期刊
MOLECULAR PHARMACEUTICS
卷 16, 期 9, 页码 3831-3841出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.9b00464
关键词
boron neutron capture therapy (BNCT); prostate cancer; prostate-specific membrane antigen (PSMA) inhibitor; carborane; boron uptake
资金
- American Cancer Society Individual Research Grant [IRG-97-150-13]
- New Directions in Prostate Cancer Research Award of the University of California, San Francisco Prostate Cancer Research Program
- Helen Diller Family Comprehensive Cancer Center Support Grant of the National Institutes of Health [P30 CA 82103]
- David Blitzer Young Investigator Award of the Prostate Cancer Foundation
- Physician Research Training Grant from the Department of Defense [PC 150932]
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( 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 mu g/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.
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