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

Autor: Wang S; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Blaha C; Department of Bioengineering and Therapeutic Sciences , University of California , San Francisco , California , United States., Santos R; Department of Neurological Surgery , University of California , San Francisco , California , United States., Huynh T; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Hayes TR; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Beckford-Vera DR; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Blecha JE; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Hong AS; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Fogarty M; Department of Neurological Surgery , University of California , San Francisco , California , United States., Hope TA; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Raleigh DR; Department of Neurological Surgery , University of California , San Francisco , California , United States.; Departments of Radiation Oncology , University of California , San Francisco , California , United States., Wilson DM; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Evans MJ; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., VanBrocklin HF; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States., Ozawa T; Department of Neurological Surgery , University of California , San Francisco , California , United States., Flavell RR; Department of Radiology and Biomedical Imaging , University of California , San Francisco , California , United States.; Department of Pharmaceutical Chemistry , University of California , San Francisco , California , United States.
Jazyk: angličtina
Zdroj: Molecular pharmaceutics [Mol Pharm] 2019 Sep 03; Vol. 16 (9), pp. 3831-3841. Date of Electronic Publication: 2019 Aug 16.
DOI: 10.1021/acs.molpharmaceut.9b00464
Abstrakt: 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 (IC 50 from 555.7 to 20.3 nM). Three selected compounds 1a , 1d , and 1f were administered to mice, and their in vivo blocking of 68 Ga-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.
Databáze: MEDLINE
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