The development and evaluation of PSMA targeted therapeutic and imaging agents

Abstract

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).