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PubMed2004

Optimization of the epithermal neutron beam for Boron Neutron Capture Therapy at the Brookhaven Medical Research Reactor.

The use of epithermal neutron beam in clinical trials of Boron Neutron Capture Therapy for patients with malignant brain tumors had been carried out for half a decade at the Brookhaven's Medical Reactor. The decision to permanently close this reactor in 2000 cut short the efforts to implement a new conceptual design to optimize this beam in preparation for use with possible new BNCT protocols. Details of the conceptual design to produce a highly intensified and focused neutron beam with less gamma and neutron contamination in tissues are presented here for their potential applicability to other reactor facilities. Neutron-photon coupled Monte Carlo calculations were used to predict the flux, current, heating, and absorbed dose produced by the proposed design. The results were benchmarked by the dose rate and flux measurements taken at the facility then in use.

Academies and Institutes↗
PubMed2000

Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy.

Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 (10B) in the oral mucosa to the biological effectiveness of the 10B(n,alpha)7Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 +/- 0.02. This compares with a previously published CBE factor for BPA of 4.87 +/- 0.16. It was concluded that variations in the microdistribution profile of 10B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiation-induced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT.

Animals↗
PubMed1991

Biological efficacy of boronated low-density lipoprotein for boron neutron capture therapy as measured in cell culture.

Low-density lipoproteins (LDLs) are known to be internalized by the cell through receptor-mediated mechanisms. There is evidence that LDLs may be taken up avidly by tumor cells to provide cholesterol for the synthesis of cell membranes. Thus, the possibility exists that LDLs may provide an ideal vehicle for the transport of boron to tumor cells for boron neutron capture therapy. A boronated analogue of LDL has recently been synthesized for possible application in boron neutron capture therapy. The analogue was tested in cell culture for uptake and biological efficacy in the thermal neutron beam at the Brookhaven Medical Research Reactor. It was found that boron concentrations 10 times higher than that required in tumors for boron neutron capture therapy were easily obtained and that the amount of uptake was consistent with a receptor-mediated binding mechanism. The measured intracellular concentration of approximately 240 micrograms 10B/g cells is significantly higher than that obtained with any other boron compound previously evaluated for possible clinical application.

Animals↗
PubMedDate not supplied

Preparation of sulfhydrylborane-dextran conjugates for boron neutron capture therapy.

This study presents a carrier system for boron, potentially useful in boron neutron capture therapy (BNCT). Na2B12H11SH (BSH) was covalently coupled to dextran derivatives. This was accomplished in two ways. The first method comprises activation of dextran with 1-cyano-4-(dimethylamino)pyridine (CDAP) with subsequent coupling of 2-aminoethyl pyridyl disulfide (method A). The thiolated dextran could then couple BSH in a disulfide exchange reaction. In the second procedure, dextran was derivatized to a multially derivative (method B) which reacted with BSH in a free-radical-initiated addition reaction. The assessment of boron content of the conjugates was done by elemental analysis of sulfur and atomic spectroscopy of boron (ICP-AES). With method A, only limited numbers of boron cages could be coupled (10-20 cages per dextran chain). With method B, 100-125 boron cages per dextran chain was obtained, corresponding to 1200-1500 boron atoms per dextran chain. This result makes this derivative a promising template for use in the development of BNCT agents.

Boranes↗
PubMedDate not supplied

Liposomal formulations containing sodium mercaptoundecahydrododecaborate (BSH) for boron neutron capture therapy.

Sodium mercaptoundecahydrododecaborate or BSH is a compound most widely used for boron neutron capture therapy (BNCT). Liposome formulations containing BSH, with or without steric stabilization, were prepared as potential agents for delivery of boron compounds for BNCT. Liposomes composed of DPPC/CHOL in a molar ratio 1:1 (PEG concentration: 5 mol%) were prepared having an average diameter in the range of 100-110 nm 200 mu L of liposomes (l.88 mg phospholipid/mouse and 3.5-5.8 mg BSH/kg body weight) were injected in mice via the tail vein. Both types of liposomes resulted in a significant improvement in the circulation time of BSH compared to that obtained previously after injecting free BSH. The mean percent injected BSH remaining in circulation at the end of 24 h was 19% for the PEG-liposomes compared to the corresponding value of 7% for the conventional liposomes. The mean percent uptake by the liver and spleen was not significantly different for the two types of liposomes; the blood/RES ratios were higher for the PEG-liposomes at all time points indicating that a higher fraction of injected BSH was available in circulation. The PEG-liposomes could be further explored as a means of enhance boron drug delivery to tumor cells for BNCT.

