Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer

SIMPLE SUMMARY: Currently, there is no effective treatment that can cure metastatic prostate cancer. Various pros-tate specific membrane antigen (PSMA)-targeted radioimaging and radiotherapy agents have en-tered clinical trials; however, no PSMA-targeted chemotherapy is currently in clinical trials. We used a small molecular weight PSMA ligand and developed a new prodrug PSMA-1-VcMMAE. Although the linker and the payload drug monomethyl auristatin E (MMAE) have been widely used in antibody–drug conjugate (ADC) development, it has never been tried as a combination with a PSMA targeting ligand. Our PSMA-targeting drug conjugate showed potent and selective in vitro and in vivo antitumor activity with no toxicity observed. It has superior therapeutic index and will likely impact therapeutic management of lethal prostate cancers. ABSTRACT: Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand–drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule–drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body–drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.