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Biomedicines Jun 2021Boron neutron capture therapy (BNCT) is based on the ability of the boron-10 (B) isotope to capture epithermal neutrons, as a result of which the isotope becomes...
Boron neutron capture therapy (BNCT) is based on the ability of the boron-10 (B) isotope to capture epithermal neutrons, as a result of which the isotope becomes unstable and decays into kinetically active elements that destroy cells where the nuclear reaction has occurred. The boron-carrying compounds-L-para-boronophenylalanine (BPA) and sodium mercaptoundecahydro-closo-dodecaborate (BSH)-have low toxicity and, today, are the only representatives of such compounds approved for clinical trials. For the effectiveness and safety of BNCT, a low boron content in normal tissues and substantially higher content in tumor tissue are required. This study evaluated the boron concentration in intracranial grafts of human glioma U87MG cells and normal tissues of the brain and other organs of mice at 1, 2.5 and 5 h after administration of the boron-carrying compounds. A detailed statistical analysis of the boron biodistribution dynamics was performed to find a 'window of opportunity' for BNCT. The data demonstrate variations in boron accumulation in different tissues depending on the compound used, as well as significant inter-animal variation. The protocol of administration of BPA and BSH compounds used did not allow achieving the parameters necessary for the successful course of BNCT in a glioma orthotopic xenograft mouse model.
PubMed: 34201895
DOI: 10.3390/biomedicines9070722 -
Cells Oct 2021Boron neutron capture therapy (BNCT) is a cancer-selective radiotherapy that utilizes the cancer targeting B-compound. Cancer cells that take up the compound are... (Review)
Review
Boron neutron capture therapy (BNCT) is a cancer-selective radiotherapy that utilizes the cancer targeting B-compound. Cancer cells that take up the compound are substantially damaged by the high liner energy transfer (LET) particles emitted mainly from the B(n, αLi reaction. BNCT can minimize the dose to normal tissues, but it must be performed within the tolerable range of normal tissues. Therefore, it is important to evaluate the response of normal tissues to BNCT. Since BNCT yields a mixture of high and low LET radiations that make it difficult to understand the radiobiological basis of BNCT, it is important to evaluate the relative biological effectiveness (RBE) and compound biological effectiveness (CBE) factors for assessing the responses of normal tissues to BNCT. BSH and BPA are the only B-compounds that can be used for clinical BNCT. Their biological behavior and cancer targeting mechanisms are different; therefore, they affect the CBE values differently. In this review, we present the RBE and CBE values of BPA or BSH for normal tissue damage by BNCT irradiation. The skin, brain (spinal cord), mucosa, lung, and liver are included as normal tissues. The CBE values of BPA and BSH for tumor control are also discussed.
Topics: Animals; Borohydrides; Boron Neutron Capture Therapy; Humans; Neoplasms; Phenylalanine; Relative Biological Effectiveness; Sulfhydryl Compounds; Tissue Distribution
PubMed: 34831105
DOI: 10.3390/cells10112883 -
Cancer Communications (London, England) Jun 2018Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope,... (Review)
Review
Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.
Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Humans; Isotopes; Liposomes; Neoplasms; Neutrons; Tissue Distribution
PubMed: 29914561
DOI: 10.1186/s40880-018-0299-7 -
Journal of Clinical and Diagnostic... Dec 2016Boron Neutron Capture Therapy (BNCT) is a radiation science which is emerging as a hopeful tool in treating cancer, by selectively concentrating boron compounds in... (Review)
Review
Boron Neutron Capture Therapy (BNCT) is a radiation science which is emerging as a hopeful tool in treating cancer, by selectively concentrating boron compounds in tumour cells and then subjecting the tumour cells to epithermal neutron beam radiation. BNCT bestows upon the nuclear reaction that occurs when Boron-10, a stable isotope, is irradiated with low-energy thermal neutrons to yield α particles (Helium-4) and recoiling lithium-7 nuclei. A large number of 10 Boron (10B) atoms have to be localized on or within neoplastic cells for BNCT to be effective, and an adequate number of thermal neutrons have to be absorbed by the 10B atoms to maintain a lethal 10B (n, α) lithium-7 reaction. The most exclusive property of BNCT is that it can deposit an immense dose gradient between the tumour cells and normal cells. BNCT integrates the fundamental focusing perception of chemotherapy and the gross anatomical localization proposition of traditional radiotherapy.
