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PubMed2004

A microdosimetric approach to the thermal neutron fluence prescription for clinical BNCT.

A microdosimetric estimation has been performed to investigate the stochastic variations in doses to the target cell nuclei in boron neutron capture therapy (BNCT). The 9L gliosarcoma cells and the capillary endothelial cells were the targets of our interest. More than 80% of tumour control and less than 50% of myeloparesis incidence were taken as the biological endpoints to be accomplished. Estimation was performed for two major boron carriers, sulfhydryl borane (BSH) and boronophenylalanine (BPA). From the macrodosimetric point of view, the effective thermal neutron fluence in BNCT ranges from 3.96 x 10(12) to 5.17 x 10(12). From the microdosimetric point of view however, the prescription regarding thermal neutron irradiation becomes much more complex. According to the microdosimetric analysis, the difference between the tumour and the normal tissue in BSH or BPA concentration is not large enough to guarantee the 80% control of 9L gliosarcoma along with the myeloparesis incidence limited below 50%.

Boron Compounds↗
PubMed1999

Enhanced delivery of boronophenylalanine for neutron capture therapy of brain tumors using the bradykinin analog Cereport (Receptor-Mediated Permeabilizer-7).

OBJECTIVE: Using the well-characterized F98 rat glioma model, the purpose of the present study was to determine whether the delivery of boronophenylalanine (BPA) could be enhanced by prior administration of the bradykinin analog Cereport (Alkermes, Inc., Cambridge, MA) (previously known as Receptor-Mediated Permeabilizer-7), which produces a transient, pharmacologically mediated opening of the blood-brain barrier. METHODS: Two series of experiments were performed in F98 glioma-bearing rats that had received either intracarotid (i.c.) or intravenous infusions of Cereport (at doses ranging from 1.5 to 7.5 microg/kg of body weight), followed by i.c. (or intravenous) injection of BPA (300 mg/kg of body weight). Animals were killed 0.5, 2.5, or 4 hours later, samples of blood, skin, muscle, and eye were obtained, brains were removed, and tumors were excised for boron determination by direct current plasma-atomic emission spectroscopy. RESULTS: Averaged over all time points, i.c. infusion of Cereport significantly enhanced tumor boron uptake (P = 0.0001), compared with the excipient (saline) control values. Tumor boron values were equivalent at 0.5 (36.0 microg/g) and 2.5 hours (38.5 microg/g) after i.c. administration of Cereport and BPA and then decreased by 33% (to 25.7 microg/g) at 4 hours. These tumor boron uptake values were significantly different (alpha = 0.05), compared with values measured at the corresponding times after i.c. administration of BPA without Cereport (22.6, 21.8, and 15.3 microg/g, respectively). Although no time-related effects were observed, i.c. administration of Cereport followed by intravenous administration of BPA also significantly enhanced (alpha = 0.05) tumor boron uptake at 0.5, 2.5, and 4 hours (27.4, 30.3, and 28.0 microg/g, respectively), compared with values obtained without Cereport (11.3, 13.4, and 15.2 microg/g, respectively). Boron levels in normal brain tissue from tumor-bearing and non-tumor-bearing cerebral hemispheres and in blood were not significantly different from those measured in saline-treated control animals. CONCLUSION: This study established that i.c. infusion of Cereport significantly increased delivery of BPA to F98 rat gliomas, and this could enhance the efficacy of boron neutron capture therapy of this tumor.

Animals↗
PubMed2000

Improved survival after boron neutron capture therapy of brain tumors by Cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine.

OBJECTIVE: Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model. METHODS: For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 microg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 10(3) F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. RESULTS: At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean +/- standard deviation) were 55.7 +/- 9.6 microg/g with Cereport versus 33.6 +/- 3.9 microg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 +/- 9.9 microg/g with Cereport versus 15.4 +/- 3.5 microg/g without Cereport (P < 0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 +/- 0.6, and the tumor-to-brain ratio was 5.2 +/- 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 +/- 16 days for i.c. administration of BPA with Cereport versus 40 +/- 6 days without Cereport (P = 0.05), 38 +/- 4 days for i.v. administration of BPA with Cereport versus 34 +/- 3 days without Cereport (P = 0.02), 28 +/- 5 days for irradiated controls, and 23 +/- 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86% increase in lifespan in rats that received i.c. administration of BPA without Cereport. CONCLUSION: These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.

Animals↗
PubMed1999

Pharmacokinetics of 10B-p-boronophenylalanine in tumours, skin and blood of melanoma patients: a study of boron neutron capture therapy for malignant melanoma.

