TY - JOUR
T1 - Exploring the Biochemical Foundations of a Successful GLUT1-Targeting Strategy to BNCT
T2 - Chemical Synthesis and in Vitro Evaluation of the Entire Positional Isomer Library of ortho-Carboranylmethyl-Bearing Glucoconjugates
AU - Matović, Jelena
AU - Järvinen, Juulia
AU - Sokka, Iris K.
AU - Imlimthan, Surachet
AU - Raitanen, Jan Erik
AU - Montaser, Ahmed
AU - Maaheimo, Hannu
AU - Huttunen, Kristiina M.
AU - Peräniemi, Sirpa
AU - Airaksinen, Anu J.
AU - Sarparanta, Mirkka
AU - Johansson, Mikael P.
AU - Rautio, Jarkko
AU - Ekholm, Filip S.
N1 - Funding Information:
The authors would like to thank MSc. Helena Bland (University of Helsinki) and laboratory technician Tarja Ihalainen (University of Eastern Finland) for laboratory assistance, Olli Aitio (Glykos Finland Ltd.) and PhD. Juri Timonen (University of Eastern Finland) for fruitful discussions, and Prof. Hélder A. Santos and Alexandra Correia (University of Helsinki) for the kind permission to use their cell culturing facilities and microplate reader in the cytotoxicity assays. CSC—The Finnish IT Center for Science is acknowledged for providing ample computing resources. Financial support from the Cancer foundation in Finland, the Jane and Aatos Erkko Foundation, the Swedish Cultural Foundation, the Ruth and Nils-Erik Stenbäck Foundation, the University of Helsinki research funds, the Academy of Finland (projects: 289179, 319453, 320102, and 308329), the Waldemar von Frenckell foundation, and the Finnish Cultural Foundation is gratefully acknowledged.
Publisher Copyright:
© 2020 American Chemical Society.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - Boron neutron capture therapy (BNCT) is a noninvasive binary therapeutic modality applicable to the treatment of cancers. While BNCT offers a tumor-targeting selectivity that is difficult to match by other means, the last obstacles preventing the full harness of this potential come in the form of the suboptimal boron delivery strategies presently used in the clinics. To address these challenges, we have developed delivery agents that target the glucose transporter GLUT1. Here, we present the chemical synthesis of a number of ortho-carboranylmethyl-substituted glucoconjugates and the biological assessment of all positional isomers. Altogether, the study provides protocols for the synthesis and structural characterization of such glucoconjugates and insights into their essential properties, for example, cytotoxicity, GLUT1-affinity, metabolism, and boron delivery capacity. In addition to solidifying the biochemical foundations of a successful GLUT1-targeting approach to BNCT, we identify the most promising modification sites in d-glucose, which are critical in order to further develop this strategy toward clinical use.
AB - Boron neutron capture therapy (BNCT) is a noninvasive binary therapeutic modality applicable to the treatment of cancers. While BNCT offers a tumor-targeting selectivity that is difficult to match by other means, the last obstacles preventing the full harness of this potential come in the form of the suboptimal boron delivery strategies presently used in the clinics. To address these challenges, we have developed delivery agents that target the glucose transporter GLUT1. Here, we present the chemical synthesis of a number of ortho-carboranylmethyl-substituted glucoconjugates and the biological assessment of all positional isomers. Altogether, the study provides protocols for the synthesis and structural characterization of such glucoconjugates and insights into their essential properties, for example, cytotoxicity, GLUT1-affinity, metabolism, and boron delivery capacity. In addition to solidifying the biochemical foundations of a successful GLUT1-targeting approach to BNCT, we identify the most promising modification sites in d-glucose, which are critical in order to further develop this strategy toward clinical use.
KW - boron neutron capture therapy
KW - cancer therapeutics
KW - carbohydrates
KW - drug delivery
KW - glucose transporters
KW - medicinal chemistry
UR - http://www.scopus.com/inward/record.url?scp=85097802070&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.0c00917
DO - 10.1021/acs.molpharmaceut.0c00917
M3 - Article
C2 - 33390018
AN - SCOPUS:85097802070
SN - 1543-8384
VL - 18
SP - 285
EP - 304
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 1
ER -