Prostate cancer (PCa) is a significant health concern, particularly in its advanced
stages when metastasis occurs, causing immense suffering for patients. Prostate
specific membrane antigen (PSMA) is overexpressed on the surface of PCa cells and
its expression is associated with disease progression. The use of PSMA targeting
peptides, notably the glutamate-urea-lysine (Glu-Urea-Lys) sequence, has been
investigated for the delivery of anticancer agents, radioisotopes, and monoclonal
antibodies (mAb) to PCa lesions; however, PSMA remained less utilized for targeted
immunotherapy. Gamma-delta T cells (γδ T cells) are crucial immune cells that defend
against pathogens and have potential in anti-tumour applications. Activation and
expansion of γδ T cells ex vivo can be achieved by nitrogen-containing bisphosphates
(N-BP). The use of N-BPs in targeted delivery strategies is limited and requires further
work to improve pharmacokinetic (PK) and pharmacodynamic (PD) properties.
Zoledronic acid (ZA) is a potent N-BP that has been widely used in treating metastatic
bone cancer and in the study of γδ T cell expansion; however, ZA has unfavorable PK
and PD properties, side effects, and limited structural features for modification, thus
efforts are required in its development.
In this project, PSMA-targeted BP were investigated to develop PCa specific
immunotherapies. This included the development of a conjugatable ZA derivative with
efficacy in expanding γδ T cell populations. To aid cell uptake, prodrug strategies
utilizing the cleavable pivaloyloxymethyl (POM) group were investigated. A lead
compound was selected to conjugate with a PSMA-targeted peptide which employed
the conjugation chemistry developed in this project. In addition, a novel PSMA targeted
radiopharmaceutical labelled using 19F/18F SuFEx isotopic exchange chemistry was
developed and evaluated, showing PSMA specific in vivo uptake. This included a fully
automated radiosynthesis using the GE FASTLab™ cassette-based platform,
providing radioconjugate in a 25.0 ± 2.6% radiochemical yield (decay corrected).