To optimize the neutron dose for boron neutron capture therapy (BNCT), the boron-10 (10B) concentration kinetics of 10B-p-boronophenylalanine (BPA) were analysed in 22 melanoma patients with primary or metastatic melanomas who received BPA and subsequently underwent BNCT or surgery. The blood concentration in nine patients receiving 179.7+/-14.9 mg/kg BPA increased with time during intravenous infusion, peaked at the end of administration and decreased thereafter. The peak values at the end of administration were 9.4 2.6 microg 10B/g blood, and half-lives for the initial and second components of the blood clearance were 2.8 and 9.2 h, respectively. Skin concentrations in the 10 patients varied from case to case; however, skin-to-blood ratios were relatively constant at 1.31+/-0.22 during the 6 h after the end of administration. Boron concentrations in the tumours resected from the seven patients who were operated on decreased in parallel to the blood values, the tumour-to-blood ratio being relatively constant at 3.40+/-0.83. The present analytical data of BPA pharmacokinetics support our previous approach for optimizing the timing of irradiation and setting the neutron flux large enough for tumour eradication but still tolerable for normal skin.

Adult↗
PubMed2004

A 1,3,2-oxazaborolidine dimer derived from (S)-alpha,alpha-diphenylprolinol.

The reaction of (S)-alpha,alpha-diphenylprolinol with an excess of borane-tetrahydrofuran complex yields a stable crystalline material with the composition C34H38B2N2O2, which features a borane adduct of a spirocyclic structure with two oxazaborolidine rings joined by a central tetrahedral B atom. This dimeric oxazaborolidine complex, viz. 3,3,3',3'-tetraphenyl-1,1'-spirobi(3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole)-7-borane, is the dominant product under various reaction conditions; its crystal structure is consistent with 11B, 1H and 13C NMR and IR analyses.

Biphenyl Compounds↗
PubMed1998

A 2-alkyl substituted 2,3,1-benzodiazaborine.

The structure of the fourth member of a family of structurally related 2,3,1-benzodiheteroborines has been solved by crystallographic means, providing data for proper direct comparison with the others. The title compound, 1,2-dihydro-1-hydroxy-2-methyl-2,3,1-benzodiazaborine (C8H9BN2O) is obtained via condensation of 2-formylbenzeneboronic acid and methylhydrazine, and is similar in most respects to its 2-unsubstituted parent, in internal geometry and intramolecular association topography, but has some subtle oxazaborine-like characteristics.

Aza Compounds↗
PubMed2004

Effects of a metal etchant and two primers on resin bonding durability to titanium.

The purpose of this study was to investigate the efficacy of an etchant in titanium bonding. The aqueous etchant consisted of 0, 5, or 10 wt% ammonium hydrogen fluoride (AHF) in combination with 0, 0.03, 0.3, or 3 wt% cupric chloride (CC). The two primers used were a phosphate-methacrylate primer and a thiophosphate-methacrylate primer, and two self-curing resins (Super-Bond C&B and MT) were employed as luting agents. Disk specimens were cast with a commercially pure titanium. The surface was air-abraded with 50 microm alumina, etched for 10 s, rinsed with water, and then air-dried. The primer was applied to the bonding area (5 mm in diameter), and an acrylic rod was bonded to the specimen with the luting agent. Shear bond strengths were evaluated after 24 h of water storage and following 10,000 thermocycles (4 degrees C and 60 degrees C). The post-thermocycling bond strength was significantly increased with each of the two primers compared with the unprimed controls. The etchant containing 5 wt% AHF and 0.3 wt% CC further increased their durability, and microscopic observation revealed that innumerable submicron crystals were created on the etched specimen. The present results suggest that the chemical etching improved the resin bonding durability to titanium in combination with the primer used.

Ammonium Compounds↗
PubMed1996

Bonding of a mica-based castable ceramic material with a tri-n-butylborane-initiated adhesive resin.

Adhesive bonding of a mica-based castable ceramic material (Olympus Castable Ceramics, OCC) was evaluated in vitro with the use of a silane primer in conjunction with an adhesive luting material. The primer contained a silane coupler and 4-methacryloxyethyl trimellitate anhydride (4-META), while the methyl methacrylate (MMA)-based luting agent was initiated with a tri-n-butylborane derivative (TBB) and contained 4-META (4-META/MMA-TBB resin). Ceramic specimens were sanded with No. 600 silicon carbide paper followed by blasting with alumina and/or etching with ammonium bifluoride. The specimens were bonded with various combinations and shear bond strengths were determined. Both priming and alumina blasting enhanced the bond between 4-META resin and OCC. Although etching with ammonium bifluoride roughened the ceramic surface, this procedure did not improve the bond strength. Electron probe microanalysis of the ceramic surface revealed a decrease in silicon and aluminium elements after etching with ammonium bifluoride.

