Boron neutron capture therapy of brain tumors: biodistribution, pharmacokinetics, and radiation dosimetry sodium borocaptate in patients with gliomas.

OBJECTIVE: The purpose of this study was to obtain tumor and normal brain tissue biodistribution data and pharmacokinetic profiles for sodium borocaptate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was performed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were candidates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and they constituted the study population. METHODS: BSH (non-10B-enriched) was infused intravenously, in a 1-hour period, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 26.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tissue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic studies were obtained at times up to 120 hours after termination of the infusion. Sixteen of the patients underwent surgery at the Beijing Neurosurgical Institute and three at The Ohio State University, where all tissue samples were subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTS: Blood boron values peaked at the end of the infusion and then decreased triexponentially during the 120-hour sampling period. At 6 hours after termination of the infusion, these values had decreased to 20.8, 29.1, and 62.6 microg/ml for boron doses of 15, 25, and 50 mg/kg body weight, respectively. For a boron dose of 50 mg/kg body weight, the maximum (mean +/- standard deviation) solid tumor boron values at 3 to 7 hours after infusion were 17.1+/-5.8 and 17.3+/-10.1 microg/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 microg/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged across all samples, were 4.6+/-5.1 and 5.5+/-3.9 microg/g and the tumor/normal brain tissue ratios were3.8 and 3.2 for patients with GBMs and AAs, respectively. The large standard deviations indicated significant heterogeneity in uptake in both tumor and normal brain tissue. Regions histopathologically classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron concentrations in blood decreased from 104 microg/ml at 2 hours to 63 microg/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 microg/g, respectively, during the 3- to 7-hour sampling period. CONCLUSION: When tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.

Secondary ion mass spectrometric characterization of nail polishes and paint surfaces.

A variety of paint and fingernail polish samples, which were visually similar, but had different chemical compositions and formulations, was analyzed using quadrupole static secondary ion mass spectrometry (SIMS). Coating distinction was easily achieved in many cases because of the presence of dominant ions derived from the components of the coating, which could be observed in the SIMS spectra. In other instances, coating distinction was difficult within a product line because of spectral complexity; for this reason and because of the large numbers of spectra generated in this study, multivariate statistical techniques were employed, which allowed the meaningful classification and comparison of spectra. Partial Least Squares (PLS) and Principal Component Analysis (PCA) were applied to quadrupole SIMS data. PCA showed distinct spectral differences between most spectral groups, and also emphasized the reproducibility of the SIMS spectra. When using PLS analysis, reasonably accurate coating identification was achieved with the data. Overall, the PLS model is more than 90% effective in identifying the spectrum of a particular coating, and nearly 100% effective at telling which coating components represented in the PLS models are not present in a spectrum. The level of spectral variation caused by sample bombardment in the SIMS analysis was investigated using Fourier transform infrared spectroscopy (FT-IR) and quadrupole static SIMS. Changes in the FT-IR spectra were observed and were most likely a result of a number of factors involving the static SIMS analysis. However, the bulk of the sample is unaltered and may be used for further testing.

Plasma pharmacokinetics and tissue biodistribution of boron following administration of a boronated porphyrin in dogs.

This study was undertaken to determine the plasma pharmacokinetics and tissue biodistribution of boron in dogs following the administration of a boronated porphyrin (BOPP) compound, a potential sensitizing agent for binary therapies of cancer. An intravenous dose of 35 mg/kg of BOPP was administered to a total of sixteen dogs and plasma samples obtained at multiple time points for up to 28 days after administration. Groups of four dogs each were studied for 25, 79, 240, and 672 h. At the end of each study period, subjects were sacrificed and tissue samples obtained. Boron concentrations were determined for all tissue and plasma samples, and pharmacokinetic parameters were determined using mixed effects modeling. Plasma boron levels displayed triexponential kinetics with a long terminal half-life and small volume of distribution. Liver, lymph node, adrenal, and kidney tissues accumulated the highest levels of boron, with very low levels associated with most tissues of the head. We conclude that BOPP has pharmacokinetic and tissue distribution properties that suggest that it may be a suitable compound for use as a sensitizing agent in binary therapy of cancer.

Boronated protoporphyrin (BOPP): localization in lysosomes of the human glioma cell line SF-767 with uptake modulated by lipoprotein levels.

