Potential for boron neutron capture therapy (BNCT) with ASCT2-targeted boron agents.

Abstract

233 Background: Boron Neutron Capture Therapy (BNCT) is a cutting-edge particle irradiation technique that utilizes the nuclear reaction triggered by the irradiation of non-radioactive boron-10 with thermal neutrons, selectively annihilating tumor cells that have incorporated boron. In the clinical arena, Boronophenylalanine (BPA), a phenylalanine compound targeting amino acid receptors, has been the cornerstone of BNCT. While BNCT has been effective against malignant gliomas, its dependency on BPA uptake has illuminated the existence of inherent resistance within specific cells, tissues, and cancer types. This study pivots towards the Alanine-serine-cysteine transporter 2 (ASCT2)—a transporter distinct from LAT1—investigating its potential as a gateway for the development of innovative boron carriers, with the aim of expanding the clinical applicability and effectiveness of BNCT. Methods: This research embarked on in vitro investigations to evaluate boron accumulation in F98 and C6 rat glioma cells, and 9L rat gliosarcoma, following 24 hours of exposure to BPA and GluB-2 (10 μg B/ml each). Complementary in vivo studies involved the intravenous administration of these compounds to an F98 rat brain tumor model, with the subsequent measurement of boron distribution at 2.5, 6, and 24 hours post-administration. The efficacy of these treatments was then ascertained through neutron irradiation experiments, gauging therapeutic outcomes via the survival periods of the subjects. Results: In vitro findings highlighted that GluB-2 facilitated a significantly higher intracellular boron concentration compared to BPA in F98 cells (p=0.02, Student's t-test). In vivo results indicated that the apex of boron biodistribution in tumors was achieved at 2.5 hours post-BPA treatment and at 6 hours post-GluB-2 treatment, with GluB-2 securing a superior maximum intratumor boron concentration. Survival analysis revealed a mean survival of 28.0±2.5 days for the neutron alone group, 37.7±5.0 days for the group receiving BPA IV + BNCT at 2.5 hours, 55.1±19.9 days for the group treated with GluB-2 IV + BNCT at 6 hours, and 25.3±1.4 days for the untreated group. Remarkably, the group treated with GluB-2 demonstrated significantly prolonged survival compared to the BPA-treated group (p<0.001, log-rank test). Conclusions: Combining BNCT with GluB-2 showed superior efficacy over BPA. Further research is needed to optimize boron concentration timing and ASCT2 expression levels, yet GluB-2 presents a promising advancement in BNCT, potentially transforming malignant brain tumor treatment.