Acid Etching, Dental↗
PubMed2004

Effects of a fluoride etchant on resin bonding to titanium-aluminum-niobium alloy.

This investigation was carried out in order to evaluate ammonium hydrogen fluoride (AHF) and cupric chloride (CC) as components of a metal etchant. The surface of cast titanium-aluminum-niobium (Ti-6Al-7Nb) was air-abraded with alumina, etched for 10 s, and rinsed with water. A phosphate or a thiophosphate primer was applied to the bonding area, and an acrylic rod was bonded to the specimen with a tri-n-butylborane-initiated self-curing luting agent. Shear bond strengths were determined after thermocycling (4 degrees C and 60 degrees C) for 10,000 cycles. The average bond strength was significantly influenced by thermocycling, AHF, and primer, but was not influenced by CC. The maximum average bond strengths were obtained when the etchant consisted of 5mass% AHF, with and without 0.3mass% CC. Microphotographs showed that numerous micropits were created on the etched surface, suggesting increased micromechanical retention. In conclusion, chemical etching with 5mass% AHF significantly improved the durability of resin bonding to Ti-6Al-7Nb.

Acid Etching, Dental↗
PubMed1998

Enhanced melanogenesis induced by tyrosinase gene-transfer increases boron-uptake and killing effect of boron neutron capture therapy for amelanotic melanoma.

Specific and powerful cancer killing effect for melanoma by boron neutron capture therapy (BNCT) using DOPA analogue, 10B-p-boronophenylalanine (10B-BPA), has been established, but amelanotic melanoma is insufficiently responsive to 10B-BPA BNCT in comparison with actively melanin-producing melanoma. Although the accumulation mechanism of 10B-BPA within melanoma was not established, we have recently obtained findings suggesting that melanin monomers, key intermediates for melanin polymer formation, play a critical role in 10B-BPA accumulation. In addition, there are some kinds of human amelanotic melanomas, such as MEL2A, in which expression of tyrosinase is repressed or lacking though tyrosinase-related protein (TRP)-1 and TRP-2 are well expressed. Thus, by using a similarly tyrosinase-lacking mouse amelanotic melanoma cell line, A1059, we constructed TA1059 cells by transfecting human tyrosinase-cDNA into these cells. TA1059 cells acquired higher DOPA-oxidase and DOPAchrome tautomerase activity as well as eumelanin content at even higher levels than those of B16F10 cells. TA1059 cells showed about 2.5 times higher P-boronophenylalanine (BPA) uptake than A1059 cells in culture. In animal experiments, by using these cell lines, tumor growth of TA1059 was significantly suppressed by 10B-BPA BNCT as compared with A1059. These findings indicate that the induction of active melanin biosynthesis by melanogenic gene-transfer effectively improves the treatment of amelanotic melanoma by BNCT.

Animals↗
PubMed1999

Proton nuclear magnetic resonance measurement of p-boronophenylalanine (BPA): a therapeutic agent for boron neutron capture therapy.

Noninvasive in vivo quantitation of boron is necessary for obtaining pharmacokinetic data on candidate boronated delivery agents developed for boron neutron capture therapy (BNCT). Such data, in turn, would facilitate the optimization of the temporal sequence of boronated drug infusion and neutron irradiation. Current approaches to obtaining such pharmacokinetic data include: positron emission tomography employing F-18 labeled boronated delivery agents (e.g., p-boronophenylalanine), ex vivo neutron activation analysis of blood (and very occasionally tissue) samples, and nuclear magnetic resonance (NMR) techniques. In general, NMR approaches have been hindered by very poor signal to noise achieved due to the large quadrupole moments of B-10 and B-11 and (in the case of B-10) very low gyromagnetic ratio, combined with low physiological concentrations of these isotopes under clinical conditions. This preliminary study examines the feasibility of proton NMR spectroscopy for such applications. We have utilized proton NMR spectroscopy to investigate the detectability of p-boronophenylalanine fructose (BPA-f) at typical physiological concentrations encountered in BNCT. BPA-f is one of the two boron delivery agents currently undergoing clinical phase-I/II trials in the U.S., Japan, and Europe. This study includes high-resolution 1H spectroscopic characterization of BPA-f to identify useful spectral features for purposes of detection and quantification. The study examines potential interferences, demonstrates a linear NMR signal response with concentration, and presents BPA NMR spectra in ex vivo blood samples and in vivo brain tissues.

Boron Compounds↗
PubMed1999

Boron self-shielding effects on dose delivery of neutron capture therapy using epithermal beam and boronophenylalanine.

