10-b

Boron neutron capture therapy (BNCT) requires the selective delivery of sufficient amounts of ¹⁰B to tumors. However, its clinical efficacy remains limited because the approved ¹⁰B agent L-4‑boronophenylalanine (BPA) relies primarily on the L-type amino acid transporter 1 (LAT1), leaving LAT1-low tumors refractory to treatment. Here, we report GluB-2, a water-soluble, alanine-serine-cysteine transporter 2 (ASCT2)-targeted small-molecule ¹⁰B carrier that expands BNCT applicability beyond BPA. GluB-2 exhibited high solubility, low cytotoxicity, and preferential ASCT2-mediated uptake in multiple cancer cell lines, particularly those with low LAT1 and high ASCT2 expression. In vivo, GluB-2 achieved tumor boron concentrations exceeding the therapeutic threshold (>20 μg [¹⁰B]/g tissue) after both intravenous and intraperitoneal administration, representing the first non-BPA small-molecule ¹⁰B carrier to reach this level. Upon thermal neutron irradiation, GluB-2 induced pronounced tumor suppression in both the CT26 allograft and the BPA-refractory U87MG xenograft models without evidence of systemic toxicity. These findings demonstrate that GluB-2 enables therapeutic small-molecule delivery of ¹⁰B to tumors through multiple dosing routes and expands the clinical applicability of BNCT beyond BPA, highlighting its translational potential.