Boron neutron capture therapy: boron biodistribution and pharmacokinetics of Na2B12H11SH in patients with glioblastoma.

Data on biodistribution and pharmacokinetics of Na2B12H11SH are few and lack in standardization. This study comprises a uniform series of 10 patients with glioblastoma administered Na2B12H11SH i.v. 24 h before surgery at a dose level used in earlier therapeutical trials (75 mg/kg body weight). Boron concentrations in tumor, normal brain, peritumoral edematous brain, blood, and urine were determined by inductively coupled plasma-atomic emission spectroscopy 24 h after Na2B12H11SH administration; boron uptake in tumor (mean, 12.2 micrograms/g) was sufficiently selective compared to concentrations in normal and edematous brain (1.2 and 2.3 micrograms/g, respectively). Mean concentration ratio of tumor:blood was slightly above unity. Boron concentration in blood decreased according to an open two-compartment model, mean excretion in urine over 24 h was 81.9%. The only side effect was an inconstant facial flush. Among efforts aiming at an optimized treatment protocol a dose escalation study seems to be justified.

Optimal timing of neutron irradiation for boron neutron capture therapy after intravenous infusion of sodium borocaptate in patients with glioblastoma.

PURPOSE: A cooperative study in Europe and Japan was conducted to determine the pharmacokinetics and boron uptake of sodium borocaptate (BSH: Na(2)B(12)H(11)SH), which has been introduced clinically as a boron carrier for boron neutron capture therapy in patients with glioblastoma. METHODS AND MATERIALS: Data from 56 patients with glioblastoma who received BSH intravenous infusion were retrospectively reviewed. The pharmacokinetics were evaluated in 50 patients, and boron uptake was investigated in 47 patients. Patients received BSH doses between 12 and 100 mg/kg of body weight. For the evaluation, the infused boron dose was scaled linearly to 100 mg/kg BSH. RESULTS: In BSH pharmacokinetics, the average value for total body clearance, distribution volume of steady state, and mean residence time was 3.6 +/- 1.5 L/h, 223.3 +/- 160.7 L, and 68.0 +/- 52.5 h, respectively. The average values of the boron concentration in tumor adjusted to 100 mg/kg BSH, the boron concentration in blood adjusted to 100 mg/kg BSH, and the tumor/blood boron concentration ratio were 37.1 +/- 35.8 ppm, 35.2 +/- 41.8 ppm, and 1.53 +/- 1.43, respectively. A good correlation was found between the logarithmic value of T(adj) and the interval from BSH infusion to tumor tissue sampling. About 12-19 h after infusion, the actual values for T(adj) and tumor/blood boron concentration ratio were 46.2 +/- 36.0 ppm and 1.70 +/- 1.06, respectively. The dose ratio between tumor and healthy tissue peaked in the same interval. CONCLUSION: For boron neutron capture therapy using BSH administered by intravenous infusion, this work confirms that neutron irradiation is optimal around 12-19 h after the infusion is started.

Metabolism of borono-phenylalanine-fructose complex (BPA-fr) and borocaptate sodium (BSH) in cancer patients--results from EORTC trial 11001.

Within the clinical trial EORTC 11001, patients were infused with (10)B-enriched borono-phenylalanine-fructose complex (BPA-fr), or borocaptate sodium (BSH) solutions, which are used as boron carriers for boron neutron capture therapy. Urine samples were periodically collected and analyzed by (10)B NMR spectroscopy. The results revealed time-dependent metabolic changes of the administered compounds. BPA-fr dissociated to the constituents BPA and fructose, and the borate group was partly cleaved from BPA. BSH was partly aggregated to a dimer form, BSSB. These observations were previously reported for cultured cells and animal models, and are confirmed here in human cancer patients.

Quantitative analysis of mercaptoundecahydrododecaborate by Fourier transform infrared spectroscopy.

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.

Liquid chromatographic determination of sodium mercaptoundecahydrododecaborate in rat urine and plasma after precolumn derivatization.

A high-performance liquid chromatographic (HPLC) method was developed for the determination of disodium mercaptoundecahydrododecaborate (BSH) in biological fluids. Monobromobimane was used as a precolumn derivatizing agent. A stable derivative was obtained. The derivative was separated on a C18 column using reversed-phase ion-pairing chromatography and detected by a spectrophotometric detector at 373 nm. The detection limit was 200 ng/ml (0.1 ppm boron). Calibration curves were prepared for rat urine and plasma samples. The calibration curves were linear in the range of 1 microgram/ml to 100 micrograms/ml for urine samples and 0.2 micrograms/ml to 50 micrograms/ml for plasma samples.

Boron neutron capture therapy of brain tumors: investigation of urinary metabolites and oxidation products of sodium borocaptate by electrospray ionization mass spectrometry.

Boron neutron capture therapy (BNCT) is based on a nuclear capture reaction that occurs when boron-10, a stable isotope, is irradiated with low energy neutrons to produce high-energy alpha particles and recoiling lithium-7 nuclei. The purpose of the present study was to determine what urinary metabolites, if any, could be detected in patients with brain tumors who were given sodium borocaptate (BSH), a drug that has been used clinically for BNCT. BSH was infused intravenously over a 1-h time period at doses of 26.5, 44.1, or 88.2 mg/kg of body weight to patients with high-grade brain tumors. Electrospray ionization mass spectrometry has been used to investigate possible urinary metabolites of BSH. Chemical and instrument conditions were established to detect BSH and its possible metabolites in both positive and negative electrospray ionization modes. Using this methodology, boronated ions were found in patients' urine samples that appeared to be consistent with the following chemical structures: BSH sulfenic acid (BSOH), BSH sulfinic acid (BSO(2)H), BSH disulfide (BSSB), BSH thiosulfinate (BSOSB), and a BSH-S-cysteine conjugate (BSH-CYS). Although BSH has been used clinically for BNCT since the late 1960s, this is the first report of specific biotransformation products following administration to patients. Further studies will be required to determine both the biological significance of these metabolites and whether any of these accumulate in significant amounts in brain tumors.