Development of a Prostate-Specific Antigen Targeted Dual Drug Conjugate for Prostate Cancer Therapy

Prostate cancer (PC) is the most frequently diagnosed cancer and the second leading cause of cancer deaths in American men. While localized cases can be cured through surgery or local radiation, metastatic PC lacks curative therapy. The challenges to the success of treating advanced PC include the adverse effects of current treatment strategies, the continuous generation of cancer cells by cancer stem cells, and tumor heterogeneity. To overcome these challenges, researchers have explored the prodrug approach for targeted, combination drug delivery or release of cytotoxic agents specifically to sites of metastatic PC to improve therapeutic efficacy while decreasing systemic toxicity. The objective of this study is to develop a dual drug conjugate with a prostate-specific antigen (PSA) peptide recognition sequence for PC-specific combination SN-38 and cabazitaxel delivery in the treatment of advanced PC. To achieve this, His-Ser-Ser-Lys-Leu-Glu terminated with the dibenzocyclooctyne (DBCO) functional group conjugated to SN-38 via a leucine spacer was synthesized. Similarly, His-Ser-Ser-Lys-Leu-Glu terminated with azido poly(ethylene glycol) conjugated to cabazitaxel via a leucine spacer was synthesized. The conjugates were linked together via click chemistry to synthesize a dual drug conjugate. In vitro exposure to exogenous PSA was found to trigger the release of cytotoxic drugs. The dual drug conjugate exhibited time- and concentration-dependent cytotoxicity in PC-3 and LNCaP PC cells. The observed cytotoxicity was also dependent on PSA expression in the cellular models tested. This study demonstrates the potential of peptide-drug conjugates for the delivery of combination chemotherapeutics for selective cytotoxicity to PC cells.