Previous dosimetry studies for boron neutron capture therapy have often neglected the thermal neutron self-shielding effects caused by the 10B accumulation in the brain and the tumor. The neglect of thermal neutron flux depression, therefore, results in an overestimation of the actual dose delivery. The relevant errors are expected to be more pronounced when boronophenylalanine is used in conjunction with an epithermal neutron beam. In this paper, the boron self-shielding effects are calculated in terms of the thermal neutron flux depression across the brain and the dose delivered to the tumors. The degree of boron self-shielding is indicated by the difference between the thermal neutron fluxes calculated with and without considering a 10B concentration as part of the head phantom composition. The boron self-shielding effect is found to increase with increasing 10B concentrations and penetration depths from the skin. The calculated differences for 10B concentrations of 7.5-30 ppm are 2.3%-8.3% at 2.3 cm depth (depth of the maximum brain dose) and 4.6%-17% at 7.3 cm depth (the center of the brain). The additional self-shielding effects by the 10B concentration in a bulky tumor are investigated for a 3-cm-diam spherical tumor located either near the surface (3.3 cm depth) or at the center of the brain (7.3 cm depth) along the beam centerline. For 45 ppm of 10B in the tumor and 15 ppm of 10B in the brain, the dose delivered to the tumors is approximately 10% lower at 3.3 cm depth and 20% lower at the center of the brain, compared to the dose neglecting the boron self-shielding in transport calculations.

Boron Compounds↗
PubMed2006

Improvement of the tumor-suppressive effect of boron neutron capture therapy for amelanotic melanoma by intratumoral injection of the tyrosinase gene.

Boron neutron capture therapy (BNCT) is successful when there is a sufficient (10)B concentration in tumor cells. In melanoma, (10)B-para-boronophenylalanine (BPA) accumulation is proportional to melanin-producing activity. This study was done to confirm enhancement of the tumor-suppressive effect of BNCT on amelanotic melanoma by intratumoral injection of the tyrosinase gene. D178 or FF amelanotic melanomas were implanted s.c. in Syrian hamsters. One group of D178- or FF-bearing hamsters (TD178 or TFF group) received intratumoral injections of pcDNA-Tyrs constructed as a tyrosinase expression plasmid. The other hamsters (pD178 and pFF groups) were injected with pUC119, and control hamsters (D178 and FF groups) only with transfection reagents. All the groups underwent immunofluorescence analysis of tyrosinase expression and BPA biodistribution studies. BNCT experiments were done at the Kyoto University Research Reactor. Tyrosinase expression increased in the tumors of the TD178 and TFF groups but remained the same in the pD178 and pFF groups. Tumor boron concentrations in the TD178 and TFF groups increased significantly (TD178: 49.7 +/- 12.6 versus D178: 27.2 +/- 4.9 microg/g, P < 0.0001; TFF: 30.7 +/- 6.6 versus FF: 13.0 +/- 4.7 microg/g, P < 0.0001). The BNCT tumor-suppressive effect was marked in the TD178 and TFF groups. In vivo transfection with the tyrosinase gene increased BPA accumulation in the tumors, the BNCT tumor-suppressive effect on amelanotic melanoma being significantly enhanced. These findings suggest a potential new clinical strategy for the treatment of amelanotic melanoma with BNCT.

Animals↗
PubMed2006

Molecular targeting and treatment of EGFRvIII-positive gliomas using boronated monoclonal antibody L8A4.

