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

A critical challenge\nin boron neutron capture therapy (BNCT) is\nexpanding its effectiveness through the development of novel boron\nagents with different mechanisms of action than the approved drug\n4-borono-l-phenylalanine (BPA). In this study, we developed\na small molecule boron carrier, biotinyl-<i>closo</i>-dodecaborate\nconjugate with an iodophenyl moiety (BBC-IP), incorporating biotin\nas a ligand for biotin receptors overexpressed in various cancer cells,\nalongside an albumin ligand and boron source. BBC-IP exhibited high\nwater solubility, minimal cytotoxicity, and superior cellular uptake\ncompared to BPA in both human and mouse cancer cells. Biodistribution\nstudies revealed that BBC-IP achieved enhanced tumor accumulation\n(9.7 μg [B]/g, 3 h) in mouse colon tumors, surpassing BPA’s\naccumulation levels (7.2 μg [B]/g, 3 h) at a dose of 15 mg [B]/kg.\nHowever, despite this improved tumor accumulation, BPA demonstrated\nsuperior BNCT efficacy. The intracellular localization of boron agents\nin tumor cells revealed that BPA localized throughout the cell, whereas\nBBC-IP localized mainly in the cytoplasm. These results indicate the\nintratumoral localization, as well as tumor accumulation are critical\nfor the efficacy of novel BNCT agents.