Intercomparison of inductively coupled plasma mass spectrometry, quantitative neutron capture radiography, and prompt gamma activation analysis for the determination of boron in biological samples

Boron determination in blood and tissue samples is a crucial task especially for treatment planning, preclinical research, and clinical application of boron neutron capture therapy (BNCT). Comparison of clinical findings remains difficult due to a variety of analytical methods, protocols, and standard reference materials in use. This paper addresses the comparability of inductively coupled plasma mass spectrometry, quantitative neutron capture radiography, and prompt gamma activation analysis for the determination of boron in biological samples. It was possible to demonstrate that three different methods relying on three different principles of sample preparation and boron detection can be validated against each other and yield consistent results for both blood and tissue samples. The samples were obtained during a clinical study for the application of BNCT for liver malignancies and therefore represent a realistic situation for boron analysis.     

Transport properties of boron and aluminum

Transport cross sections and collision integrals are tabulated for a wide range of energies and temperatures for the interactions B–B and Al–Al. For aluminum, a semiclassical approximation was used to determine the scattering phase shifts from which the transport cross sections were calculated. For boron, the smaller reduced mass and the deep potential wells required the phase shifts at lower energies to be determined from a numerical solution of the time-independent Schroedinger equation; the semiclassical approximation was used at higher energies where the two methods agree. The variations of the collision integrals for viscosity and diffusion are presented graphically as a function of temperature. The results are applied to estimate the transport properties of gallium. Received: 9 July 1999 / Accepted: 18 August 1999 / Published online: 2 November 1999     

Application of cycloaddition reactions to the syntheses of novel boron compounds

This review covers the application of cycloaddition reactions in forming the boron-containing compounds such as symmetric star-shaped boron-enriched dendritic molecules, nano-structured boron materials and aromatic boronic esters. The resulting boron compounds are potentially important reagents for both materials science and medical applications such as in boron neutron capture therapy (BNCT) in cancer treatment and as drug delivery agents and synthetic intermediates for carbon-carbon cross-coupling reactions. In addition, the use of boron cage compounds in a number of cycloaddition reactions to synthesize unique aromatic species will be reviewed briefly.     

Avidin self-associates with boric acid gel suspensions: an affinity boron carrier that might be developed for boron neutron-capture therapy

It has been shown in preliminary studies that the antibacterial protein avidin self-associates with the boric acid gel polymer, and avidin-coated gel particles in the micrometer and submicrometer size ranges are of interest for boron neutron-capture therapy (BNCT), which is neutron-induced fission of boron-10 to produce intense alpha radiation for tumor destruction. The gel particles carry large amounts of boron-10 and are theoretically able effect a meaningful tissue dosing through BNCT. A gross precipitation of gel particles occurs within 46 min of mixing when the avidin/colloid ratio is about 0.34 g avidin/g colloid. This is a minimum time if gel and avidin concentrations are in the low microgram/milliliter range, but at higher proportions of avidin the time delay to precipitation increases significantly; i.e., the colloid surface becomes blocked, inhibiting lattice formation. The avidin-coated gel particles eventually cross-link, forming a solid matrix and precipitating on a timescale measured on the order of an hour. At shorter exposure times rapid agglutination-like reactions were observed with biotinylated bovine albumin, suggesting that two-stage pretargeting of specific tissues should be possible with biotinylated antitumor antibodies. However, for BNCT to be practical, avidin's interaction with the gel needs to be strengthened, and all aryl-B(OH)(2) groups on the particle surfaces must be blocked, or else the particles will interact strongly and nonspecifically with each other and with the carbohydrate groups present on most cell surfaces. Glyceric acid delays the precipitation of the particle suspensions while most simple and complex carbohydrates accelerate it.     

