Synthesis and Initial Biological Evaluation of Boron-Containing Prostate-Specific Membrane Antigen Ligands for Treatment of Prostate Cancer Using Boron Neutron Capture Therapy

• Published in: Molecular pharmaceutics Vol. 16; no. 9; pp. 3831 - 3841
• Main Authors: Wang, Sinan, Blaha, Charles, Santos, Raquel, Huynh, Tony, Hayes, Thomas R, Beckford-Vera, Denis R, Blecha, Joseph E, Hong, Andrew S, Fogarty, Miko, Hope, Thomas A, Raleigh, David R, Wilson, David M, Evans, Michael J, VanBrocklin, Henry F, Ozawa, Tomoko, Flavell, Robert R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03.09.2019
• Subjects: prostate cancer; carborane; boron uptake; boron neutron capture therapy (BNCT); prostate-specific membrane antigen (PSMA) inhibitor
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.9b00464

Boron neutron capture therapy (BNCT) is a therapeutic modality which has been used for the treatment of cancers, including brain and head and neck tumors. For effective treatment via BNCT, efficient and selective delivery of a high boron dose to cancer cells is needed. Prostate-specific membrane antigen (PSMA) is a target for prostate cancer imaging and drug delivery. In this study, we conjugated boronic acid or carborane functional groups to a well-established PSMA inhibitor scaffold to deliver boron to prostate cancer cells and prostate tumor xenograft models. Eight boron-containing PSMA inhibitors were synthesized. All of these compounds showed a strong binding affinity to PSMA in a competition radioligand binding assay (IC50 from 555.7 to 20.3 nM). Three selected compounds 1a, 1d, and 1f were administered to mice, and their in vivo blocking of 68Ga-PSMA-11 uptake was demonstrated through a positron emission tomography (PET) imaging and biodistribution experiment. Biodistribution analysis demonstrated boron uptake of 4–7 μg/g in 22Rv1 prostate xenograft tumors and similar tumor/muscle ratios compared to the ratio for the most commonly used BNCT compound, 4-borono-l-phenylalanine (BPA). Taken together, these data suggest a potential role for PSMA targeted BNCT agents in prostate cancer therapy following suitable optimization.