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7 January 2020 Comparative Study on Neutron Irradiation Sensitization Effects of Nucleotide Borate Esters and Several Other Boron Agents
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Abstract

More effective boron-containing compounds are needed for use in boron neutron capture therapy (BNCT). Here, borate esters were synthesized by heating and dehydrating nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), the nucleoside (inosine) or glycerol in the presence of boric acid (H3BO3). Borate ester products were compared to clinical boron agent boronophenylalanine (BPA) and several other borate esters for neutron-sensitization effects using the A549 cell line. Cells were incubated with boron agent solutions (2.3 mM) for 5 h, then washed, resuspended in fresh media, and irradiated with a neutron dose of 0.33 Sv followed by cell survival assessment using the CCK-8 method. Calculated radiosensitization values (control group cell survival rate/boron agent-treated experimental group cell survival rate) were 3.9 ± 0.2 (ATP borate ester), 2.4 ± 0.1 (BPA), 2.1 ± 0.1 (ADP borate ester), 1.9 ± 0.2 (AMP borate ester), 1.7 ± 0.3 (glycerin borate ester), 1.4 ± 0.1 (inosine borate ester), 1.3 ± 0.3 (triethanolamine borate ester) and 1.3 ± 0.5 (H3BO3). Borate esters derived from nucleotides ATP, ADP or AMP exhibited significantly higher sensitization values than did those derived from glycerol, inosine or triethanolamine. Notably, due to its relatively higher water solubility and degree of tumor cell enrichment, ATP borate ester exhibited the highest sensitization rate overall, significantly exceeding rates obtained for BPA and borate esters of ADP and AMP. Flow cytometric determinations of boron agent-treated cell survival at 24 h postirradiation revealed long-term apoptosis rates of 4.8–6.6 ± 0.2% (nucleotide borate ester groups) and 5.6 ± 0.3% (BPA group) compared to 3.9 ± 0.1% (irradiation control group without boron agent) and 2.6 ± 0.2% (blank control group). Significant differences between experimental and control groups demonstrated that nucleotide borate esters and BPA induced long-term radiosensitization effects. In particular, postirradiation percentages of ATP borate ester-treated cells progressing to DNA replication prophase (G1 phase) increased significantly, while percentages of cells progressing to S phase significantly decreased, demonstrating cellular DNA replication inhibition. Meanwhile, boron content values of tumor tissue, measured using inductively coupled plasma mass spectrometry (ICP-MS) and expressed as tumor-to-normal tissue boron ratios (T/N), were not significantly different between nucleotide borate ester- and BPA-fed groups of tumor-bearing mice. However, tumor tissue boron concentrations of nucleotide borate ester-fed mice (0.81–0.88 ± 0.04 µg/g) significantly exceeded those of BPA-fed mice (0.52 ± 0.05 µg/g) and thus provided greater tumor tissue boron enrichment for achieving a stronger neutron radiation-sensitizing effect. In conclusion, nucleotide borate esters, especially ATP borate ester, exhibited superior neutron radiosensitization effects than did other representative borate ester compounds and significantly greater long-term radiation effects as well. Thus, nucleotide borate esters have several advantages over other borate esters for BNCT and therefore warrant further study.

©2020 by Radiation Research Society. All rights of reproduction in any form reserved.
Miao Wang, Yongpeng Tong, Qi Luo, and Shipeng Hu "Comparative Study on Neutron Irradiation Sensitization Effects of Nucleotide Borate Esters and Several Other Boron Agents," Radiation Research 193(3), 249-262, (7 January 2020). https://doi.org/10.1667/RR15473.1
Received: 17 July 2019; Accepted: 9 December 2019; Published: 7 January 2020
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