Synthesis and characterisation of functionalized borosilicate nanoparticles for boron neutron capture therapy applications

Boron Neutron Capture Therapy (BNCT) is a promising therapy for the cure of diffuse tumors. The successful clinical application of BNCT requires finding new boron-based compounds suitable for an efficient ¹⁰B delivery to the cancerous tissues. The purpose of this work is to synthesize borosilicate nanoparticles by a sol?Cgel recipe, and to functionalize them with folic acid in order to promote their capture by the tumor cells. Whereas sol?Cgel is a promising technique for the synthesis of nanoparticles, in case of borosilicate systems this approach is affected by significant boron loss during preparation. Here we show that functionalization of borosilicate nanoparticles with folic acid can reduce the boron loss. Moreover, preliminary biocompatibility tests indicate that functionalization strongly changes the reactivity of NPs towards blood cells, so favouring the potential use of these materials for clinical applications.     

Novel carboranylporphyrins for application in boron neutron capture therapy (BNCT) of tumors

Condensation of a new carboranylpyrrole 1 with benzaldehydes leads to β-carboranylporphyrins 2 and 3 in good yields. These new porphyrins of high boron content (32-43%) have potential as boron delivery agents for BNCT. The X-ray structures of one β-carboranylporphyrin, of a carboranylpyrrole, and of a side-product are presented.     

Synthesis and cellular uptake of boron-rich pyrazolopyrimidines: exploitation of the translocator protein for the efficient delivery of boron into human glioma cells

New 1,2-closo- and 7,8-nido-carboranylpyrazolopyrimidines bind to the translocator protein (TSPO) with high affinity, providing the first evidence of a unique two-site binding profile for the closo-carborane derivative. The boron-rich compounds can also deliver boron to human glioma cells far more effectively than clinical agents used in boron neutron capture therapy (BNCT).     

Determination of boron and nitrogen in boron nitride

Improved techniques are described for the determination of boron and nitrogen in pure boron nitride. Controlled fusion of boron nitride with sodium carbonate in a muffle furnace is followed by a potentiometric titration of the boric acid. A special quartz vessel is described for the determination of nitrogen. The boron nitride is fused with sodium hydroxide and the resulting ammonia is swept into a receiver and titrated with standard hydrochloric acid. Boron and nitrogen values with their standard deviation are given for a typical pure boron nitride.     

Reactions of sterically protected phosphaalkenes with some boron reagents

The reactions of sterically protected phosphaalkenes with some boron reagents, such as boron hydrides, were carried out leading to hydroboration products depending on the substrates and boron reagents. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 187–196, 1999     

The determination of microgram and sub-microgram amounts of boron : II. The separation of boron by distillation and the evaporation of distillates

Methyl alcohol distillates containing μg amounts of boron may be evaporated without loss of boron by first adding water, sodium hydroxide and glycerol. The resulting residues can be used directly in the curcumin absorptiometric methods previously described. The distillation techniques developed over the last decade by the United Kingdom Atomic Energy authority are briefly described, as these can be used for the separation of boron from practically all types of sample, including organic matter after it has been ashed with lime. In all cases aqueous solutions of the samples are made slightly acid (pH 1.5–5) and evaporated nearly to dryness Residues are then treated with methyl alcohol in one of three ways according to their properties. It is essential to use all-silica distillation apparatus and platinum dishes for collecting distillates. Notes are given of other precautions necessary to minimize contamination from reagents and other sources. The methods are rapid and suitable for routine analysis on up to 10 g of sample. Under favourable conditions, the limit of detection is of the order of 0.01 p.p.m. of boron. A precision of better than 5% can be obtained with amounts exceeding about 0.2 p.p m.     

[C2B10]---[B12] double cage boron compounds—a new approach to the synthesis of water-soluble boron-rich compounds for BNCT

A new approach in the synthesis of water-soluble boron-rich compounds was proposed. The closo-dodecaborate cage is used as a hydrophilic substitutent providing for the water-solubility of the molecule whereas the carborane cage can be used for attachment to biomolecules using earlier developed methods. The double-cage molecules [o-, m-, and p-CB₁₀H₁₀C(CH₂)₄OB₁₂H₁₁]²⁻ were prepared by the reaction of the tetramethylene oxonium derivative of the closo-dodecaborate anion, [B₁₂H₁₁O(CH₂)₄]⁻, with the corresponding lithiated carboranes. The compounds obtained have doubled the boron contents and could serve for the synthesis of agents for boron neutron capture therapy (BNCT).     

