RESUMEN
Background and Purpose; (10)B deriving from (10)B-para-boronophenylalanine (BPA) and (10)B-borocaptate sodium (BSH) have been detected in blood samples of patients undergoing boron neutron capture therapy (BNCT) using prompt gamma ray spectrometer or Inductively Coupled Plasma (ICP) method, respectively. However, the concentration of each compound cannot be ascertained because boron atoms in both molecules are the target in these assays. Here, we propose a simple and rapid method to measure only BPA by detecting fluorescence based on the characteristics of phenylalanine. Material and Methods; (10)B concentrations of blood samples from human or mice were estimated by the fluorescence intensities at 275 nm of a BPA excited by light of wavelength 257 nm using a fluorescence spectrophotometer. Results; The relationship between fluorescence to increased BPA concentration showed a positive linear correlation. Moreover, we established an adequate condition for BPA measurement in blood samples containing BPA, and the estimated (10)B concentrations of blood samples derived from BPA treated mice were similar between the values obtained by our method and those by ICP method. Conclusion; This new assay will be useful to estimate BPA concentration in blood samples obtained from patients undergoing BNCT especially in a combination use of BSH and BPA.
Asunto(s)
Bioensayo/métodos , Análisis Químico de la Sangre/métodos , Borohidruros/sangre , Compuestos de Boro/sangre , Terapia por Captura de Neutrón de Boro/métodos , Fenilalanina/análogos & derivados , Espectrometría de Fluorescencia/métodos , Compuestos de Sulfhidrilo/sangre , Animales , Humanos , Ratones , Ratones Endogámicos C3H , Fenilalanina/sangre , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
In order to improve the effectiveness of boron neutron capture therapy (BNCT) for malignant gliomas, we examined the optimization of the administration of boron compounds in brain tumor animal model. We analyzed the concentration of boron atoms in intracranial C6 glioma -bearing rats using inductively coupled plasma atomic emission spectrometry. Each tumor-bearing rat received one of two different amounts of sodium borocaptate (BSH) and/or 500 mg/kg of boronophenylalanine (BPA) via intraperitoneal injection. We compared the boron concentrations of the tumor, the contralateral normal brain and the blood in rats of 3 different treatment groups (BSH alone, BPA alone and a combination of both BSH and BPA). Our results show that the tumor boron concentration increased much more than 30 microg/g by the coadministration of both compounds. Additionally, the blood boron concentration remained below 30 microg/g and the boron concentration in the normal brain was low (mean 4.7+/-1.1 microg/g). Even in comparison with the administration of BPA alone, coadministration of BPA and BSH shows an improved tumor/normal brain ratio of boron concentrations.
Asunto(s)
Borohidruros/farmacocinética , Compuestos de Boro/farmacocinética , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Fenilalanina/análogos & derivados , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Compuestos de Sulfhidrilo/farmacocinética , Animales , Borohidruros/administración & dosificación , Borohidruros/sangre , Compuestos de Boro/administración & dosificación , Compuestos de Boro/sangre , Encéfalo/metabolismo , Neoplasias Encefálicas/radioterapia , Combinación de Medicamentos , Sinergismo Farmacológico , Glioma/radioterapia , Masculino , Fenilalanina/administración & dosificación , Fenilalanina/sangre , Fenilalanina/farmacocinética , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Dosificación Radioterapéutica , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/sangreRESUMEN
The interference of colloidal tin oxides on the biodistribution of (99m)Technetium radiolabeled chitosan nanoparticles has been overcome by using sodium borohydride instead of commonly used stannous salts as reducing agent for the reduction of (99m)Tc (VII) to lower valency states. Biodistribution of radiolabeled chitosan nanoparticles prepared by using stannous chloride method revealed localization of the radioactivity mainly in the liver and spleen while that of radiolabeled chitosan nanoparticles prepared by using sodium borohydride method manifested the presence of radioactivity in blood up to an extent of 10% even after 2 h. Interestingly, the reduction of radioactivity in the latter case with the progress of time was not manifested through an increase in activity in the liver. Rather, a time dependent increased accumulation of radioactive materials was observed in the stomach. From the results it has been concluded that the biodistribution is strongly influenced by the presence of colloidal particles of tin oxides and (99m)Tc labeled chitosan nanoparticles are RES evading and long circulating in blood when Tc (VII) is reduced by sodium borohydride and not by stannous chloride during radiolabeling process.
