Sesamol is a compound reported to have anti-melanogenesis and anti-melanoma actions. Sesamol, however, has low intracellular drug concentration and fast excretion, which can limit its benefits in the clinic. To overcome this drawback and increase intracellular delivery of sesamol into the target melanoma, research has focused on L-type amino acid transporter 1 (LAT1)-mediated prodrug delivery into melanoma cells. The sesamol prodrug was designed by conjugating sesamol with L-phenylalanine at the para position with a carbamate bond. LAT1 targeting was evaluated vis-à-vis a competitive [¹⁴C]-leucine uptake inhibition. The sesamol prodrug has a higher [¹⁴C]-leucine uptake inhibition than sesamol in human LAT1-transfected HEK293 cells. Moreover, the sesamol prodrug was taken up by LAT1-mediated transport into SK-MEL-2 cells more effectively than sesamol. The sesamol prodrug underwent complete hydrolysis, releasing the active sesamol at 72 h, which significantly exerted its cytotoxicity (IC₅₀ of 29.3 µM) against SK-MEL-cells more than sesamol alone. Taken together, the strategy for LAT1-mediated prodrug delivery has utility for the selective uptake of sesamol, thereby increasing its intracellular concentration and antiproliferation activity, targeting melanoma SK-MEL-2 cells that overexpress the LAT1 protein. The sesamol prodrug thus warrants further evaluation in an in vivo model.

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.

This research investigates boronated tryptophans as potential boron delivery agents for boron neutron capture therapy (BNCT) of cancer. We synthesized both enantiomers of 5- and 6-boronotryptophans (1a and 1b) using simple and inexpensive methods. Their uptake was assessed in two human cancer cell lines, CAL27 (head and neck cancer) and U87-MG (brain cancer), and compared to l-p-boronophenylalanine (l-BPA) as a reference. To determine whether these tryptophan derivatives are substrates for large amino acid transporter 1, we performed molecular dynamics simulations to explore their transport mechanism. Our findings reveal differences in boron compound accumulation between the cancer cell lines, indicating that tryptophan derivatives could serve as effective boron carriers when the clinically used boron carrier, BPA, is ineffective.