Animals↗
PubMed1995

Head phantoms for neutron capture therapy.

A water-filled head phantom that is designed for use in boron neutron capture therapy is described. The shape of this ellipsoidal phantom, based on the Synder head model, and its composition are designed to simulate the neutron slowing down properties of the human skull and brain. Small ion chambers or activation foils can be placed in many locations within the phantom volume. This permits accurate three-dimensional mapping of all relevant dose components and use of these dose contours for beam development as well as for benchmarking of computer-based patient treatment codes.

Brain↗
PubMed2001

Optimal detection of the neutron capture therapy agent borocaptate sodium (BSH): a comparison between 1H and 10B NMR.

Boron Neutron Capture Therapy (BNCT), an experimental binary cancer treatment modality, requires selective targeting of 10B containing compounds to tumors. One of the compounds under evaluation in an EORTC phase I trial, and used in Japan for patient treatments for many years, is borocaptate sodium (BSH, also known as sulfhydril boron hydride). To optimize the clinical applications, a noninvasive method is needed to monitor the distribution of the boron compound, and NMR may offer such a possibility. A comparison between the relative sensitivities for detecting BSH by 10B or 1H NMR was conducted at two magnetic field strengths: 2 and 4.7 T. At each field strength, similar-sized radio frequency (rf) coils were used for both nuclei. Theoretical predictions for the intrinsic signal to noise (S/N) advantage of 1H over 10B detection vary between a factor of 5.4 and a factor of 28.9, depending on whether the effective resistance is dominated by coil losses or sample losses. Our tests, conducted on relatively small aqueous samples, which loaded the coils less than expected for animal or human subjects, resulted nevertheless in advantage factors close to the lower limit of this range. The measured S/N detection advantage factors for 1H were about 5.2 at 4.7 T, using a dedicated 1H coil, and 7.7 at 2 T, where the measurements were conducted with a double-tuned coil. However, when predicting the expected performance for in vivo MRS or MRI, one should bear in mind that proton detection has to be conducted by spectral-editing pulse sequences with an inherent S/N loss by at least a factor of 2, and that the T1 relaxation time for 10B in BSH is about 30 times shorter than the 1HT1 value. In view of these considerations, direct 10B detection could well be the preferred strategy for MRI/MRS of BSH in vivo.

Biophysical Phenomena↗
PubMed1988

A new monitoring system for the thermal neutron fluence rate and gamma dose rate in boron neutron capture therapy.

A new monitoring system for the thermal neutron fluence rate and gamma dose rate is described for boron neutron capture therapy (BNCT). A small pn junction Si diode was used as a new detector which was mechanically stronger and had better stability than a surface barrier detector. The pulse height of signals due to thermal neutrons was sufficiently high and was separated from signals due to gamma rays. The radiation damage to the detectors which results in a reduction of the pulse height was found to be quite small. By using the detectors, the thermal neutron fluence rate and gamma dose rate, not only in the head but also in the body, were measured simultaneously during therapy, and the new system has been efficiently used for BNCT of brain tumours.

Humans↗
PubMed1999

The combined effect of boronophenylalanine and borocaptate in boron neutron capture therapy for SCCVII tumors in mice.