Asunto(s)
Coloides/farmacología , Marcaje Isotópico/métodos , Nanoestructuras/química , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/metabolismo , Compuestos de Estaño/farmacología , Distribución Tisular , Animales , Borohidruros/sangre , Borohidruros/química , Borohidruros/farmacología , Quitosano/sangre , Quitosano/química , Quitosano/farmacología , Coloides/química , Coloides/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Marcaje Isotópico/tendencias , Ratones , Ratones Endogámicos , Compuestos de Organotecnecio/farmacología , Conejos , Tecnecio , Tecnología Farmacéutica/métodos , Tecnología Farmacéutica/tendencias , Compuestos de Estaño/sangre , Compuestos de Estaño/química , Compuestos de Estaño/metabolismoRESUMEN
We have developed a quantitative assay using electrospray ionization mass spectrometry coupled to reversed-phase ion-pair liquid chromatography (LC/MS) for quantitation of sodium borocaptate (BSH) in human plasma. The assay was developed using a Micromass Q-TOF II mass spectrometer equipped with an orthogonal electrospray source. The mobile phase was a 1:1 solution of methanol and 5 mM aqueous tetrabutylammonium acetate flowing at 0.2 mL/min, and the chromatography was performed using a Machery-Nagel Nucleosil C18 column. Plasma samples from patients who had received an intravenous infusion of sodium borocaptate (Na2B12H11SH), frequently referred to as BSH, were prepared for analysis by precipitation with acetonitrile. Following this, the supernatants were collected, and 40 microL was injected onto the column for analysis. The LC/MS assay was linear over a BSH plasma concentration range of 20-0.5 microg/mL with acceptable variability for both intra- and interassay precision. The LC/MS assay was used to generate pilot pharmacokinetic data for the plasma disposition of BSH in humans. The disposition of BSH was found to be consistent with a two-compartment model with first-order elimination from the central compartment. The mean total body plasma clearance was 95.7 +/- 30.8 m/min and the harmonic mean terminal half-life was 3.6 h.
Asunto(s)
Borohidruros/sangre , Borohidruros/farmacocinética , Espectrometría de Masa por Ionización de Electrospray/métodos , Compuestos de Sulfhidrilo/sangre , Compuestos de Sulfhidrilo/farmacocinética , Borohidruros/administración & dosificación , Terapia por Captura de Neutrón de Boro , Calibración , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Humanos , Tasa de Depuración Metabólica , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray/instrumentación , Compuestos de Sulfhidrilo/administración & dosificaciónRESUMEN
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.
Asunto(s)
Borohidruros/farmacocinética , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Compuestos de Sulfhidrilo/farmacocinética , Adulto , Anciano , Borohidruros/administración & dosificación , Borohidruros/sangre , Borohidruros/orina , Neoplasias Encefálicas/radioterapia , Niño , Femenino , Glioblastoma/radioterapia , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/sangre , Compuestos de Sulfhidrilo/orina , Factores de TiempoRESUMEN
Longitudinal and transverse relaxation rates for the 11B resonances in sodium borocaptate (BSH) at varying concentrations were measured in undiluted horse serum in a 4.7 Tesla field. The results could be fit by a model that assumes fast exchange of the BSH molecule between a free and a bound state, using values of 0.77+/-0.7 MHz for the 11B quadrupole coupling constant and (6.3+/-0.9) x 10(-9) s for the rotational correlation time in the bound state. These results were used as a basis for assessing the requirements and limitations of quantitative determination of BSH concentrations in vivo, using 11B NMR. Surface coil 11B NMR spectroscopy was performed on a total of 14 mice injected with BSH. Some of the animals (n=9) had implanted M2R melanoma tumors grown to various sizes in the rear thigh, in which case the surface coil was placed against the tumor, whereas for the other animals (without tumor), the coil was placed against the rear thigh muscle. NMR spectra were acquired under fully relaxed conditions. The spectra were quantitated by peak integration; apparent absolute BSH concentrations were derived by comparison with spectra from a phantom with known BSH concentration, using extrapolation of the time-domain data to zero preacquisition delay. The results indicate significantly higher 11B BSH signal intensities in tumors, compared with muscle tissue, whereas the uptake and clearance kinetics were similar.
