Combined BNCT and PET for theranostics

This short review summarizes the issue of boron distribution monitoring in boron neutron capture therapy (BNCT), which remains a serious drawback of this powerful oncological treatment. Here we present the monitoring methods that are presently used with particular emphasis on the positron emission tomography (PET) which has the highest potential to be used for the real-time monitoring of boron biodistribution. We discuss the possibility of using present PET scanners to determine the boron uptake in vivo before the BNCT treatment with the use of p-boronphenylalanine (BPA) labeled with 18F isotope. Several examples of preclinical studies and clinical trials performed with the use of [18F]FBPA are shown. We also discuss shortly the perspectives of using other radiotracers and boron carriers which may significantly improve the boron imaging with the use of the state-of-the-art Total-Body PET scanners providing a theranostic approach in the BNCT.

A Facile Synthesis of Nido-Carborane Polymers via Dynamic Self-Assembly by Poly(carboxybetaine methacrylate)

Carborane are widely applied in boron neutron capture therapy (BNCT) field, but it is difficult to perform biocompatibility with cells due to its own water solubility differences, so how to solve the water solubility problem has always been the focus of research. A simple, inexpensive and effective method was used to study the synthesis of nido-carborane azaspirodecanium poly(carboxybetaine methacrylate) by one-pot cyclization of nido-carborane azaspirodecanium under the synergistic effect of inorganic bases and conventional organic solvents. Its characterization is mainly to use 1H-NMR nuclear magnetic resonance spectrum and infrared spectroscopy to determine the characteristic peak and range of borane. Through transmission electron microscope (TEM), it can be observed that the white nanoparticles, namely carborane, are completely contained by polymer ions, which not only increases the surface area but also the concentration of boron uptake in the cell is 100 times that of borono-phenylalanine (BPA). Based on the successful synthesis of N-CB5-4 and N-CB6-5 without harsh conditions, a feasibility point of view was put forward, namely, super water-soluble carborane polymer.

Does Trans-Stimulation of L-Tyrosine Lead to an Increase in Boron Uptake in Head and Neck Squamous Cell Carcinoma Cells?

(1) Background: For advanced head and neck squamous cell carcinoma (HNSCC), boron neutron capture therapy (BNCT) is a potential therapeutic option, but high concentrations of boron within HNSCC are necessary. Therefore, this in vitro pilot study examined the uptake and concentration of boron in HNSCC cells using the trans-stimulation effect of L-tyrosine when compared to non-stimulated samples. (2) Methods: Two HNSCC cell lines were incubated with L-tyrosine for up to two hours, followed by incubation with three L-para-boronophenylalanine (BPA) concentrations (5, 20, 50 ppm) at eight incubation times (1–4.5 h in half-hour steps). Subsequently, cellular boron uptake was measured via inductively coupled plasma mass spectrometry. (3) Results: No differences between laryngeal and oral SCC cells were seen; therefore, data were pooled. In total, boron uptake was not significantly increased in trans-stimulated samples when compared to the control group (all p > 0.05). Nevertheless, with trans-stimulation, higher BPA concentrations resulted in higher intracellular boron concentrations (5 < 20 < 50 ppm; all: p < 0.05), whereas these differences were less distinct in the non-trans-stimulated group. (4) Conclusions: The effect of trans-stimulation for up to two hours seems to be less relevant for HNSCC, though trans-stimulated HNSCC cells seem to have a more distinct BPA-dose-dependent cellular boron uptake that might be addressed in further research.

Effect on forage yield and nutrient uptake of long-term surface application of manure at various rates and times in the growing season to timothy grown on two contrasting soils.

Although much of the manure in Canada is surface applied to forages, little research exists evaluating time of year (Time) and rate (Rate) of its application on forage yield and nutrient uptake. Field trials (10 yr) on two soils (sandy loam upland and silty clay loam dykeland) investigated this. Experimental arrangement was a factorial [Time (spring, summer, early and late fall manure applications)] plus control [spring applied ammonium nitrate fertilizer (ANF)] in a Latinized split plot. ANF at 0, 25, 50, 100 and 200 kg N ha-1; 0, 75, 150, and 300 as semi-solid beef (SSM) and 150 kg N ha-1 as liquid dairy manure (LDM), constituted respective splits. The Time X Rate interaction, later in the trial on the upland soil, showed higher yields and nutrient uptakes with fall manure application. There was little interaction on the dykeland soil; summer application resulted in higher yields at times. For both soils, optimal long-term application rate of SSM was approximately 150 kg N ha-1 while that of ANF was approximately 100 kg N ha-1. Inherent fertility of dykelands resulted in flatter responses to manure addition. Negligible and significant residual N occurred with fertilizer and manure, respectively. Nitrogen, phosphorus, potassium, calcium, magnesium, manganese, copper, zinc and boron uptake was due to amendment impact on yield. Recommended is 150 kg N ha-1 of SSM or LDM applied in fall and summer to Maritime grasslands grown on upland and dykeland soils, respectively. Yield differences may not warrant producers adjusting timing of in-season manure application.

