New targeted chemotherapeutics are urgently needed to minimize off-target toxicity and reduce the high mortality rate associated with metastatic prostate cancer (PCa). We report on the modular synthesis, pharmacokinetics, and efficacy of two small-molecule drug-conjugates (SMDCs) targeted to prostate-specific membrane antigen (PSMA) incorporating either: (1) a cathepsin-B cleavable valine-citrulline, or (2) an acid-responsive phosphoramidate linker. Key to the selectivity of these conjugates is CTT1298, a nanomolar affinity ligand that binds irreversibly to PSMA and has been shown to rapidly internalize payloads into PSMA-expressing PCa cells. Other crucial components in the design of the conjugates include: (1) MMAE, a known potent cytotoxic payload, and (2) an albumin-binder, proven to improve residence time of drug conjugates. At a dose of 0.8 mg/kg (~250 nmol/kg), both SMDCs showed significant efficacy in a PSMA(+) PC3-PIP mouse model of human PCa compared to controls, without inducing systemic toxicity. Though localization of the SMDCs was observed in tissues apart from the tumor, release of MMAE was observed predominantly in tumor tissue, at levels 2-3 orders of magnitude higher than non-target tissues. Furthermore, SMDC 2, which incorporated a novel pH-responsive phosporamidate linker, demonstrated improved efficacy over SMDC 1 that has a valine-citrulline linker, with a 100% survival over 90 days and 4 out of 8 mice showing complete tumor growth inhibition after 6 weekly doses of 0.8 mg/kg (244 nmol/kg). Our findings demonstrate the potential of irreversible PSMA inhibitors combined with pH-responsive linkers as a way to specifically deliver chemotherapeutic drugs to PCa tumors with minimal toxicity.
Molecular cancer therapeutics. 2022 Aug 23 [Epub ahead of print]
Feyisola P Olatunji, Michael Pun, Jacob W Herman, Oscar Romero, Mitchell Maniatopoulos, Joseph D Latoche, Robert A Parise, Jianxia Guo, Jan H Beumer, Carolyn J Anderson, Clifford E Berkman
Washington State University, Pullman, WA, United States., University of Missouri, Columbia, MO, United States., Department of Chemistry, Pullman, WA, United States., University of Pittsburgh, Pittsburgh, PA, United States., University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States., UPMC Hillman Cancer Center, Pittsburgh, PA, United States., Washington State University, PULLMAN, WA, United States.