Kohonen classification applying ‘missing variables’ criterion to evaluate the p‐boronophenylalanine human‐body‐concentration decreasing profile of boron neutron capture therapy patients

The irradiation dose in tumor and healthy tissue of a boron neutron capture therapy (BNCT) patient depends on the boron concentration in blood. In most treatments, this concentration is experimentally determined before and after irradiation but not while irradiation is being carried out because it is troublesome to take the blood samples when the patient remains isolated in the irradiation room. A few models are used to predict the boron profile during that period, which until now involves a biexponential decay. For the prediction of decay concentration profiles of the p‐boronophenylalanine (BPA) in the human body during BNCT treatment, a Kohonen‐based neural network method is suggested. The results of various (20 × 20 × 40 Kohonen network) models based on different trainings on the data set of 67 concentration sets (profiles) are described and discussed. The prediction ability and robustness of the modeling method were tested by the leave‐one‐out procedure. The results show that the method is very robust and mostly independent of small variations. It can yield predictions, root mean squared prediction error (RMSPE), with a maximum of 3.30 µg g⁻¹ for the present cases. In order to show the abilities and limitations of the method, the best and the few worst results are discussed in detail. It should be emphasized that one of the main advantages of this method is the automatic improvement in the prediction ability and robustness of the model by feeding it with an increasing number of data. Copyright © 2011 John Wiley & Sons, Ltd.     

Depth dose evaluation for prostate cancer treatment using boron neutron capture therapy

Considering the advantages of boron neutron capture therapy (BNCT) in treating prostate cancer, the amount of dose delivered to tumour and healthy tissues must be determined. Therefore, in this study, Monte Carlo analyses were performed to evaluate physical doses of adjacent healthy tissues and prostate tumours located at different depths of reference phantom developed by International Commission on Radiological Protection. According to the results, when prostate depth decreases, the amount of physical dose in tumour increases but the physical doses of healthy organs around the tumour remain constant. As expected, lithium filter decreases the damages to normal tissues. The estimations of physical dose, dose uniformity and dose distribution suggested that using BNCT with a filtered neutron beam could be applicable for prostates locate at the depths less than 7 cm from the body surface, which occurs in 5 % of all subjects.     

Synthesis and characterization of azanonaborane-containing purine derivatives for boron neutron capture therapy

Derivatives of purine, adenine, guanine, and 2,6-diaminopurine linked to the azanonaborane (B₈N cluster) have been prepared, for possible use as powerful agents for boron neutron capture therapy (BNCT). The synthesis was carried out via a ligand exchange reaction. The exo-NH₂R group of the azanonaborane of the type [(RH₂N)B₈H₁₁NHR] can be exchanged by one hetero-nitrogen atom of the pyrimidine ring, and except for guanine, also by an N atom of the imidazole ring. The identity of the products was confirmed by NMR, elemental analysis, IR, and mass spectrometry. No reaction was found to occur with caffeine and theophylline under the same reaction conditions.      

Design of multivalent galactosyl carborane as a targeting specific agent for potential application to boron neutron capture therapy

A multivalent galactosyl carborane derivative 10 (dendritic glyco-borane, DGB) was synthesized and demonstrated as a potential cell-targeting agent in BNCT with HepG2 cells. DGB 10 improved the delivery of boron to HepG2 cells and neutron irradiation data show DGB 10 with ten-fold improvement at killing the HepG2 cells over BSH.     

Improvement of the moderator’s thermalization efficiency for 14 MeV neutrons in boron neutron capture therapy

In boron neutron capture therapy (BNCT), the proportion of the fast neutron in the tumor (PFN) must be no more than 3%. If a D–T neutron generator is used as a thermal neutron source in BNCT, the moderator must be optimized to decrease the PFN. Based on the analysis of the theory, water, heavy water, polythene, graphite, lead, and tungsten were used to moderate the fast neutrons. If the three-layer material is composed of a 4 cm thickness layer of tungsten, a 13 cm thickness layer of lead, and a 23 cm thickness layer of heavy water, its thermalization efficiency (TE) is highest, which is increased by 191.5% than the maximum TE moderated by single-layer materials and by 19.3% than the maximum TE moderated by double-layer materials.     