Influence of lime, phosphorus and boron on performance of maize (Zea mays L.)in acidic soil of Nagaland

A pot experiment was conducted in an acidic sandy clay loam soil during the kharif season of 2016 and 2017 to study the performance of maize using two lime levels (0 and ¼ lime of LR), four phosphorus levels (0, 13.4, 26.8 and 40.2 mg P2O5 kg-1) and three boron levels (0, 0.45 and 0.90 mg B kg-1) with maize as test crop. The experiment was designed in complete randomized design with three replications. Results revealed that plant height, number of leaves and leaf area index increased appreciably with the advancement of age of the crop and maximum values were recorded at harvest. Application of ¼ lime of LR increased plant height at harvest, grain and stover yield to the extent of 13.1, 24.6 and 23.0%, respectively over control. Phosphorus and boron uptake increased significantly with lime application and enhanced by 45.9, 27.0% in grain and 44.5 and 29.3% in stover, respectively over control. Application of phosphorus significantly enhanced the growth attributes, yield attributes, grain and stover yield and P and B uptake except rows per cob and test weight and the highest values of these parameters were recorded with 40.2 mg P2O5 kg-1. However, grain and stover yield and P and B uptake in grain and stover remained statistically at par with 26.8 mg P2O5 kg-1application.Application of 26.8 mg P2O5 kg-1 enhanced plant height at harvest, grain and stover yield by 21.2, 23.2 and 19.8%, respectively over control. Plant height, leaves plant-1, cob length, cob girth, grains row-1, grains cob-1, grain and stover yield and P and B uptake were influenced significantly with boron application and maximum values were recorded with 0.90 mg B kg-1. At harvest plant height, grain and stover yield was increased by 4.9, 10.9 and 10.6%, respectively with application of 0.90 mg B kg-1 over control. Lime application significantly increased the available P and B status of post harvest soil. Application of P and B significantly improved their respective status in post harvest soil.Thus, results suggested that application of ¼ lime of LR along with 26.8 mg kg-1 P2O5 and 0.90 mg kg-1 boron proved beneficial for cultivation of maize in acidic soil condition of Nagaland.

Sodium tetraphenylborate displays selective bactericidal activity against N. meningitidis and N. gonorrhoeae and is effective at reducing bacterial infection load.

Neisseria meningitidis and Neisseria gonorrhoeae, two highly related species that may have emerged from a common commensal ancestor, constitute major human threats. Vaccines are available to prevent N. meningitidis infection, whereas for N. gonorrhoeae, there are only a limited number of antibiotics available. Unfortunately, some strains of these species are rapidly evolving and capable of escaping human interventions. Thus, it is now urgent to develop new avenues to fight these bacteria. This study reports that a boron-based salt, sodium tetraphenylborate (NaBPh4), displays high bactericidal activity and remarkable specificity against N. meningitidis and N. gonorrhoeae. Other closely related commensal species such as N. lactamica, found in the normal flora of healthy individuals were found to be less affected even at 5-fold higher doses of NaBPh4. This specificity was further observed where much lower sensitivity was found for the more distant Neisseriaceae (such as N. elongata or Kingella oralis) and completely unrelated species. A significant boron uptake by N. meningitidis cells was observed after incubation with 5 μM of NaBPh4, as measured by ICP-MS, suggesting that this drug candidate's target(s) could be located intracellularly or within the cell envelope. Furthermore, mutants with a slightly decreased susceptibility displayed an alteration in genes coding for cell-envelope elements, which reduced their virulence in an animal model of infection. Finally, a single dose of NaBPh4 resulted in a significant reduction in bacterial burden in a mouse model of N. meningitidis bacteremia. Although numerous boron-containing species were previously reported for their complex biological activities, the observation of this narrow selectivity is unprecedented and of potential importance from a therapeutic standpoint.

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

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.