Abstract
Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.
Highlights
As one of the leading causes of morbidity and mortality on a global scale, cancer is a significant societal economic burden with annual global costs of 723−930 billion euros
In addition to synthesizing the glucoconjugates and conducting the most detailed structural characterization of such conjugates to date, we have addressed the biochemical foundations of the GLUT1-targeting approach through a preliminary, yet, comprehensive in vitro evaluation study featuring cytotoxicity, computational/experimental receptor affinity, and cellular uptake experiments in the relevant human head and neck cancer cell line CAL 27
Each new synthetic target requires the development of a suitable strategy, and unlike the 3-O-carboranylmethyl,[40] the carboranylmethyl-glucosides,[41] and other types of glucoconjugates previously evaluated,[23,42,43] the 6-O-carboranylmethyl glucoconjugates (Figure 2) have been explicitly designed for clinical boron neutron capture therapy (BNCT) of head and neck cancers
Summary
As one of the leading causes of morbidity and mortality on a global scale, cancer is a significant societal economic burden with annual global costs of 723−930 billion euros. In head and neck cancers, the inoperable recurrent ones are accompanied by a poor survival rate with a mean survival time of only a few months.[3] A number of novel treatment strategies have recently gained ground. These include antibody−drug conjugates,[4] proton therapy,[5,6] and, especially, boron neutron capture therapy (BNCT).[7] BNCT represents one of the most promising noninvasive binary treatment modalities for head and neck cancers since it can eradicate cancer cells while simultaneously sparing healthy cells (the basis of our approach is displayed in Figure 1).[8,9] The selectivity in BNCT arises from a 2-fold effect. New in-hospital neutron accelerators[10] have emerged revolutionizing the clinical aspects of patient treatments; a renewed interest in the BNCT
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