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PubMedDate not supplied

In vivo evaluation of phosphorous-containing derivatives of dodecahydro-closo-dodecaborate for boron neutron capture therapy of gliomas and sarcomas.

The in vivo uptake of dodecahydro-closo-dodecaborate derivatives substituted with phosphate- and bisphosphonate groups was evaluated in two different experimental tumor model systems and compared to other boronated and non-boronated compounds. These phosphorous-containing boron clusters may have potential for use in boron neutron capture therapy, a chemoradiotherapeutic form of cancer treatment. Using the F98 rat glioma as a brain tumor model in syngeneic Fischer rats, there was selective tumor uptake of the phosphate derivative with 21.5 micrograms boron/g tumor versus 5.2 micrograms/g normal brain and a tumor:blood ratio of 2.7. However, this compound was toxic to test animals and lethal at relatively low doses. The uptake of the bisphosphonate by the murine K8 osteosarcoma was approximately 18 micrograms boron/g tumor with a T:Bl ratio of 7.6 and a tumor:bone ratio of 1.5. This compound was non toxic to the test animals. The results indicate that phosphate- and bisphosphonate derivatives of dodecahydro-closo-dodecaborate may have potential for BNCT of gliomas and osteosarcomas, respectively.

Animals↗
PubMed1992

Boron neutron capture therapy of anterior chamber melanoma with p-boronophenylalanine.

Boron neutron capture therapy (BNCT) is a form of radiation therapy that requires selective uptake of boron by the tumor and irradiation with thermal neutrons. Phenylalanine is an amino acid precursor of melanin and when boronated (p-boronophenylalanine [BPA]) was found to be selectively taken up by Greene melanoma cells in the anterior chamber of rabbits. This tumor model was irradiated 24 hr after oral administration of BPA and was used for biodistribution studies that compared BPA and sodium pentaborate. Three groups were irradiated: group 1 (11 rabbits) received BPA followed by thermal neutron irradiation, group 2 (9 rabbits) received thermal neutron irradiation only, and group 3 (9 rabbits) served as unirradiated, undrugged control animals. Eight of the 11 tumors in group 1 were treated successfully; all tumors in groups 2 and 3 grew. Histopathologic examination did not reveal vascular or retina damage in group 1. These preliminary experiments confirm that newer boronated compounds, such as BPA, used in BNCT and improved neutron beams can provide selective irradiation of ocular melanomas.

Administration, Oral↗
PubMedDate not supplied

Toxicology and health impact of environmental exposure to boron. A review.

The presence of high concentrations of boron in community water supplies has been reported as a localized problem in certain areas of United States, USSR and Italy. In this paper, current information on sources, occurrence, pollution potential and toxicity of environmental boron is reviewed. In animals, chronic low-level boron exposure has been shown to cause reduced growth, cutaneous disorders and suppression of male reproductive system function. The mechanisms underlying these effects and available data on dose-response relationships are discussed in connection with human health hazards possibly associated with continuous low-level absorption of boron compounds.

Adult↗
PubMed1995

The equal effectiveness ratio: a quantitative approach to the evaluation of compounds for boron neutron capture therapy.

The resurgence of interest in boron neutron capture therapy (BNCT) as a potential treatment for glioblastomas and melanomas has resulted in a quest to identify and synthesize candidate compounds which can physiologically target the 10B atoms to tumor cells. Numerous boron-carrying compounds are now available and awaiting evaluation. Because the products of the boron neutron capture (BNC) reaction generally contribute greater than 50% of the dose in BNCT, the evaluation of the efficacy of boron compounds would be more precise if it were possible to remove, quantitatively, the dose contributed by the external reactor radiations. The purpose of this study is to report a method which does just that, i.e., leaves for precise evaluation the biological effect that is ascribable to the BNC products only. The evaluation involves a series of separately quantifiable factors, the product of which provides an overall "figure of merit" for the compound.

Animals↗
PubMed1993

Boron neutron capture therapy: long-term effects on the skin and spinal cord of the rat.