PURPOSE: Boronated protoporphyrin (BOPP) is a candidate for use in both boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) of glioblastoma multiforme (GBM). Our objectives are to identify factors that influence the uptake and retention of BOPP in vitro and to determine BOPP distribution in a human glioma cell line in vitro. This information will aid the development of compounds and treatment strategies that increase the effectiveness of BNCT therapy for GBM. METHODS AND MATERIALS: The amount, distribution pattern, and site of internalization of BOPP were assessed using fluorescence microscopy. Living human glioma (SF-767) cells were imaged after a 24-h exposure to BOPP (20-135.6 microg/ml, normal serum). Dose-dependent uptake of BOPP was determined using both fluorescence microscopy of individual living cells and inductively-coupled plasma-atomic emission spectroscopy (ICP-AES) analysis of cell pellets. Lysosome- or mitochondria-specific fluorescent probes were used to identify the cellular compartment containing BOPP. Two human fibroblast cell lines, AG-1522 (LDL receptor-positive) and GM019-15C (LDL receptor-deficient), were used to investigate LDL receptor-dependent BOPP uptake. The dependence of BOPP uptake on lipoproteins in the media was determined by exposing each of the three cell types to BOPP in medium containing either normal (NS) or lipoprotein deficient serum (LPDS). RESULTS: BOPP accumulated in the lysosomes of human glioma cells in vitro, and not in the mitochondria, as reported for C6 rat glioma cells in vitro. BOPP uptake was concentration-dependent and was also dependent on the amount of lipoproteins in the medium. Over the range of incubation concentrations studied and at the single exposure duration time point investigated (24 h), all cells retained a similar amount of BOPP. At the lowest incubation concentration (20 microg/ml, NS), the amount of boron retained was near 10(9) atoms per cell (15 microg B/g cells). Lysosomes containing high concentrations of BOPP were randomly distributed throughout the cytoplasm; however, larger lysosomes containing BOPP were concentrated around the cell nucleus. Little or no BOPP accumulated in the cell nucleus. At incubation concentrations of 20 and 40 microg/ml (24-h time point), BOPP uptake in SF-767 cells was reduced in LPDS compared with NS (66% reduction). A similar result was observed for normal human fibroblasts (AG-1522 cells, 40 microg/ml, 24 h). At 40 microg/ml, in both NS and LPDS at 24 h, BOPP accumulation in LDL receptor-deficient human fibroblasts (GM019-15C cells) was reduced relative to AG-1522 cells. BOPP accumulation in GM019-15C cells (40 microg/ml, 24 h) was not affected by serum lipoprotein levels. CONCLUSION: In cell culture, BOPP is taken up by human glioma cells via the LDL pathway and is compartmentalized into cellular lysosomes. Knowledge of this mechanism of BOPP uptake and retention will be important in attempts to modify toxicity and efficacy of this drug.

11B nuclear magnetic resonance studies of the interaction of borocaptate sodium with serum albumin.

The interaction between borocaptate sodium, Na2B12H11SH (BSH), and three types of serum albumin--bovine, human and dog (BSA, HSA and DSA)--has been investigated quantitatively using 11B NMR. The 11B chemical shifts and relaxation rates of BSH were studied with various concentrations of serum albumin (1-5%, w/v) at 295-310 degrees K. Correction of the longitudinal relaxation rate (R1) due to protein viscosity effects was accomplished. The corrected R1 values were analyzed mathematically using a saturation function and linear regression. The linewidths of 11B resonances, which are related to the spin-spin relaxation rates (R2), were also measured. The binding fractions (P), the number of binding sites (NBS), and the binding constants (Kb) of BSH at various concentrations of the three types of serum albumin (1-5%, w/v) were determined at 295 and 310 degrees K. We speculate that the nature of this interaction may be electrostatic.

Biodistribution of boron in dogs with spontaneous intracranial tumors following borocaptate sodium administration.

Borocaptate sodium (Na2B12H11SH) is a potentially useful compound for boron neutron capture therapy of intracranial tumors. Tumor and normal tissue boron concentrations were evaluated in 30 dogs with naturally occurring intracranial tumors after i.v. borocaptate sodium infusion (55 mg boron/kg). Postmortem tissue boron concentrations were measured for three postinfusion time periods (2, 6, and 12 h) by inductively coupled plasma atomic emission spectroscopy. Mean boron concentrations for extracerebral tumors were 40.6 +/- 16.9 (2 h; n = 8), 25.9 +/- 11.7 (6 h; n = 5), and 8.6 +/- 4.5 micrograms boron/g (12 h; n = 6). Mean boron concentrations for intracerebral tumors were 30.6 +/- 17.5 (2 h; n = 7) and 2.9 +/- 1.8 micrograms boron/g (6 h; n = 4). Mean tumor boron concentrations were lower at longer postinfusion times. The tumor:normal brain boron concentration ranged from 0.8 to 19.8. Tumor:blood boron concentrations were less than one for all but three dogs and ranged from 0.04 to 1.4. Mean peritumor boron concentrations were highly variable but exceeded that of normal brain in 10 of 20 dogs. In some dogs, the mean peritumor boron concentration was similar to or exceeded the tumor boron concentration. Distant or contralateral normal brain had consistently low boron concentrations. Some cranial and systemic tissues had high boron concentrations, indicating substantial extravascular boron. The spontaneous animal tumors provided a realistic spectrum of data and enabled extensive sampling of diseased and normal tissues. The biodistribution of boron from borocaptate sodium administration was partially favorable because of high tumor boron concentrations. Empirical radiation dose tolerance studies should be used to determine the impact of the unfavorably high boron concentration of blood and some cranial tissues.