PURPOSE: To increase the effect of boron neutron capture therapy (BNCT) on tumors in vivo, the combined effects of para-boronophenylalanine (BPA) and borocaptate sodium (BSH) were investigated. METHODS AND MATERIALS: 10B-enriched BPA and BSH were administered to C3H/He mice bearing SCCVII tumors by intragastric and intravenous injections, respectively. The colony formation and tumor control assays were employed for investigating antitumor effects of BNCT. The extent of homogeneity of tumor cell killing effect was examined by the distribution of frequencies of binuclear cells (BNC) producing a certain number of micronuclei (0,1,2,--,> or =5) to total number of BNC and by the comparison between surviving cell fraction (SF) in colony formation assay and the normal nuclear division fraction (NNDF) at first mitosis following BNCT. RESULTS: The relationships between SF and radiation dose in Gy (D) at around 10 ppm of 10B in tumors were as follow: -InSF = -0.101 + 0.648 Gy(-1) x D, 0.0606+0.435 Gy(-1) x D, and -0.0155 + 0.342 Gy(-1) x D for BPA, BPA + BSH, and BSH, respectively. In tumor control assay, BPA was also more effective than BSH, but the difference of effectiveness significantly decreased: 1.9 times more effective in colony assay vs. 1.2 times in tumor control assay. The most effective treatment to achieve tumor cure was BNCT using BPA + BSH, and it was 1.9 times more effective than BSH-BNCT. In BSH-BNCT, NNDF decreased exponentially with radiation dose and was equal to SF. However, NNDF following BPA-BNCT showed a biphasic decrease with radiation dose, and SF was much lower than NNDF. In the combination of BPA and BSH, the discrepancy between NNDF and SF decreased in comparison with BPA-BNCT. The distribution of frequency of BNC with a certain number of micronuclei to total BNC was very close to Poisson distribution in BSH-BNCT tumors; however, it deviated from the Poisson in BPA-BNCT tumors. In combination with BPA and BSH, the distribution showed an intermediate pattern. These findings indicate that BSH distributes homogeneously with a heterogeneous distribution of BPA in tumors, and the heterogeneous effect of BPA-BNCT was improved by the combination of two boron compounds. CONCLUSION: The heterogeneous cell killing effect of BPA-BNCT was improved by the combination of BSH, and increased tumor control rates. Therefore, this combination may improve clinical outcome of BNCT although the effects on normal tissues have to be examined before clinical application.

Animals↗
PubMed1988

Experience of boron-neutron capture therapy for malignant brain tumours--with special reference to the problems of postoperative CT follow-ups.

Boron-neutron capture therapy (BNCT) is theoretically a highly selective treatment of infiltrating tumours, in that the tumoricidal heavy particle radiation is limited to a sphere of 10 microns around a tumour cell which is loaded with non-radioactive boron-10 atoms. There were 73 gliomas among the 83 cases treated by boron-neutron capture therapy. For grade III-IV cerebral gliomas, 5 and 10 year survival rates were an unimpressive 19 and 10% respectively. This was the result of technical problems such as unsatisfactory reactors and inadequate craniotomies for the majority of the patients. If the analysis was limited to those whose tumours had been irradiated with more than 2.5 x 10(12) neutrons/cm2 (yielding more than 3,000 rem or more), the 5 and 10 year survival were almost 100 and 50%. The longest surviving glioblastoma (grade IV) patient has lived in a satisfactory manner for the past 15 years. For the cases who had been treated with borderline doses (lethal or sublethal), interpretation of the postoperative CTs was frequently intriguing. Several cases had to undergo re-opening and occasionally even another BNCT, only to find no viable tumour tissue. Death occurred in some, either due to discontinuation of supportive treatments by local physicians, or due to excessive therapies by the author directly involved in the patient's care, both of whom had erroneously believed in recurrence. At autopsy, residual tumour cells were recognized only in the areas where the above-mentioned neutron fluence had not been delivered at the time of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

Postmortem neuropathological features secondary to boron neutron capture therapy for glioblastoma multiforme.

This postmortem study of 12 patients with glioblastoma multiforme (GBM) treated with boron neutron capture therapy (BNCT) employing an epithermal neutron beam and p-boronophenylalanine describes the neuropathological findings in patients receiving a relatively high radiation dose to the tumor, but a relatively low radiation dose to the normal brain. In addition to a standardized neuropathology panel of sections, we used individual treatment dosimetry maps to select sections along the projected maximum radiation beam pathway. We found that the normal neuroparenchyma exposed to the highest radiation dose exhibited a single instance of radiation-induced focal venular fibrinoid necrosis and a single instance of multifocal demyelination. Semiquantitative analysis of pretreatment neurosurgical and postmortem tumor samples revealed only two radiation ascribed histopathological findings to be particular to therapy, fibrinoid necrosis and vascular hyalinization. In this relatively small series of cases we found an unexpectedly high frequency of cases (3 of 12) with neurodegenerative histopathology (Lewy bodies, neurofibrillary tangles, and neuritic senile plaques), which appeared, by distribution, to be independent of the radiation beam. Two of these patients were over 70 yr of age. One was only 41. Our findings suggest an acceptable radiation-induced level of neurotoxicity at the lower doses employed, but raise the possibility of unexpected boron neurodegenerative toxicity.

