Boronotyrosine, a Borylated Amino Acid Mimetic with Enhanced Solubility, Tumor Boron Delivery, and Retention for the Re-emerging Boron Neutron Capture Therapy Field

Abstract

Boron neutron capture therapy (BNCT) is a reemerging binary cellular level cancer intervention that occurs through the interaction of a cancer-specific 10 boron ( 10 B) drug and neutrons. We created a new 10 B drug, 3-borono-L-tyrosine (BTS), that improves on the characteristics of the main historical BNCT drug 4-borono-L-phenylalanine (BPA). BTS has up to 4 times greater uptake in vitro than BPA and increased cellular retention. Like BPA, BTS uptake is mediated by the L-type amino acid transporter-1 (LAT1) but is less sensitive to natural amino acid competition. BTS can be formulated and bolus dosed at much higher levels than BPA, resulting in 2−3 times greater boron delivery in vivo. Fast blood clearance and greater tumor boron delivery result in superior tumor-to-blood ratios. BTS boron delivery appears to correlate with LAT1 expression. BTS is a promising boron delivery drug that has the potential to improve modern BNCT interventions.

Amino Acid-Based Boron Carriers in Boron Neutron Capture Therapy (BNCT)

“…In the re-evaluation of 3 , its water solubility was shown to be remarkably higher than BPA (125 g/L vs. 0.72 g/L), but in vitro and in vivo studies did not show remarkable differences in boron accumulation in four different tumor cell lines (B16F10 mouse melanoma, T3M-4 human pancreatic adenocarcinoma, A549 human lung carcinoma and U-87 MG human glioblastoma ( Table S1 , entry 5; Table S3 , entry 11 and 12; Table S2 , entry 6, respectively)) or statistically significant difference in biodistribution in vivo studies ( Table S4 , entry 10) except higher accumulation of boron into kidneys when using 3 or its fructose complex. In a very recent research paper accepted during the writing process of this review, 3-borono tyrosine ( 51 ) inspired by the above-mentioned research has been synthesized and evaluated in vivo and in vitro [ 133 ]. The compound was also studied for its solubility by dissolving its hydrochloric salt into water and neutralizing this solution with a 10 M NaOH solution.…”