Apoptosis of Tumor Cells in Response to Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is a form of tumor-cell selective particle irradiation using low-energy neutron irradiation of boron-10 (10B) to produce high-linear energy transfer (LET) alpha particles and recoiling 7Li nuclei (10B [n, alpha] 7Li) in tumor cells. Therefore, it is important to achieve the selective delivery of large amounts of 10B to tumor cells, with only small amounts of 10B to normal tissues. To develop practical materials utilizing 10B carriers, we designed and synthesized novel dodecaboranethiol (BSH)-containing kojic acid (KA-BSH). In the present study, we evaluated the effects of this novel 10B carrier on cytotoxicity, 10B concentrations in F98 rat glioma cells, and micro-distribution of KA-BSH in vitro. Furthermore, biodistribution studies were performed in a rat brain tumor model. The tumor boron concentrations showed the highest concentrations at 1 h after the termination of administration. Based on these results, neutron irradiation was evaluated at the Kyoto University Research Reactor Institute (KURRI) with KA-BSH. Median survival times (MSTs) of untreated and irradiated control rats were 29.5 and 30.5 days, respectively, while animals that received KA-BSH, followed by neutron irradiation, had an MST of 36.0 days (p = 0.0027, 0.0053). Based on these findings, further studies are warranted in using KA-BSH as a new B compound for malignant glioma.

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YC-1 sensitizes the antitumor effects of boron neutron capture therapy in hypoxic tumor cells

Journal of Radiation Research ◽

10.1093/jrr/rraa024 ◽

2020 ◽

Vol 61 (4) ◽

pp. 524-534

Author(s):

Takaomi Harada ◽

Katsumi Hirose ◽

Yuki Wada ◽

Mariko Sato ◽

Koji Ichise ◽

...

Keyword(s):

Tumor Cells ◽

Boron Neutron Capture Therapy ◽

Neutron Capture ◽

Neutron Capture Therapy ◽

Boron Uptake ◽

Antitumor Effects ◽

Hypoxic Conditions ◽

Boron Neutron Capture ◽

Hypoxic Tumor ◽

In Cells

Abstract The uptake of boron into tumor cells is a key factor in the biological effects of boron neutron capture therapy (BNCT). The uptake of boron agents is suppressed in hypoxic conditions, but the mechanism of hypoxia-induced modulation of suppression of boron uptake is not clear. Therefore, we evaluated whether hypoxia-inducible factor 1α (HIF-1α) contributes to attenuation of the antitumor effects of BNCT in hypoxic tumor cells. We also tested whether YC-1, a HIF-1α-targeting inhibitor, has therapeutic potential with BNCT. To elucidate the mechanism of attenuation of the effects of BNCT caused by hypoxia, deferoxamine (DFO) was used in experiments. Cells were incubated in normal oxygen, hypoxic conditions (1% O2) or 5 μM DFO for 24 h. Then, cells were treated with 10B-boronophenylalanine (BPA) for 2 h and boron accumulation in cells was evaluated. To clarify the relationship between HIF-1α and L-type amino acid transporter 1 (LAT1), gene expression was evaluated by a using HIF-1α gene knockdown technique. Finally, to improve attenuation of the effects of BNCT in hypoxic cells, BNCT was combined with YC-1. Boron uptake was continuously suppressed up to 2 h after administration of BPA by 5 μM DFO treatment. In cells treated with 5 μM DFO, LAT1 expression was restored in HIF-1α-knocked down samples in all cell lines, revealing that HIF-1α suppresses LAT1 expression in hypoxic cells. From the results of the surviving fraction after BNCT combined with YC-1, treatment with YC-1 sensitized the antitumor effects of BNCT in cells cultured in hypoxia.

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Preparation of polymeric boron-containing nanoparticles by emulsion polymerization for application in boron neutron capture therapy (BNCT)

10.32469/10355/64003 ◽

2010 ◽

Author(s):

◽

Shuo Yang

Keyword(s):

