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The neutron capture reaction 10B(1n,4He)7Li produces two energetic particles, 4He2+ and 7Li3+ that are strongly cell toxic. Due to the short range of these nuclear fragments (5-9 microns) mainly those cells that have bound or internalized a 10B-containing substance are growth-inactivated. The most critical and difficult step in an efficient boron neutron capture therapy (BNCT) is the tumour targeting. It is today possible to synthesize a large number of boron compounds and conjugate them to tumour-seeking macromolecules, such as monoclonal antibodies or different polypeptides. The boron-containing substances presently considered for therapy are sulfhydryl boron hydride (BSH) and boron-phenylalanine, (BPA) for the treatment of gliomas and malignant melanomas respectively. Other boronated compounds considered are ligands for receptor-amplified tumour cells, antibodies for tumour cells with specific antigens and thioureas for treatment of melanotic melanomas. The required boron concentration is given by the relative dose due to neutron capture in 10B and that of the competing capture reactions in nitrogen and hydrogen. Capture in nitrogen produces protons with a range of about 10-11 microns and this gives a radiation dose to all cells in the neutron activated area. Calculations show that the local concentration of 10B near the critical radiation target, DNA, must be higher than 10 ppm (10 micrograms/g). Increased emphasis will be put on the development of combinations of treatments that fulfil the requirements for attacking the microscopic spread of the tumour.
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PMID:Present status of boron neutron capture therapy. 129 Jun 30

Mercaptoundecahydrododecaborate (BSH) is an important agent in boron neutron capture therapy (BNCT) of various cancers. A simple and rapid analytical method for the measurement of mercaptoundecahydrododecaborate in aqueous solution and in urine by Fourier transform infrared spectroscopy has been developed. A thin-pathlength sampling apparatus was used to minimize the strong absorption of water. The subtraction of water absorbance from sample spectra resolved a B-H band at 2493 cm-1. The quantitative measurement of BSH concentration was carried out by integrating the B-H band above baseline in the range of 2534-2440 cm-1. The lower limit of measuring the concentration of sodium BSH (Na2B12H11SH) in our experiment was 10 micrograms/ml (about 5 ppm of boron). This method measures the hydroborate (B-H) concentration instead of total boron and, thus, may be utilized to measure the BSH concentration in in vivo samples for metabolic studies.
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PMID:Quantitative analysis of mercaptoundecahydrododecaborate by Fourier transform infrared spectroscopy. 140 4

Sulfhydryl boron hydride (BSH) (10B enriched) is presently used for boron neutron capture therapy of malignant gliomas. BSH must be close to the target cells to be effective in the inactivation of cell proliferation because of the short range of the reaction products (5-9 microns). Clinical experience indicates that BSH is taken up in gliomas but it is not known to which structures it binds at the cellular level. In vitro tests on monolayer cultured cells have indicated that BSH does not bind, or only shows very weak binding, to single isolated cells. It is possible that BSH accumulates in tumor regions due to the special conditions in poorly vascularized tumor tissue, such as low pO2, low extracellular pH, metabolic gradients, and degenerative changes. To test this we incubated three types of multicellular tumor spheroids with BSH for different times and analyzed both penetration and binding. The spatial distribution of 10B in sections of the spheroids was analyzed by neutron capture autoradiography. We found extensive accumulation of 10B in the central regions of both glioma and colon carcinoma spheroids. The accumulation closely followed the pattern of the degenerative changes which were characterized by massive necrosis in the central regions of the colon carcinoma spheroids and by a continuously increasing frequency of pyknotic nuclei as a function of depth in the glioma spheroids. The accumulation of 10B in the prostatic carcinoma spheroids was much lower. The penetration assay, based on freeze-drying and vapor fixation, showed that BSH penetrated easily since 10B equilibrated within 5-15 min in the studied spheroids. Thus, the low accumulation in the prostatic carcinoma spheroids was not due to penetration difficulties. The results of the present study on cellular spheroids and the results from previous studies on transplanted tumors support the observation that BSH penetrates easily into the degenerative tumor areas and that 10B, for some tumor types, might accumulate in these regions as a result of the BSH administration.
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PMID:Accumulation of 10B in the central degenerative areas of human glioma and colon carcinoma spheroids after sulfhydryl boron hydride administration. 154 Sep 68