PubMed: 28209015
DOI: 10.7860/JCDR/2016/19890.9024 -
Radiation Oncology (London, England) Nov 2021Boron neutron capture therapy (BNCT) was first proposed as early as 1936, and research on BNCT has progressed relatively slowly but steadily. BNCT is a potentially... (Review)
Review
Boron neutron capture therapy (BNCT) was first proposed as early as 1936, and research on BNCT has progressed relatively slowly but steadily. BNCT is a potentially useful tool for cancer treatment that selectively damages cancer cells while sparing normal tissue. BNCT is based on the nuclear reaction that occurs when B capture low-energy thermal neutrons to yield high-linear energy transfer (LET) α particles and recoiling Li nuclei. A large number of B atoms have to be localized within the tumor cells for BNCT to be effective, and an adequate number of thermal neutrons need to be absorbed by the B atoms to generate lethal B (n, α)Li reactions. Effective boron neutron capture therapy cannot be achieved without appropriate boron carriers. Improvement in boron delivery and the development of the best dosing paradigms for both boronophenylalanine (BPA) and sodium borocaptate (BSH) are of major importance, yet these still have not been optimized. Here, we present a review of this treatment modality from the perspectives of radiation oncology, biology, and physics. This manuscript provides a brief introduction of the mechanism of cancer-cell-selective killing by BNCT, radiobiological factors, and progress in the development of boron carriers and neutron sources as well as the results of clinical study.
Topics: Animals; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Humans
PubMed: 34743756
DOI: 10.1186/s13014-021-01939-7 -
Nanoscale Advances May 2023Boron neutron capture therapy (BNCT), a method based on the fission of boron-10 upon neutron irradiation, has emerged as an attractive option for radiation therapy. To...
Organosilica nanoparticles containing sodium borocaptate (BSH) provide new prospects for boron neutron capture therapy (BNCT): efficient cellular uptake and enhanced BNCT efficacy.
Boron neutron capture therapy (BNCT), a method based on the fission of boron-10 upon neutron irradiation, has emerged as an attractive option for radiation therapy. To date, the main drugs used in BNCT are 4-boronophenylalanine (BPA) and sodium borocaptate (BSH). While BPA has been extensively tested in clinical trials, the use of BSH has been limited, mainly due to its poor cellular uptake. Here, we describe a novel type of mesoporous silica-based nanoparticle containing BSH covalently attached to a nanocarrier. Synthesis and characterization of these nanoparticles (BSH-BPMO) are presented. The synthetic strategy involves a click thiol-ene reaction with the boron cluster, providing hydrolytically stable linkage with the BSH in four steps. The BSH-BPMO nanoparticles were efficiently taken up into cancer cells and accumulated in the perinuclear region. Inductively coupled plasma (ICP) measurements of boron uptake in cells highlight the important role of the nanocarrier in the enhancement of boron internalization. BSH-BPMO nanoparticles were also taken up and distributed throughout tumour spheroids. BNCT efficacy was examined by the neutron exposure of the tumour spheroids. BSH-BPMO loaded spheroids were completely destroyed upon neutron irradiation. In contrast, neutron irradiation of tumour spheroids loaded with BSH or BPA resulted in significantly less spheroid shrinkage. The significant difference in BNCT efficacy of the BSH-BPMO was correlated with the improved boron uptake the nanocarrier. Overall, these results demonstrate the critical role of the nanocarrier in BSH internalization and the enhanced BNCT efficacy of the BSH-BPMO compared with BSH and BPA, two drugs used in BNCT clinical trials.
PubMed: 37143818
DOI: 10.1039/d2na00839d -
Cells May 2020Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine...
Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine (BPA) and sodium borocaptate (BSH) used as B delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient B concentration within tumors. To address the issue of B accumulation and retention in tumor tissue, we developed MMT1242, a novel boron-containing α-d-mannopyranoside. We evaluated the uptake, intracellular distribution, and retention of MMT1242 in cultured cells and analyzed biodistribution, tumor-to-normal tissue ratio and toxicity in vivo. Fluorescence imaging using nitrobenzoxadiazole (NBD)-labeled MMT1242 and inductively coupled mass spectrometry (ICP-MS) were performed. The effectiveness of BNCT using MMT1242 was assessed in animal irradiation studies at the Kyoto University Research Reactor. MMT1242 showed a high uptake and broad intracellular distribution in vitro, longer tumor retention compared to BSH and BPA, and adequate tumor-to-normal tissue accumulation ratio and low toxicity in vivo. A neutron irradiation study with MMT1242 in a subcutaneous murine tumor model revealed a significant tumor inhibiting effect if injected 24 h before irradiation. We therefore report that B-MMT1242 is a candidate for further clinical BNCT studies.
Topics: Animals; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Intracellular Space; Mannose; Melanoma, Experimental; Mice; Optical Imaging; Rats; Tissue Distribution; Toxicity Tests
PubMed: 32455737
DOI: 10.3390/cells9051277 -
Proceedings of the National Academy of... Dec 1992Borocaptate sodium (Na2B12H11SH) is a boron-carrying compound under consideration for use in boron neutron capture therapy. The biodistribution of boron from borocaptate...
Borocaptate sodium (Na2B12H11SH) is a boron-carrying compound under consideration for use in boron neutron capture therapy. The biodistribution of boron from borocaptate sodium administration will partly determine boron neutron capture therapy efficacy and normal tissue radiation tolerance. The biodistribution of boron was determined in 30 dogs with spontaneous intracranial tumors at 2, 6, or 12 hr after intravenous borocaptate sodium infusion. Blood and tissue boron concentrations were measured using inductively coupled plasma atomic emission spectroscopy. Mean tumor boron concentration (mean +/- standard error) was 35.9 +/- 4.6 (n = 15), 22.5 +/- 6.0 (n = 9), and 7.0 +/- 1.1 micrograms of boron per g (n = 6) at 2, 6, and 12 hr, respectively, after borocaptate sodium infusion. Peritumor boron concentrations were elevated above that of normal brain in half of the dogs. Normal brain boron concentration (mean +/- standard error) was 4.0 +/- 0.5, 2.0 +/- 0.4, and 2.0 +/- 0.3 micrograms of boron per g at 2, 6, and 12 hr after infusion, respectively. Some cranial and systemic tissues, and blood, had high boron concentration relative to tumor tissue. Geometric dose sparing should partly offset these relatively high normal tissue and blood concentrations. Borocaptate sodium biodistribution is favorable because tumor boron concentrations of recommended magnitude for boron neutron capture therapy were obtained and there was a high tumor-to-normal brain boron concentration ratio.
Topics: Animals; Boranes; Borohydrides; Boron; Brain Neoplasms; Dogs; Female; Male; Neutron Capture Therapy; Sulfhydryl Compounds
PubMed: 1465427
DOI: 10.1073/pnas.89.24.11973 -
Cells Sep 2020Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the...
In Vitro Studies to Define the Cell-Surface and Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a Potential Delivery Agent for Boron Neutron Capture Therapy.
Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44 cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44 cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.
Topics: Borohydrides; Boron Neutron Capture Therapy; Brain Neoplasms; Humans; Peptides; Phenylalanine; Sodium; Sulfhydryl Compounds
PubMed: 32977522
DOI: 10.3390/cells9102149 -
Coordination Chemistry Reviews Nov 2008There is a wide range of potential applications of inorganic compounds, and metal coordination complexes in particular, in medicine but progress is hampered by a lack of... (Review)
Review
There is a wide range of potential applications of inorganic compounds, and metal coordination complexes in particular, in medicine but progress is hampered by a lack of methods to study their speciation. The biological activity of metal complexes is determined by the metal itself, its oxidation state, the types and number of coordinated ligands and their strength of binding, the geometry of the complex, redox potential and ligand exchange rates. For organic drugs a variety of readily observed spin = 1/2 nuclei can be used (H, C, N, F, P), but only a few metals fall into this category. Most are quadrupolar nuclei giving rise to broad lines with low detection sensitivity (for biological systems). However we show that, in some cases, heteronuclear NMR studies can provide new insights into the biological and medicinal chemistry of a range of elements and these data will stimulate further advances in this area.
PubMed: 32226090
DOI: 10.1016/j.ccr.2008.01.016