PURPOSE: The purpose of the present study was to evaluate a boronated EGFRvIII-specific monoclonal antibody, L8A4, for boron neutron capture therapy (BNCT) of the receptor-positive rat glioma, F98(npEGFRvIII). EXPERIMENTAL DESIGN: A heavily boronated polyamido amine (PAMAM) dendrimer (BD) was chemically linked to L8A4 by two heterobifunctional reagents, N-succinimidyl 3-(2-pyridyldithio)propionate and N-(k-maleimidoundecanoic acid)hydrazide. For in vivo studies, F98 wild-type receptor-negative or EGFRvIII human gene-transfected receptor-positive F98(npEGFRvIII) glioma cells were implanted i.c. into the brains of Fischer rats. Biodistribution studies were initiated 14 days later. Animals received [(125)I]BD-L8A4 by either convection enhanced delivery (CED) or direct i.t. injection and were euthanized 6, 12, 24, or 48 hours later. RESULTS: At 6 hours, equivalent amounts of the bioconjugate were detected in receptor-positive and receptor-negative tumors, but by 24 hours the amounts retained by receptor-positive gliomas were 60.1% following CED and 43.7% following i.t. injection compared with 14.6% ID/g by receptor-negative tumors. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (<0.5 microg/g) at the corresponding times. Based on these favorable biodistribution data, BNCT studies were initiated at the Massachusetts Institute of Technology Research Reactor-II. Rats received BD-L8A4 ( approximately 40 microg (10)B/ approximately 750 mug protein) by CED either alone or in combination with i.v. boronophenylalanine (BPA; 500 mg/kg). BNCT was carried out 24 hours after administration of the bioconjugate and 2.5 hours after i.v. injection of BPA for those animals that received both agents. Rats that received BD-L8A4 by CED in combination with i.v. BPA had a mean +/- SE survival time of 85.5 +/- 15.5 days with 20% long-term survivors (>6 months) and those that received BD-L8A4 alone had a mean +/- SE survival time of 70.4 +/- 11.1 days with 10% long-term survivors compared with 40.1 +/- 2.2 days for i.v. BPA and 30.3 +/- 1.6 and 26.3 +/- 1.1 days for irradiated and untreated controls, respectively. CONCLUSIONS: These data convincingly show the therapeutic efficacy of molecular targeting of EGFRvIII using either boronated monoclonal antibody L8A4 alone or in combination with BPA and should provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.

Animals↗
PubMed2005

Vascular endothelial growth factor selectively targets boronated dendrimers to tumor vasculature.

Tumor neovasculature is a potential but, until very recently, unexplored target for boron neutron capture therapy (BNCT) of cancer. In the present report, we describe the construction of a vascular endothelial growth factor (VEGF)-containing bioconjugate that potentially could be used to target up-regulated VEGF receptors (VEGFR), which are overexpressed on tumor neovasculature. A fifth-generation polyamidoamine dendrimer containing 128 reactive amino groups was reacted with 105 to 110 decaborate molecules to produce a macromolecule with 1,050 to 1,100 boron atoms per dendrimer. This was conjugated to thiol groups of VEGF at a 4:1 molar ratio using the heterobifunctional reagent sulfo-LC-SPDP. In addition, the boronated dendrimer was tagged with a near-IR Cy5 dye to allow for near-IR fluorescent imaging of the bioconjugate in vitro and in vivo. As would be predicted, the resulting VEGF-BD/Cy5 bioconjugate was not cytotoxic to HEK293 cells engineered to express 2.5 x 10(6) VEGFR-2 per cell. Furthermore, it showed binding and activation of VEGFR-2 comparable with that of native VEGF. Internalization of VEGF-BD/Cy5 by PAE cells expressing 2.5 x 10(5) VEGFR-2 per cell was inhibited by excess VEGF, indicating a VEGFR-2-mediated mechanism of uptake. Near-IR fluorescent imaging of 4T1 mouse breast carcinoma revealed selective accumulation of VEGF-BD/Cy5, but not BD/Cy5, particularly at the tumor periphery where angiogenesis was most active. Accumulation of VEGF-BD/Cy5 in 4T1 breast carcinoma was diminished in mice pretreated with a toxin-VEGF fusion protein that selectively killed VEGFR-2-overexpressing endothelial cells. Our data lay the groundwork for future studies using the VEGF-BD/Cy5 bioconjugate as a targeting agent for BNCT of tumor neovasculature.

Animals↗
PubMed2003

Boron neutron capture therapy: cellular targeting of high linear energy transfer radiation.

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with (10)B and subsequent activation with thermal neutrons to produce a highly localized radiation. In theory, it is possible to selectively irradiate a tumor and the associated infiltrating tumor cells with large single doses of high-LET radiation while sparing the adjacent normal tissues. The mixture of high- and low-LET dose components created in tissue during neutron irradiation complicates the radiobiology of BNCT. Much of the complexity has been unravelled through a combination of preclinical experimentation and clinical dose escalation experience. Over 350 patients have been treated in a number of different facilities worldwide. The accumulated clinical experience has demonstrated that BNCT can be delivered safely but is still defining the limits of normal brain tolerance. Several independent BNCT clinical protocols have demonstrated that BNCT can produce median survivals in patients with glioblastoma that appear to be equivalent to conventional photon therapy. This review describes the individual components and methodologies required for effect BNCT: the boron delivery agents; the analytical techniques; the neutron beams; the dosimetry and radiation biology measurements; and how these components have been integrated into a series of clinical studies. The single greatest weakness of BNCT at the present time is non-uniform delivery of boron into all tumor cells. Future improvements in BNCT effectiveness will come from improved boron delivery agents, improved boron administration protocols, or through combination of BNCT with other modalities.

Animals↗