Emulsion Polymerization ◽

Tumor Cells ◽

Boron Neutron Capture Therapy ◽

Neutron Capture ◽

Polymeric Nanoparticles ◽

Rapid Development ◽

The United States ◽

Neutron Capture Therapy ◽

University Of Missouri ◽

Boron Neutron Capture

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction of isotope [superscript 10]B irradiated by low energy thermal neutron to produce high linear energy transfer (LET) alpha particles and recoiling lithium nuclei. BNCT has used clinically to treat glioblastoma multiforme, melanomas, head, neck and liver cancer. The clinical trials of BNCT have completed in Japan, Europe and the United States since the limited neutron source from reactors are available in these countries. The delivery agents of BNCT are required to achieve high boron concentration (10[superscript 9] boron atoms per targeted cell) and selective uptake on tumor cells with the minimal normal tissue damage and toxicity. With the rapid development of biological engineering and boron chemistry, many delivery agents have been proposed and synthesized such as boron-rich antibody conjugates, boron-containing liposomes, oligomeric phosphate diesters, etc. The first chapter gives the introduction of BNCT. The second chapter describes the preparation of boron-containing polymeric nanoparticles by emulsion polymerization technology for application in BNCT. Particle size is controlled by changing the amount of surfactant. The third chapter discusses the modifications of the surface of boron-containing polymeric nanoparticles by acrylic acid and polyethylene glycol (PEG) to enhance the solubility, stability and circulation time, to reduce toxicity and immunogenicity in vivo. Specific bioligands are going to be attached to boron-containing nanoparticles to improve the targeting of delivery to tumor cells. The sixth chapter describes the work I did for my Master's degree in chemistry at University of Missouri-Columbia.

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Gold Nanoparticles Permit In Situ Absorbed Dose Evaluation in Boron Neutron Capture Therapy for Malignant Tumors

Pharmaceutics ◽

10.3390/pharmaceutics13091490 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1490

Author(s):

Alexander Zaboronok ◽

Sergey Taskaev ◽

Olga Volkova ◽

Ludmila Mechetina ◽

Anna Kasatova ◽

...

Keyword(s):

Gold Nanoparticles ◽

Tumor Cells ◽

Boron Neutron Capture Therapy ◽

Neutron Capture ◽

Malignant Tumors ◽

Absorbed Dose ◽

Alpha Particles ◽

Neutron Capture Therapy ◽

Linear Quadratic ◽

Boron Neutron Capture

Boron neutron capture therapy (BNCT) is an anticancer modality realized through 10B accumulation in tumor cells, neutron irradiation of the tumor, and decay of boron atoms with the release of alpha-particles and lithium nuclei that damage tumor cell DNA. As high-LET particle release takes place inside tumor cells absorbed dose calculations are difficult, since no essential extracellular energy is emitted. We placed gold nanoparticles inside tumor cells saturated with boron to more accurately measure the absorbed dose. T98G cells accumulated ~50 nm gold nanoparticles (AuNPs, 50 µg gold/mL) and boron-phenylalanine (BPA, 10, 20, 40 µg boron-10/mL), and were irradiated with a neutron flux of 3 × 108 cm−2s−1. Gamma-rays (411 keV) emitted by AuNPs in the cells were measured by a spectrometer and the absorbed dose was calculated using the formula D = (k × N × n)/m, where D was the absorbed dose (GyE), k—depth-related irradiation coefficient, N—number of activated gold atoms, n—boron concentration (ppm), and m—the mass of gold (g). Cell survival curves were fit to the linear-quadratic (LQ) model. We found no influence from the presence of the AuNPs on BNCT efficiency. Our approach will lead to further development of combined boron and high-Z element-containing compounds, and to further adaptation of isotope scanning for BNCT dosimetry.

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Boron Neutron Capture Therapy: Cellular Targeting of High Linear Energy Transfer Radiation

Technology in Cancer Research & Treatment ◽

10.1177/153303460300200502 ◽

2003 ◽

Vol 2 (5) ◽

pp. 355-375 ◽

Cited By ~ 70

Author(s):

Jeffrey A. Coderre ◽

Julie C. Turcotte ◽

Kent J. Riley ◽

Peter J. Binns ◽

Otto K. Harling ◽

...

Keyword(s):

Tumor Cells ◽

Boron Neutron Capture Therapy ◽

Neutron Capture ◽

Analytical Techniques ◽

Neutron Capture Therapy ◽

Normal Brain ◽

Normal Tissues ◽

Boron Neutron Capture ◽

Subsequent Activation ◽

The Individual

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with10 B and subsequent activation with thermal neutrons to produce a highly localized radiation. In theory, it is possible to selectively irradiate a tumor and the associated infiltrating tumor cells with large single doses of high-LET radiation while sparing the adjacent normal tissues. The mixture of high- and low-LET dose components created in tissue during neutron irradiation complicates the radiobiology of BNCT. Much of the complexity has been unravelled through a combination of preclinical experimentation and clinical dose escalation experience. Over 350 patients have been treated in a number of different facilities worldwide. The accumulated clinical experience has demonstrated that BNCT can be delivered safely but is still defining the limits of normal brain tolerance. Several independent BNCT clinical protocols have demonstrated that BNCT can produce median survivals in patients with glioblastoma that appear to be equivalent to conventional photon therapy. This review describes the individual components and methodologies required for effect BNCT: the boron delivery agents; the analytical techniques; the neutron beams; the dosimetry and radiation biology measurements; and how these components have been integrated into a series of clinical studies. The single greatest weakness of BNCT at the present time is non-uniform delivery of boron into all tumor cells. Future improvements in BNCT effectiveness will come from improved boron delivery agents, improved boron administration protocols, or through combination of BNCT with other modalites.

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