Kinetics of boron disposition after single intravenous injections of two different doses (25 and 50 mg/kg) of mercaptoundecahydrododecaborate sodium (Na2B12H11SH; BSH) was studied in rabbits. Residual boron concentrations in various organs and tissues (heart, lungs, liver, spleen, kidney, adrenals, and brain) were also determined after seven daily injections of the same doses of BSH. Boron blood and tissue concentrations were measured by atomic emission spectrometry. In the majority of animals, the decline of boron blood concentrations after a single intravenous injection of either dose was biphasic, being consistent with a two-compartment model of boron disposition in the body. Although mean boron blood concentrations were roughly proportional to the BSH dose delivered, the mean total body clearance of boron from the body was 3 times lower (6.5 +/- 1.9 ml min-1 kg-1) after a dose of 50 mg/kg than after the injection of 25 mg/kg (22.4 +/- 7.9 ml min-1 kg-1), the difference between the means being statistically significant (P less than 0.05). Moreover, the mean terminal half-life of boron in blood was prolonged after the injection of 50 mg/kg (14.5 +/- 5.5 h) as compared with that found after the 25-mg/kg dose (3.5 +/- 0.9 h). On the other hand, the different BSH doses did not result in marked differences in the mean values obtained for the volume parameters - the volume of the central compartment (1.3 +/- 0.4 vs 1.3 +/- 0.5 l kg-1) and the volume of distribution at steady state (4.7 +/- 1.3 vs 6.0 +/- 4.0 l kg-1) - both of which were high, indicating extensive binding of the compound not only in the blood but also in tissues. Residual concentrations of boron found after seven daily injections of both doses of BSH were highest in the kidneys, the difference in the mean values being relatively small (33.6 +/- 6.1 vs 39.0 +/- 10.7 micrograms/g tissue). In the majority of other organs (heart, lung, liver, spleen, brain, adrenals), the residual concentrations after a dose of 50 mg/kg were disproportionately higher than those measured after the injection of 25 mg/kg, and the mean values corresponded to the reduced total body clearance rather than to the increased BSH dose. The saturability of BSH binding to blood and tissue proteins is suggested as a possible explanation for the dose dependency of the total clearance of boron from the body and the accumulation of BSH in organs and tissues.
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PMID:Dose-dependent disposition kinetics and tissue accumulation of boron after intravenous injections of sodium mercaptoundecahydrododecaborate in rabbits. 156 87

The following boron-containing nucleoside and glucose derivatives have been synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT): 2'-O-(o-carboran-1-ylmethyl)uridine (4a), 3'-O-(o-carboran-1-ylmethyl)uridine (4b), sodium 7-(uridin-2'-ylmethyl)dodecahydro-7,8-dicarba-++ +nido-undecaborate (5), 5'-O-(o-carboran-1-ylmethyl)uridine (9), and 3'-O-(o-carboran-1-ylmethyl)-D-glucose (13). In vitro cellular uptake studies were performed with F98 rat glioma cells. Following 16 h incubation, cellular boron concentrations were determined by direct current plasma atomic emission spectroscopy (DCP-AES). Boron concentrations ranged from 65 to 103 micrograms/g of cells for the neutral closo structures compared with 1.5 micrograms/g of cells for the charged nido species. Cellular uptake of sodium mercaptoundecahydro-closo-dodecaborate (BSH), the compound currently being used in Japan for the treatment of malignant brain tumors by BNCT, was 2 micrograms/g of cells.
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PMID:Synthesis and in vitro evaluation of boronated uridine and glucose derivatives for boron neutron capture therapy. 157 91

A three-dimensional projection reconstruction technique is described for imaging boron-11 distributions, with potential application to boron neutron capture therapy. The method samples a spherical volume of k space uniformly to obtain a 32 x 32 x 32 matrix with voxel size of 0.42 cm3. A signal-to-noise ratio (S/N) of 3 was obtained in 8.5 minutes in a phantom containing 75 micrograms/mL of boron in borocaptate sodium (BSH). Images were obtained in a dog after cessation of an intravenous infusion of BSH and again 30 minutes later, with a maximum boron S/N of about 12. Boron levels in the brain dropped about 6%-8% and were more diffusely distributed on the images obtained 30 minutes after BSH infusion.
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PMID:Boron-11 imaging with a three-dimensional reconstruction method. 162 80