Borocaptate sodium: a potential boron delivery compound for boron neutron capture therapy evaluated in dogs with spontaneous intracranial tumors.

Borocaptate sodium (Na2B12H11SH) is a boron-carrying compound under consideration for use in boron neutron capture therapy. The biodistribution of boron from borocaptate sodium administration will partly determine boron neutron capture therapy efficacy and normal tissue radiation tolerance. The biodistribution of boron was determined in 30 dogs with spontaneous intracranial tumors at 2, 6, or 12 hr after intravenous borocaptate sodium infusion. Blood and tissue boron concentrations were measured using inductively coupled plasma atomic emission spectroscopy. Mean tumor boron concentration (mean +/- standard error) was 35.9 +/- 4.6 (n = 15), 22.5 +/- 6.0 (n = 9), and 7.0 +/- 1.1 micrograms of boron per g (n = 6) at 2, 6, and 12 hr, respectively, after borocaptate sodium infusion. Peritumor boron concentrations were elevated above that of normal brain in half of the dogs. Normal brain boron concentration (mean +/- standard error) was 4.0 +/- 0.5, 2.0 +/- 0.4, and 2.0 +/- 0.3 micrograms of boron per g at 2, 6, and 12 hr after infusion, respectively. Some cranial and systemic tissues, and blood, had high boron concentration relative to tumor tissue. Geometric dose sparing should partly offset these relatively high normal tissue and blood concentrations. Borocaptate sodium biodistribution is favorable because tumor boron concentrations of recommended magnitude for boron neutron capture therapy were obtained and there was a high tumor-to-normal brain boron concentration ratio.

Model studies directed toward the boron neutron-capture therapy of cancer: boron delivery to murine tumors with liposomes.

The successful treatment of cancer by boron neutron-capture therapy (BNCT) requires the selective concentration of boron-10 within malignant tumors. The potential of liposomes to deliver boron-rich compounds to tumors has been assessed by the examination of the biodistribution of boron delivered by liposomes in tumor-bearing mice. Small unilamellar vesicles with mean diameters of 70 nm or less, composed of a pure synthetic phospholipid (distearoyl phosphatidylcholine) and cholesterol, have been found to stably encapsulate high concentrations of water-soluble ionic boron compounds. The hydrolytically stable borane anions B10H10(2-), B12H11SH2-, B20H17OH4-, B20H19(3-), and the normal form and photoisomer of B20H18(2-) were encapsulated in liposomes as their soluble sodium salts. The tissue concentration of boron in tumor-bearing mice was measured at several time points over 48 h after i.v. injection of emulsions of liposomes containing the borane anions. Although the boron compounds used do not exhibit an affinity for tumors and are normally rapidly cleared from the body, liposomes were observed to selectively deliver the borane anions to tumors. The highest tumor concentrations achieved reached the therapeutic range (greater than 15 micrograms of boron per g of tumor) while maintaining high tumor-boron/blood-boron ratios (greater than 3). The most favorable results were obtained with the two isomers of B20H18(2-). These boron compounds have the capability to react with intracellular components after they have been deposited within tumor cells by the liposome, thereby preventing the borane ion from being released into blood.

Macroscopic geometric heterogeneity effects in radiation dose distribution analysis for boron neutron capture therapy.

Calculations of radiation flux and dose distributions for boron neutron capture therapy (BNCT) of brain tumors are typically performed using sophisticated three-dimensional analytical models based on either a homogeneous approximation or a simplified few-region approximation to the actual highly heterogeneous geometry of the irradiation volume. Such models should be validated by comparison with calculations using detailed models in which all significant macroscopic tissue heterogeneities and geometric structures are explicitly represented as faithfully as possible. This paper describes such a validation exercise for BNCT of canine brain tumors. Geometric measurements of the canine anatomical structures of interest for this work were performed by dissecting and examining two essentially identical Labrador retriever heads. Chemical analyses of various tissue samples taken during the dissections were conducted to obtain measurements of elemental compositions for the tissues of interest. The resulting geometry and tissue composition data were then used to construct a detailed heterogeneous calculational model of the Labrador head. Calculations of three-dimensional radiation flux distributions pertinent to BNCT were performed for this model using the TORT discrete-ordinates radiation transport code. The calculations were repeated for a corresponding volume-weighted homogeneous-tissue model. Comparison of the results showed that peak neutron and photon flux magnitudes were quite similar for the two models (within 5%), but that the spatial flux profiles were shifted in the heterogeneous model such that the fluxes in some locations away from the peak differed from the corresponding fluxes in the homogeneous model by as much as 10%-20%. Differences of this magnitude can be therapeutically significant, emphasizing the need for proper validation of simplified treatment planning models.