Our studies of the pharmacokinetics of boron focused on the variations in the concentration in blood of Sprague-Dawley rats with time after the administration of single intravenous doses of 50-200 mg/kg of 10B-enriched sodium mercaptoundecahydro-closo-dodecaborate (BSH). After the lowest dose of BSH there was a progressive decline in the boron content of the blood, with a biological half-life (t1/2) of approximately 4.5 h. Higher doses of BSH resulted in slower boron clearance rates. A dose of 100 mg/kg of BSH was the maximum safely tolerated by the rats. The boron content of the skin at this dose of BSH was a factor of 0.6 lower than that in the blood. To determine the dose-related changes in the response of the central nervous system to BNCT-type radiation exposures, a well-established and clinically relevant model, the rat spinal cord, was used. The spinal cords (20 mm field length) of rats, infused with 100 mg/kg of BSH, were irradiated for 3 to 5 h with cold thermal neutrons from the H6 beam on the DIDO reactor (AERE, Harwell). The skin surface neutron flux was 4.8 x 10(8) n/cm2/s. Exposure times of > or = 4 h resulted in vigorous, biphasic skin reactions, indicative of long-term vascular damage in the dermis. Rats were monitored closely for 84 weeks after irradiation. No abnormal neurological responses were observed and there was no histological evidence of lesions in the spinal cord at the end of the study. These findings indicate that the central nervous system has a high tolerance to BNCT-type radiation using BSH as the neutron capture agent.

Animals↗
PubMed1995

A novel method for boronating antibodies without loss of immunoreactivity, for use in neutron capture therapy.

The search for suitable boron containing compounds for 10B neutron capture therapy (BNCT) is based on the principle that boron atoms must be delivered specifically to tumour cells at a concentration high enough to be effective without being toxic to normal cells. Specificity may be achieved through monoclonal antibodies. However, it has been difficult to conjugate large numbers of boron atoms to the antibody molecules without inactivating them. We have devised a strategy to do this indirectly through the use of a boronated glutamate-lysine polymer in conjunction with biotin and streptavidin.

Antibodies↗
PubMed1997

Intratumoral delivery of boronated epidermal growth factor for neutron capture therapy of brain tumors.

The gene for epidermal growth factor receptor (EGFR) is amplified or overexpressed in high-grade gliomas but is low or undetectable in normal brain. Recently, there has been increasing interest in using epidermal growth factor (EGF)-based bioconjugates as targeting agents for brain tumors. In the present study, we have investigated the potential use of boronated EGF as a delivery agent for boron neutron capture therapy, which is based on the capture reaction that occurs when 10B, a stable isotope, is irradiated with low-energy thermal neutrons. A fourth generation starburst dendrimer was boronated and linked to EGF using heterobifunctional reagents. Either wild-type or EGFR gene transduced C6 glioma cells (C6EGFR), which expressed 10(5)-10(6) receptor sites/cell, were stereotactically implanted into the right cerebral hemisphere of Fischer rats. Four weeks later, the rats received either i.v. or intratumoral (i.t.) injection of 131I-labeled boronated starburst dendrimer (BSD) or BSD-EGF. The biodistribution of 131I-BSD-EGF and 131I-BSD was studied by means of whole-body scintigraphy, autoradiography, and gamma scintillation counting. Following i.t. injection of 131I-BSD-EGF, 21.8% of the injected dose per gram tissue (% ID/g) was localized in C6EGFR tumors at 24 h and 16.3% at 48 h compared to 5 and 1.3% ID/g in C6 wild-type tumors, respectively, and 0.01 and 0.006% ID/g, respectively, for i.v. injected animals at the corresponding times. In contrast, following i.t. injection of BSD-EGF, only 0.01-0.1% ID/g was localized in the liver and spleen at 24 and 48 h compared to 5-12% ID/g following i.v. injection. Our data indicate that direct i.t. injection can selectively deliver BSD-EGF to EGFR-positive gliomas and suggest that intracerebral administration may be the most effective way for delivering EGF-based bioconjugates to EGFR-positive brain tumors.

Animals↗
PubMed1997

Evaluation of fluorine-18-BPA-fructose for boron neutron capture treatment planning.