A major problem remaining in the evaluation of boronated compounds for neutron capture therapy (NCT) is the need to know the intra- or extracellular microdistribution of boron. This is a consequence of the short range of the 10B(n,alpha)7Li reaction products (approximately 10 microns), such that biological efficacy is dependent upon intracellular distribution. In particular, if boron location is predominantly extracellular, a significant reduction in efficacy would be expected. The in vitro procedure described here was developed mainly to provide information regarding the intra- and extracellular location and concentration of boron. However, use of the technique also allows the measurement of compound uptake and retention (binding) and the determination of biological efficacy by the evaluation of survival curves obtained following irradiation with thermal neutrons. Comparison is made to results obtained with boric acid (H3(10)BO3) and to results calculated for various boron distributions. Concomitantly, an indication of compound toxicity can be obtained from the plating efficiency of unirradiated control cells. Currently, most investigators utilize in vivo systems for testing and evaluating boron uptake from various carrier molecules. Given the large number of boron compounds being synthesized and needing evaluation as to their usefulness for NCT, the in vitro technique described here is simple and advantageous for initial compound screening. In addition to sparing animal lives, it is both time and cost effective and utilizes much smaller quantities of test compound than are required for an in vivo assay. A boronated porphyrin (BOPP) evaluated by the above procedure shows an uptake and retention approximately 20 times that of sulfhydryl boron hydride monomer (BSH); the latter compound is currently being used clinically for NCT in Japan and is anticipated for use in clinical trials in the United States. If the advantages demonstrated by BOPP in these in vitro studies are validated in animal experiments, BOPP should be considered for clinical application.
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PMID:In vitro determination of uptake, retention, distribution, biological efficacy, and toxicity of boronated compounds for neutron capture therapy: a comparison of porphyrins with sulfhydryl boron hydrides. 237 50

The conditions for the possible initiation of clinical trials with neutron capture therapy at a number of locations in the U.S. is reviewed. There are several new technical developments or plans at the Brookhaven Medical Research Reactor (BMRR), the Power Burst Facility (PBF) at INEL, the Massachusetts Institute of Technology Reactor (MITR) and the Georgia Institute of Technology Research Reactor (GTRR). Emphasis is on the development of epithermal beams for the treatment of deepseated tumors with neutron fluxes in between 10(9) to 10(10) n/cm2s. Therapeutic dose gains, defined as the ratio of tumour dose to maximum normal tissue dose in the treatment volume are expected to be between 2 and 4, depending on the degree of suppression of fast neutron dose. Boron concentrations considered in this case in the tumour are around 35 micrograms 10B/g and tumour/normal tissue concentrations are around 10. The compound development throughout three generations is discussed. The compound proposed nowadays, Na2B12H11SH (or BSH), employed in the treatments in Japan, will likely be replaced in the future by analogous of biomolecules being enriched in the tumour by physiological pathways. Examples are p-boronophenylalanine or boronated porphyrius. The most promising solution envisaged would be the employment of tumour cell specific brononated monoclonal antibodies. Finally the mode of therapy is discussed which will likely be based on a fractioned scheme, to achieve optimized results.
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PMID:Recent developments in neutron capture therapy. 271 46

The relative diagnostic value of ST and RAST was evaluated in 97 patients with BSH. Eighteen patients had LRs, 79 showed SRs including 18 with urticaria, 26 had bronchospasm, and 35 had anaphylactic shock. ST but not the RAST reactivity was strongly related to the severity of the clinical reaction (p less than or equal to 0.001) and found superior to the RAST in identifying patients with SRs in whom venom therapy was indicated.
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PMID:The relative value of skin tests and radioallergosorbent test in the diagnosis of bee sting hypersensitivity. 664 73

A 3D projection reconstruction (3DPR) method was used to obtain in vivo 11B images in a large canine brain tumor model and in a human infused with borocaptate sodium (BSH). Studies were performed in dogs with and without gliosarcomas implanted and grown to a size of 2-3 cm. The 3DPR method demonstrates a signal-to-noise ratio (SNR) that allows qualitative kinetic studies of the boron compound in normal and tumor tissue of the head. The measurements indicate initial uptake of the BSH compound in tumor to be less than that in muscle with no uptake in normal brain tissue. Moreover, uptake of BSH in tissue was found to lag the boron concentration in blood with delays that depend on tissue type. In addition, the first human boron images were obtained on a patient who underwent surgical resection and volumetric debulking of a large (7 cm) glioblastoma multiforme. BSH was readily taken up in residual tumor tissue, while diffusion into the resection volume was slower.
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PMID:BSH distributions in the canine head and a human patient using 11B MRI. 767 98


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