Biological evaluation of a glucose-based boron carrier as a potential agent for boron neutron capture therapy

Abstract

Boron neutron capture therapy (BNCT) is an innovative radiation oncology approach that targets tumors selectively, minimizing damage to healthy tissues through high-linear-energy-transfer particles released during the boron neutron capture reaction. Current boron carriers like sodium mercaptoundecahydrododecaborate (BSH) and L-p-boronophenylalanine (BPA) face limitations in specificity and solubility. Our recently developed 6-O-(o-carboranylmethyl)-d-glucopyranose (B-Glc) shows promise as an alternative, demonstrating strong interactions with glucose transporters in human head and neck squamous cell carcinoma (HNSCC) CAL 27 cells in vitro. This study aims to extend in vitro investigations to three additional patient-derived human HNSCC cell lines (UT-SCC-14, UT-SCC-28, and UT-SCC-42B) and to further evaluate in vivo pharmacokinetics in selected HNSCC tumor xenografts. The B-Glc showed superior uptake and favorable kinetic parameters compared to BPA and BSH in all tested cell lines. Initial positron emission tomography imaging using [¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) radiotracer confirmed increased glucose uptake in CAL 27 and UT-SCC-14 tumors in vivo, supported by glucose transporter 1 (GLUT1) expression observed in tumor section immunohistochemistry. Biodistribution studies of the B-Glc (75 mg/kg dose) revealed no significant impact of blood glucose levels on tumor uptake, with peak boron accumulation at 15-30 min post-injection, comparable uptake to the clinical BPA-fructose complex (400 mg/kg dose) performance at 60 min, achieving the required tumor boron concentration (>20 ppm) for effective BNCT. Overall, this study underscores an advancement in targeted BNCT, highlighting B-Glc as an effective GLUT1-targeting carrier for enhanced therapeutic outcome in HNSCC and the potential to use [¹⁸F]FDG as a companion diagnostic for the glucoconjugate.

Keywords: BNCT; GLUT1; boron delivery agents; boron neutron capture therapy; drug delivery; glucoconjugate; glucose transporter 1.

FIGURE 1

Targeted delivery of the B‐Glc via the glucose transporter GLUT1, followed by tumor irradiation with a homogeneous thermal neutron beam. The irradiation is specifically focused and uniformly distributed within the tumor area, inducing the emission of α and ⁷Li particles. This results in DNA double‐strand breaks and eventual cancer cell death, while sparing surrounding healthy cells. Figure created using https://BioRender.com/w46g324.

FIGURE 2

Representative static PET/CT images in coronal (left) and sagittal (right) planes in fasting and non‐fasting conditions of (A) CAL 27 and (B) UT‐SCC‐14 tumor‐bearing mice captured at 60 min after [¹⁸F]FDG administration at 14–15 days of tumor implantation, and subsequent biodistribution profiles of (C) CAL 27 and (D) UT‐SCC‐14 tumor‐bearing animals after PET/CT imaging. The presented values indicate the mean ± SD (n = 3) where statistical significance was set at p < 0.05 and ns, not significant. The %ID/g denotes percent injected dose per gram of tissue and mucous mem. for mucous membrane.

FIGURE 3

Biodistribution profiles following B‐Glc administration at 75 mg/kg in UT‐SCC‐14 tumor‐bearing mice under (A) non‐fasting and (B) fasting conditions at 5, 15, 30, and 60 min. (C) Comparative analysis of B‐Glc tumor uptake between non‐fasting and fasting groups. (D) Comparative analysis of tumor uptake in B‐Glc groups to clinically relevant BPA‐F (400 mg/kg) group. The presented values indicate the mean ± SD (n = 3–4). Statistical significance was set at *p < 0.05, and n.s., not significant. The ppm denotes parts per million unit and mucous mem. for the mucous membrane. The dashed line in pink represents the 20‐ppm cutoff, which is the minimum ¹⁰B concentration considered effective for BNCT.

FIGURE 4

Tumor‐to‐background ratios of the B‐Glc (75 mg/kg) in UT‐SCC‐14 tumor‐bearing animals in (A) non‐fasting and (B) fasting animal groups at 5, 15, 30, and 60 min and BPA‐F (400 mg/kg, investigated only in the fasting group) at 60 min. The values represent the mean ± SD (n = 3–4). Mucous indicates oral mucous membrane.