A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma
Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation has been limited by the poor tumor selectivity of agents. To address this unmet need, a boronated 2-nitroimidazole derivative (B-381) was synthesized and evaluated for its capability of targeting hypoxic glioma cells.
B-381 has been synthesized from a 1-step reaction. Using D54 and U87 glioma cell lines, the in vitro cytotoxicity and cellular accumulation of B-381 has been evaluated under normoxic and hypoxic conditions compared to L-boronophenylalanine (BPA). Furthermore, tumor retention of B-381 was evaluated in vivo.
B-381 had low cytotoxicity in normal and cancer cells. Unlike BPA, B-381 illustrated preferential retention in hypoxic glioma cells compared to normoxic glioma cells and normal tissues in vitro. In vivo, B-381 illustrated significantly higher long-term tumor retention compared to BPA, with 9.5-fold and 6.5-fold higher boron levels at 24 and 48 h, respectively.
B-381 represents a new class of BNCT agents in which their selectivity to tumors is based on hypoxic tumor metabolism. Further studies are warranted to evaluate B-381 and similar compounds as preclinical candidates for future BNCT clinical trials for the treatment of glioma.
KEY WORDSBNCT boron neutron capture therapy glioma hypoxia tumor targeting
Proton nuclear magnetic resonance spectroscopy
Area under curve
Boron neutron capture therapy
Dulbecco’s modified eagle’s medium
Fetal bovine serum
High performance liquid chromatography
Inductively coupled plasma optical emission spectrometry
Mass to charge (m/z)
Peripheral blood mononuclear cells
Positron emission tomography
Parts per billion
ACKNOWLEDGMENTS AND DISCLOSURES
The first author thanks the N.I.H. Training Grant T32 GM007200 for research support. Mr. Luderer and Dr. Azab have a pending provisional patent application describing the work reported in this manuscript. Moreover, Dr. Azab receives research support from Verastem, Selexys, Karyopharm, Cell Works, Cleave Bioscience, and Glycomimetics; and is the founder and owner of Targeted Therapeutics LLC and Cellatrix LLC. Dr. de la Puente is co-founder of Cellatrix LLC. Other authors state no conflicts of interest.
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