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.

Theranostics in Boron Neutron Capture Therapy

“…Several gold nanoparticles were labeled with iodine ( 123 I [48] or 124 I [49,50]) for mice investigations. 68 Ga [51] and 64 Cu [50] may also replace the 18 F. 64 Cu-PLGA-micelles were investigated to vectorize 10 B in subcutaneous melanoma with very high tumor/healthy tissue ratios, providing prolonged survival after BNCT [52]. A derivative of BSH fused with arginine peptide was labeled with 64 Cu and showed promising brain tumor uptake, due to the addition of the arginines that facilitate the cell internalization [53].…”

Protease-triggered bioresponsive drug delivery for the targeted theranostics of malignancy

“…Considerable achievements have also been made in PSA-mediated drug accumulation and efficacy improvement. Concretely, tumor lesions targeted delivery of PSA-specific motif-conjugated nanocomplexes carrying a variety of therapeutics either alone or in combination, mainly included DOX 181 , 182 , 183 , 184 , 185 , PTX 186 , DTX 187 , SN38 188 , camptothecin 189 , thapsigargin 190 , boron-containing reagents 191 , zinc chelator 192 , antibody-drug conjugates 193 , 194 , kinase inhibitors 195 , siRNA ( Fig. 7 ) 196 , 197 , 198 , 199 , 200 , miRNA 201 , oligonucleotide 202 , therapeutic proteins 203 , and chemotherapy-based combination regimens with molecular targeted therapy 204 , antibiotic therapy 205 , gene therapy 206 , 207 , and anti-inflammatory therapy 208 .…”

Ruthenium carboranyl complexes with 2,2′-bipyridine derivatives for potential bimodal therapy application

“…The icosahedral closo-C 2 B 10 H 12 carborane 22 and metallacarborane 23 [M(C 2 B 9 H 11 ) 2 ] À clusters are 3D aromatic moieties, possessing high symmetry and stability, 24 and generally low cytotoxicity, 25,26 being good candidates for BNCT. 25,[27][28][29] In this frame, several compositions for potential BNCT applications have been developed, [30][31][32][33][34][35] including high boron-loaded DNA-oligomers, 36 periphery-decorated and core-initiated borane polyanionic macromolecules, 37 peptide-cobalt bis(dicarbollide) conjugates, 38 nucleoside-boron cluster conjugates 39,40 and cholesterol-metallacarborane conjugates, 41 among others.…”