A Water-Soluble Small Molecule Boron Carrier Targeting Biotin Receptors for Neutron Capture Therapy

A critical challenge in boron neutron capture therapy (BNCT) is expanding its effectiveness through the development of novel boron agents with different mechanisms of action than the approved drug 4-borono-l-phenylalanine (BPA). In this study, we developed a small molecule boron carrier, biotinyl-<i>closo</i>-dodecaborate conjugate with an iodophenyl moiety (BBC-IP), incorporating biotin as a ligand for biotin receptors overexpressed in various cancer cells, alongside an albumin ligand and boron source. BBC-IP exhibited high water solubility, minimal cytotoxicity, and superior cellular uptake compared to BPA in both human and mouse cancer cells. Biodistribution studies revealed that BBC-IP achieved enhanced tumor accumulation (9.7 μg [B]/g, 3 h) in mouse colon tumors, surpassing BPA's accumulation levels (7.2 μg [B]/g, 3 h) at a dose of 15 mg [B]/kg. However, despite this improved tumor accumulation, BPA demonstrated superior BNCT efficacy. The intracellular localization of boron agents in tumor cells revealed that BPA localized throughout the cell, whereas BBC-IP localized mainly in the cytoplasm. These results indicate the intratumoral localization, as well as tumor accumulation are critical for the efficacy of novel BNCT agents.