UNLABELLED: Boron neutron capture therapy (BNCT) using 4-[10B]boronophenylalanine-fructose (BPA-Fr) is in Phase II clinical trials to validate BNCT as a treatment for glioblastoma multiforme and melanoma. Successful BNCT depends on knowledge of the distribution of boron-containing agents in both tumor and normal tissue as currently determined by chemical confirmation of boron deposition in surgically removed malignant tissue before BNCT. METHODS: We used PET to noninvasively obtain in vivo information on the pharmacokinetics of the 18F-labeled analog of BPA-Fr in two patients with glioblastoma multiforme. Time-activity curves generated from the bolus injection of 18F-BPA-Fr were coinvolved to simulate a continuous infusion used for BNCT therapy. RESULTS: Distribution of 18F-BPA-Fr by PET was found to be consistent with tumor as identified by MR imaging. The 18F-BPA-Fr tumor-to-normal brain uptake ratio was 1.9 in Patient 1 and 3.1 in Patient 2 at 52 min after injection. The 18F-BPA-Fr uptake ratio in glioblastoma paralleled that of nonlabeled BPA-Fr seen in patients as previously determined by boron analysis of human glioblastoma tissue obtained from pre-BNCT surgical biopsy. CONCLUSION: Knowledge of the biodistribution of BPA-Fr enables pre-BNCT calculation of expected tissue dosimetry for a selected dose of BPA-Fr at a specific neutron exposure. Fluorine-18-BPA-Fr PET is capable of providing in vivo BPA-Fr biodistribution data that may prove valuable for patient selection and pre-BNCT treatment planning.

Boron Compounds↗
PubMed1992

Boron neutron capture therapy for cancer. Realities and prospects.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10 (10B), is irradiated with low-energy thermal neutrons (nth) to yield (4He) alpha-particles and 7Li nuclei (10B+nth-->[11B]-->4He+7Li+2.31 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of 10B and nth to individual cancer cells to sustain a lethal 10B(n, alpha) 7Li reaction. The current review covered the radiobiologic considerations on which BNCT is based, including a brief discussion of microdosimetry and normal tissue tolerance. The development of tumor-localizing boron compounds was discussed, including the sulfhydryl-containing polyhedral borane, sodium borocaptate (Na2B12H11SH), and boronophenylalanine (BPA), both of which are currently being used clinically in Japan as capture agents for malignant brain tumors and melanomas, respectively. Compounds currently under evaluation, such as boronated porphyrins, nucleosides, liposomes, and monoclonal antibodies (MoAbs), were also considered. Nuclear reactors have been used as the exclusive source of neutrons for BNCT. The use of low-energy (0.025 eV) thermal neutrons and higher-energy (1-10,000 eV) epithermal beams, beam optimization, and possible alternative neutron sources (accelerators) were also discussed. Clinical studies performed in the United States during the 1950s and 1960s for the treatment of malignant brain tumors were reviewed. Current studies in Japan and future studies in Europe and the United States concerning the treatment of glioblastomas and melanomas by BNCT were discussed, as were critical issues that must be addressed if BNCT is ever to be a useful therapeutic modality.

Boron Neutron Capture Therapy↗
PubMed2004

Diaroyl(methanato)boron difluoride compounds as medium-sensitive two-photon fluorescent probes.

This paper evaluates the use of diaroyl(methanato)boron difluoride compounds for designing efficient fluorescent probes through two-photon absorption. Three different pathways allowing for the syntheses of symmetrical and dissymmetrical molecules are reported. The stable diaroyl(methanato)boron difluoride derivatives can be easily obtained in good yields. They exhibit a large one-photon absorption that is easily tuned in the near-UV range. Their strong fluorescence emission covers the whole visible domain. In addition to these attractive linear properties, several diaroyl(methanato)boron difluoride derivatives possess significant cross sections for two-photon absorption. The derived structure-property relationships are promising for designing new generations of molecules relying on the diaroyl(methanato)boron difluoride backbone.

Boron Compounds↗
PubMedDate not supplied

Interaction of sugars, polysaccharides and cells with boronate-containing copolymers: from solution to polymer brushes.

