Transporter-Associated Therapeutic Efficacy of an SMVT-Targeted Boron Carrier in Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) requires selective delivery of boron compounds to tumor cells to achieve therapeutic efficacy. In this study, a BNCT strategy centered on the sodium-dependent multivitamin transporter (SMVT)-targeted biotin-conjugated boron compound, BBCIP, was evaluated, with selective incorporation of p-boronophenylalanine (BPA) according to tumor transporter characteristics. To examine transporter-dependent effects, the CRL1666 metastatic brain tumor model in rats was compared with an F98 glioma model, which exhibits distinct transporter expression profiles. The F98 model is characterized by dominant L-type amino acid transporter 1 (LAT1) expression and low SMVT levels, whereas the CRL1666 model shows relatively high SMVT expression. BBCIP demonstrated stable and quantifiable intratumoral boron pharmacokinetics in both models. In BNCT experiments, BBCIP alone showed limited therapeutic efficacy in the LAT1-dominant F98 model (median survival, 29 vs. 23 days in controls), whereas survival was further improved with the addition of BPA. In contrast, in the SMVT-high CRL1666 model, BBCIP-based BNCT significantly prolonged survival (30 vs. 15.5 days in controls), with only modest additional benefit from BPA. These findings indicate that the therapeutic contribution of BBCIP-based BNCT depends on tumor transporter expression and that BPA may be advantageous in tumors with low SMVT expression. Rather than relying on a single boron carrier, these findings support a biology-driven strategy in which boron agents are selected and combined according to tumor-specific characteristics.