commun., , 54, 3227-3230 (2018)