Interaction of mono- and disaccharides, polysaccharide particles and yeast cells with boronate-containing copolymers (BCC) of N-acryloyl-m-aminophenylboronic acid (NAAPBA) with N,N-dimethylacrylamide (DMAA) or N-isopropylacrylamide (NIPAM) was studied. The binding of saccharides to BCC of NIPAM resulted in a shift of its phase transition temperature (DeltaTP), which provided a quantitative measure for the complex formation. Among the sugars typical of non-reducing ends of glycoproteins the DeltaTP decreased in the order: N-acetylneuraminic acid > xylose approximately galactose > mannose approximately fucose >> N-acetylglucosamine. Strong specific adsorption of the BCC on the cross-linked agarose gel Sepharose CL-6B (15-30 mg/ml gel at pH 9.2) was registered. The copolymers adsorption was due to boronate-sugar interactions and decreased with pH. Multivalent interaction of the BCC with the agarose gel has been proven by liquid column chromatography exhibiting a weak reversible adsorption of NAAPBA and almost irreversible adsorption of DMAA-NAAPBA copolymer from 0.1 M sodium phosphate buffer, pH 7.9. The two studied BCCs could be completely desorbed from the gel by 0.1 M fructose in aqueous buffered media with pH from 7.5 to 9.2. In turn, the agarose particles and yeast cells were found to adhere to siliceous supports end-grafted with boronate-BCC of N,N-dimethylacrylamide at pH > or = 7.5, due to the actions. Quantitative detachment of adhered particles or cells could be attained by addition of 20 mM or 100 mM fructose, respectively, in the pH range from 7.5 to 9.2. Affinity adhesion of micron-size carbohydrate particles to boronate-containing polymer brushes fixed on solid supports was considered as a model system suggesting a new approach to isolation and separation of living cells.

Acrylamides↗
PubMed1998

Boron neutron capture therapy: principles and potential.

This book on the therapeutic applications of neutrons and high-LET radiations in cancer therapy would not have been complete without a review of the present situation of boron neutron capture therapy (BNCT) and a discussion of its future perspectives. BNCT is a special type of high-LET radiation therapy that attempts to achieve a selectivity at the cellular level. The rationale is to incorporate boron atoms selectively in the cancer cells and then bombard those atoms with thermal neutrons to produce a neutron capture reaction and subsequent decay that emits alpha and lithium particles. The efficiency of the technique depends upon achieving selective incorporation of the boron atoms in the cancer cells and not (or to a lesser extent) in the normal cells. The present status and future directions are described, with emphasis on boron carriers (drugs) and their delivery, as well as physical and treatment planning aspects.

Boron Neutron Capture Therapy↗
PubMed1991

In ovo administration of boron alters bone mineralization of the chicken embryo.

It has been hypothesized that boron (B) is an essential element for animals, especially in bone metabolism. In this study, the influence of in ovo boron administration was assessed in the chicken. At 8 d of embryogenesis, carrier or B (0.1, 0.5, or 1.0 mg) was injected on to the chorioallantoic membrane of fertile eggs. At hatching, body weights were recorded and tissue samples collected. Although boron failed to alter bone mineralization, it decreased (p less than 0.05) dried bone weight, suggesting a reduction in the bone organic matrix. Furthermore, 1 mg boron decreased (p less than 0.05) hatchability and increased (p less than 0.05) the height of the proliferative zone in the growth plate, indicating an unfavorable effect on bone elongation of the developing chick.

Animals↗
PubMed1996

Immunocytochemistry by electron spectroscopic imaging using a homogeneously boronated peptide.

A linear all-L-oligopeptide containing five carboranyl amino acids (corresponding to 50 boron atoms) was synthesized and specifically attached to the free thiol group of monovalent antibody fragments F(ab)'. The boronated immunoreagent was used for the direct post-embedding detection of somatotrophic hormone in ultrathin sections of porcine pituitary embedded in Spurr resin. The specific boron-labelling of secretory vesicles in somatotrophs was detected by electron spectroscopic imaging and confirmed by conventional immunogold labelling run in parallel. In comparison with immunogold, boron-labelled F(ab)'-fragments showed higher tagging frequencies, as was expected; the small uncharged immunoreagents have an elongated shape and carry the antigen-combining structure and the detection tag at opposite ends, thus allowing for high spatial resolution in electron spectroscopic imaging.

Animals↗
PubMed1990

Immunoreactivity of boronated antibodies.