Adult↗
PubMedDate not supplied

Engineering tumor-targeted gadolinium hexanedione nanoparticles for potential application in neutron capture therapy.

Microemulsions (oil-in-water) have been employed as templates to engineer nanoparticles containing high concentrations of gadolinium for potential application in neutron capture therapy of tumors. Gadolinium hexanedione (GdH), synthesized by complexation of Gd(3+) with 2,4-hexanedione, was used as the nanoparticle matrix alone or in combination with either emulsifying wax or PEG-400 monostearate. Solid nanoparticles (<125 nm size) were obtained by simple cooling of the microemulsions prepared at 60 degrees C to room temperature in one vessel. The feasibility of tumor targeting via folate receptors was studied. A folate ligand was synthesized by chemically linking folic acid to distearoylphosphatidylethanolamine (DSPE) via a poly(ethylene glycol) (PEG; MW 3350) spacer. To obtain folate-coated nanoparticles, the folate ligand (0.75% w/w to 15% w/w) was added to either the microemulsion templates at 60 degrees C or nanoparticle suspensions at 25 degrees C. Efficiencies of folate ligand attachment/adsorption to nanoparticle formulations were monitored by gel permeation chromatography. Cell uptake studies were carried out in KB cells (human nasopharyngeal epidermal carcinoma cell line), known to overexpress folate receptors. The uptake of folate-coated nanoparticles was about 10-fold higher than uncoated nanoparticles after 30 min at 37 degrees C. The uptake of folate-coated nanoparticles at 4 degrees C was 20-fold lower than the uptake at 37 degrees C and comparable to the uptake of uncoated nanoparticles at 37 degrees C. Folate-mediated endocytosis was further verified by the inhibition of folate-coated nanoparticles uptake by free folic acid. It was observed that folate-coated nanoparticles uptake decreased to approximately 2% of its initial value with the coincubation of 0.001 mM of free folic acid. The results suggested that these tumor-targeted nanoparticles containing high concentrations of Gd may have potential for neutron capture therapy.

Drug Delivery Systems↗
PubMed2005

Pharmaco-thermodynamics of deuterium-induced oedema in living rat brain via 1H2O MRI: implications for boron neutron capture therapy of malignant brain tumours.

In addition to its common usage as a tracer in metabolic and physiological studies, deuterium possesses anti-tumoural activity and confers protection against gamma-irradiation. A more recent interest in deuterium emanates from the search for alternatives capable of improving neutron penetrance whilst reducing healthy tissue radiation dose deposition in boron neutron capture therapy of malignant brain tumours. Despite this potential clinical application, deuterium induces brain oedema, which is detrimental to neutron capture therapy. In this study, five adult male rats were titrated with deuterated drinking water while brain oedema was monitored via water proton magnetic resonance imaging. This report concludes that deuterium, as well as deuterium-induced brain oedema, possesses a uniform brain bio-distribution. At a steady-state blood fluid deuteration value of 16%, when the deuterium isotope fraction in drinking water was 25%, a mean oedematous volume change of 9 +/- 2% (p-value <0.001) was observed in the rat brain-this may account for neurological and behavioural abnormalities found in mammals drinking highly deuterated water. In addition to characterizing the pharmaco-thermodynamics of deuterium-induced oedema, this report also estimates the impact of oedema on thermal neutron enhancement and effective dose reduction factors using simple linear transport calculations. While body fluid deuteration enhances thermal neutron flux penetrance and reduces dose deposition, oedema has the opposite effect because it increases the volume of interest, e.g., the brain volume. Thermal neutron enhancement and effective dose reduction factors could be reduced by as much as approximately 10% in the presence of a 9% water volume increase (oedema).

