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

Abstract

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.

• Authors: Sinan Wang, Charles Blaha, Raquel Santos, Tony Huynh, Thomas R Hayes, Denis R Beckford-Vera, Joseph E Blecha, Andrew S Hong, Miko Fogarty, Thomas A Hope, David R Raleigh, David M Wilson, Michael J Evans, Henry F VanBrocklin, Tomoko Ozawa, Robert R Flavell
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 16 Issue 9 Pg. 3831-3841 (09 03 2019) ISSN: 1543-8392 [Electronic] United States
• PMID: 31381351 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, Surface
• Boron Compounds
• Boronic Acids
• Gallium Isotopes
• Gallium Radioisotopes
• Ligands
• Oligopeptides
• Radiation-Sensitizing Agents
• gallium 68 PSMA-11
• Phenylalanine
• Edetic Acid
• FOLH1 protein, human
• Glutamate Carboxypeptidase II
• 4-boronophenylalanine

Topics

• Animals
• Antigens, Surface (metabolism)
• Boron Compounds (chemistry, pharmacokinetics)
• Boron Neutron Capture Therapy (methods)
• Boronic Acids (chemistry, pharmacokinetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Delivery Systems (methods)
• Edetic Acid (analogs & derivatives, pharmacokinetics)
• Gallium Isotopes
• Gallium Radioisotopes
• Glutamate Carboxypeptidase II (antagonists & inhibitors, metabolism)
• Humans
• Inhibitory Concentration 50
• Ligands
• Male
• Mice
• Mice, Nude
• Oligopeptides (pharmacokinetics)
• Phenylalanine (analogs & derivatives, chemistry, pharmacokinetics)
• Positron Emission Tomography Computed Tomography
• Prostatic Neoplasms (pathology, radiotherapy)
• Radiation-Sensitizing Agents (chemistry, pharmacokinetics)
• Tissue Distribution
• Xenograft Model Antitumor Assays