Synthesis and characterization of a novel functionalized azanonaborane cluster for boron neutron capture therapy

The reactivity of an azanonaborane cluster containing free amino groups {H2N(CH2)4H2NB8H11NH(CH2)4NH2} towards ketones and aldehydes is investigated. In a one step reaction, the reductive amination of some ketones and aldehydes (namely acetone, benzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 4-nitrobenzaldehyde, 4-acetoxybenzaldehyde, and 4-acetamidobenzaldehyde) with an azanonaborane cluster in the presence of H3BNH2(CH2)4NH2 gives monoalkylamino derivatives of the azanonaborane cluster {RHN(CH2)4H2NB8H11NH(CH2)4NHR} where (R =(Me)2CH-, C6H5CH2-, 3-OHC6H4CH2-, 4-OHC6H4CH2-, 4-NO2C6H4CH2-, 4-MeOCOC6H4CH2-, or 4-NH2COC6H4CH2-). The functionalized derivatives of the {B8N} cluster can be used in boron neutron capture therapy for tumors (BNCT). Similarly, the reductive amination of 5-(4"-formylphenyl)-10,15,20-triphenylporphyrin with the {B8N} cluster gave a porphyrin bearing azanonaborane cluster, while a porphyrin dimer linked by an azanonaborane moiety was obtained following the same method, starting with a 2:1 molar ratio of porphyrin:{B8N} cluster. 5,10,15,20-Tetraformylphenylporphyrin gave the chance to increase the percentage of boron in the resulting boronated porphyrin, which is considered an important factor for a BNCT delivery agent. With these compounds, the cell toxicity using V79 cells was carried out to determine whether these compounds would have favorable biological properties.     

Monitoring of gamma emission and neutron transmission during boron neutron capture treatment delivery

The ability to map boron and hydrogen distributions in the body is paramount to the success of boron neutron capture therapy (BNCT). We investigated treatment-time quantitative mapping of these distributions by detecting (i) 0.48 MeV de-excitation photons from neutron capture by boron-10; (ii) 2.22 MeV photons from neutron capture by hydrogen; and (iii) transmitted neutrons. Monte Carlo simulations reported no detectable difference when ¹⁰B in tumour was varied from 0 to 50 ppm, and when the tumour size was varied from 0.0 to 9.5 cm³.     

Investigation of the boron nitride/polybenzoxazine interphase

The influence of a hexagonal boron nitride powder surface on the polymerization of a benzoxazine monomer is examined by differential scanning calorimetry (DSC). By varying the thickness of the benzoxazine coatings on boron nitride particles, a distinct influence of the surface substrate on the polymerization reaction could be observed. At a coating thickness calculated to be on the order of a monolayer, the heat of reaction is reduced, while the exothermic peak temperature and peak width at half height are increased relative to that of the neat resin values. The reduced heat of reaction and increased exothermic peak temperature indicate that the boron nitride surface is inhibiting the benzoxazine polymerization reaction. In the intermediate coating thickness region, the heat of reaction increases and the exothermic peak temperature and peak width at half height decrease with increasing coating thickness. With even thicker coatings, the heat of reaction and exothermic peak temperature and peak width at half height reach values corresponding to that of the neat resin and no longer change with thickness. In addition, the influence of surface treated boron nitride particles on the thermal polymerization behavior, as well as the effect of the surface treatment on the viscosity, dynamic mechanical properties, and flexural properties of the filled composites are also investigated. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 2360–2372, 1999     

Oxidation-resistant thermosets derived from thermal copolymerization of acetylenic monomers containing boron and silicon

Polymerization of acetylenic monomers containing silicon and boron produces materials that are resistant to oxidation at elevated temperature. In addition to homopolymerization, these inorganic–organic hybrid monomers can be copolymerized with an otherwise all carbon containing system. Inorganic elements incorporated by this method enhance the thermooxidative stability of the copolymer. This stability is a function of the amount of boron in the final product. We show that a thermoset containing an initial 5% by weight of boron can be charred to a material that when heated in air at 1000 °C loses less than 10% of its mass. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 4356–4359, 1999