Administration, Oral↗
PubMed1991

Application of boronated anti-CEA immunoliposome to tumour cell growth inhibition in in vitro boron neutron capture therapy model.

An immunoliposome containing a 10B-compound has been examined as a selective drug delivery system in boron neutron-capture therapy. Liposomes, conjugated with monoclonal antibodies specific for carcinoembryonic antigen (CEA) were shown to bind selectively to cells bearing CEA on their surface. The immunoliposomes attached to tumour cells suppressed growth in vitro upon thermal neutron irradiation and suppression was dependent upon the concentration of the 10B-compound in the liposomes and on the density of antibody conjugated to the liposomes. The results suggest that immunoliposomes containing the 10B-compound could act as a selective and efficient carrier of 10B atoms to target tumour cells in boron neutron-capture therapy.

Antibodies, Monoclonal↗
PubMed1990

The potential of neutron capture therapy in the management of uncontrollable localised tumours.

The role of Neutron Capture Therapy for the treatment of uncontrollable, localised tumours is examined. Several boron carrier biochemicals are already in use for the selective accumulation of boron in cancer cells, and therapeutic boron concentrations have been achieved in glioblastoma and melanoma in animal models and in patients. Local control of glioblastoma and subcutaneous melanoma has been reported after thermal neutron irradiation. Different neutron beam requirements apply for the treatment of these cancers, in the former case a thermal beam is adequate but a more penetrating epithermal beam is needed for the treatment of deep-seated tumours. A thermal facility for small animal irradiations is available in Australia, and the development of a patient thermal/epithermal facility is under active consideration.

Boron↗
PubMed1989

Recent developments in neutron capture therapy.

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.

Fast Neutrons↗
PubMed2004

GE PETtrace cyclotron as a neutron source for boron neutron capture therapy.

This paper discusses the use of a General Electric PETtrace cyclotron as a neutron source for boron neutron capture therapy. In particular, the standard PETtrace (18)O target is considered. The resulting dose from the neutrons emitted from the target is evaluated using the Monte Carlo radiation transport code MCNP at different depths in a brain phantom. MCNP-simulated results are presented at 1, 2, 3, 4, 5, 6, 7, and 8 cm depth inside this brain phantom. Results showed that using a PETtrace cyclotron in the current configuration allows treating tumors at a depth of up to 4 cm with reasonable treatment times. Further increase of a beam current should significantly improve the treatment time and allow treating tumors at greater depths.

Boron Neutron Capture Therapy↗
PubMed2003

Characterization of neutron beams for boron neutron capture therapy: in-air radiobiological dosimetry.

The survival curves and the RBE for the dose components generated in boron neutron capture therapy (BNCT) were determined separately in neutron beams at Japan Research Reactor No. 4. The surviving fractions of V79 Chinese hamster cells with or without 10B were obtained using an epithermal neutron beam (ENB), a mixed thermal-epithermal neutron beam (TNB-1), and a thermal (TNB-2) neutron beam; these beams were used or are planned for use in BNCT clinical trials. The cell killing effect of the neutron beam in the presence or absence of 10B was highly dependent on the neutron beam used and depended on the epithermal and fast-neutron content of the beam. The RBEs of the boron capture reaction for ENB, TNB-1 and TNB-2 were 4.07 +/- 0.22, 2.98 +/- 0.16 and 1.42 +/- 0.07, respectively. The RBEs of the high-LET dose components based on the hydrogen recoils and the nitrogen capture reaction were 2.50 +/- 0.32, 2.34 +/- 0.30 and 2.17 +/- 0.28 for ENB, TNB-1 and TNB-2, respectively. The RBEs of the neutron and photon components were 1.22 +/- 0.16, 1.23 +/- 0.16, and 1.21 +/- 0.16 for ENB, TNB-1 and TNB-2, respectively. The approach to the experimental determination of RBEs outlined in this paper allows the RBE-weighted dose calculation for each dose component of the neutron beams and contributes to an accurate inter-beam comparison of the neutron beams at the different facilities employed in ongoing and planned BNCT clinical trials.

Air↗