Glucose-and sodium-dependent glucose transporters (GLUTs and SGLTs) play vital roles in human biology. Of the 14 GLUTs and 12 SGLTs, the GLUT1 transporter has gained t h e most widespread recognition because GLUT1 is overexpressed in several cancers and is a clinically valid therapeutic target. We have been pursuing a GLUT1-targeting approach in boron neutron capture therapy (BNCT). Here, we report on surprising findings encountered w i t h a set of 6-deoxy-6-thio-carbora n y l D-glucoconjugates. In more detail, we show that even subtle structural changes in t h e carborane cluster, and the linker, may significantly reduce the delivery capacity of GLUT1-based boron carriers. In addition to providing new insights on the substrate specificity of this important transporter, we reach a fresh perspec t i v e on the boundaries within which a GLUT1-targeting approach in BNCT can be further refined.

Boron neutron capture therapy (BNCT) is a cancer therapy in which boron delivery agents play a crucial role. In theory, delivery agents with high tumor targeting capabilities can lead to selective eradication of tumor cells without causing harmful side effects. We have been working on a GLUT1-targeting strategy to BNCT for a number of years and found multiple promising hit compounds which outperform the clinically employed boron delivery agents in vitro. Herein, we continue our work in the field by further diversification of the carbohydrate scaffold in order to map the optimal stereochemistry of the carbohydrate core. In the sweet battle of the epimers, carborane-bearing d-galactose, d-mannose, and d-allose are synthesized and subjected to in vitro profiling studies─with earlier work on d-glucose serving as the reference. We find that all of the monosaccharide delivery agents display a significantly improved boron delivery capacity over the delivery agents approved for clinical use in vitro, thus providing a sound foundation for advancing toward in vivo preclinical assessment studies.

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.

Boron Neutron Capture Therapy (BNCT) is a cancer treatment which combines tumor-selective boron delivery agents with thermal neutrons in order to selectively eradicate cancer cells. In this work, we focus on the early-stage development of carbohydrate delivery agents for BNCT. In more detail, we expand upon our previous GLUT-targeting approach by synthesizing and evaluating the potential embedded in a representative set of fluorinated carbohydrates bearing a boron cluster. Our findings indicate that these species may have advantages over the boron delivery agents in current clinical use, e.g., significantly improved boron delivery capacity at the cellular level. Simultaneously, the carbohydrate delivery agents were found to bind strongly to plasma proteins, which may be a concern requiring further action before progression to in vivo studies. Altogether, this work brings new insights into factors which need to be accounted for if attempting to develop theranostic agents for BNCT based on carbohydrates in the future.