Asunto(s)
Borohidruros/análisis , Espectroscopía de Resonancia Magnética , Melanoma/metabolismo , Músculo Esquelético/metabolismo , Neoplasias de los Tejidos Blandos/metabolismo , Compuestos de Sulfhidrilo/análisis , Algoritmos , Animales , Borohidruros/administración & dosificación , Borohidruros/sangre , Borohidruros/farmacocinética , Boro , Terapia por Captura de Neutrón de Boro , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética/instrumentación , Tasa de Depuración Metabólica , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Fantasmas de Imagen , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/sangre , Compuestos de Sulfhidrilo/farmacocinética , Muslo , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Borohidruros/farmacocinética , Glioblastoma/metabolismo , Compuestos de Sulfhidrilo/farmacocinética , Borohidruros/sangre , Borohidruros/orina , Terapia por Captura de Neutrón de Boro , Glioblastoma/sangre , Glioblastoma/orina , Humanos , Compuestos de Sulfhidrilo/sangre , Compuestos de Sulfhidrilo/orinaRESUMEN
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.
Asunto(s)
Borohidruros/análisis , Compuestos de Sulfhidrilo/análisis , Absorción , Animales , Borohidruros/sangre , Borohidruros/orina , Compuestos Bicíclicos con Puentes , Tampones (Química) , Cromatografía Líquida de Alta Presión , Femenino , Indicadores y Reactivos , Masculino , Ratas , Ratas Sprague-Dawley , Espectrofotometría Ultravioleta , Compuestos de Sulfhidrilo/sangre , Compuestos de Sulfhidrilo/orina , Reactivos de SulfhidriloRESUMEN
Borocaptate sodium (BSH) and L-boronophenylalanine (L-BPA) are two boron carriers used for boron neutron capture therapy (BNCT) in the treatment of glioblastoma and melanoma, respectively. The suitability of these two compounds was evaluated on the basis of pharmacokinetic studies aiming at characterizing their biodistribution, tumor uptake and tumor selectivity. Boric acid was also used as a reference compound since it is nonselective and relatively freely diffusible. The compounds were investigated in two tumor models, a B16 pigmented melanoma and the RIF1 sarcoma. Mice were sacrificed after different boron doses at various post-injection times and tissue and plasma levels measured using inductively coupled plasma atomic emission spectroscopy (ICP-AES). The proposed minimum effective tumor boron concentration of 15 ppm was achieved in both tumor models for the three compounds tested, although only for L-BPA in the melanoma was this achieved when tumor-plasma ratios were above 1. In the RIF1 model, maximum tumor concentrations of 44 and 31 ppm B were reached after administration of 50 micrograms B/g body weight for boric acid and BSH, respectively. After administration of 12.5 micrograms B/g of L-BPA, maximum concentrations of 15 and 21 ppm were found in the RIF1 and B16 models, respectively. Tumor-plasma ratios (TPR) for BSH remained close to or below unity at all times studied in both tumors. Brain levels of BSH were very low, however, leading to tumor-brain ratios markedly greater than 1 at all times. L-BPA and boric acid showed TPR values above unity in both tumor models, reaching 3.2 in B16.(ABSTRACT TRUNCATED AT 250 WORDS)