Boronated antibodies have already been evaluated as agents in neutron capture therapy. Because the boronation procedure may alter the properties of the antibody it is important to study the immunoreactivity of the conjugated antibody before in vivo use. In our studies of two dextran-boronated monoclonal antibodies, anti-glial fibrillary acidic protein antibody, and anti-hyaluronectin antibody, we have used ELISA and immunohistological methods to determine antibody activity and specificity. A ten-fold decrease in activity was observed for both antibodies in ELISA, and non-specific interactions were seen in both immunohistological and ELISA procedures. The boron compound used was shown to be at least partly responsible for these non-specific interactions.

Animals↗
PubMed1994

Large animal normal tissue tolerance with boron neutron capture.

PURPOSE: Normal tissue tolerance of boron neutron capture irradiation using borocaptate sodium (NA2B12H11SH) in an epithermal neutron beam was studied. METHODS AND MATERIALS: Large retriever-type dogs were used and the irradiations were performed by single dose, 5 x 10 dorsal portal. Fourteen dogs were irradiated with the epithermal neutron beam alone and 35 dogs were irradiated following intravenous administration of borocaptate sodium. RESULTS: Total body irradiation effect could be seen from the decreased leukocytes and platelets following irradiation. Most values returned to normal within 40 days postirradiation. Severe dermal necrosis occurred in animals given 15 Gy epithermal neutrons alone and in animals irradiated to a total peak physical dose greater than 64 Gy in animals following borocaptate sodium infusion. Lethal brain necrosis was seen in animals receiving between 27 and 39 Gy. Lethal brain necrosis occurred at 22-36 weeks postirradiation. A total peak physical dose of approximately 27 Gy and blood-boron concentrations of 25-50 ppm resulted in abnormal magnetic resonance imaging results in 6 months postexamination. Seven of eight of these animals remained normal and the lesions were not detected at the 12-month postirradiation examination. CONCLUSION: The bimodal therapy presents a complex challenge in attempting to achieve dose response assays. The resultant total radiation dose is a composite of low and high LET components. The short track length of the boron fission fragments and the geometric effect of the vessels causes much of the intravascular dose to miss the presumed critical target of the endothelial cells. The results indicate a large dose-sparing effect from the boron capture reactions within the blood.

Animals↗
PubMed1996

Monte Carlo-based treatment planning for boron neutron capture therapy using custom designed models automatically generated from CT data.

PURPOSE: A Monte Carlo-based treatment planning code for boron neutron capture therapy (BNCT), called NCTPLAN, has been developed in support of the New England Medical Center-Massachusetts Institute of Technology program in BNCT. This code has been used to plan BNCT irradiations in an ongoing peripheral melanoma BNCT protocol. The concept and design of the code is described and illustrative applications are presented. METHODS AND MATERIALS: NCTPLAN uses thin-slice Computed Tomography (CT) image data to automatically create a heterogeneous multimaterial model of the relevant body part, which is then used as input to a Monte Carlo simulation code, MCNP, to derive distributions within the model. Results are displayed as isocontours superimposed on precisely corresponding CT images of the body part. Currently the computational slowness of the dose calculations precludes efficient treatment planning per se, but does provide the radiation oncologist with a preview of the doses that will be delivered to tumors and to various normal tissues, and permits neutron irradiation times in Megawatt-minutes (MW-min) to be calculated for specific dose prescriptions. The validation of the NCTPLAN results by experimental mixed-field dosimetry is presented. A typical application involving a cranial parallel-opposed epithermal neutron beam irradiation of a human subject with a glioblastoma multiforme is illustrated showing relative biological effectiveness-isodose (RBE) distributions in normal CNS structures and in brain tumors. Parametric curves for the MITR-II M67 epithermal neutron beam, showing the gain factors (gain factor = minimum tumor dose/maximum normal brain dose) for various combinations of boron concentrations in tumor and in normal brain, are presented. RESULTS: The NCTPLAN code provides good computational agreement with experimental measurements for all dose components along the neutron beam central axis in a head phantom. For the M67 epithermal beam the gain factor for 1, boronophenylalanine for a small midline brain tumor under typical distribution assumptions is 1.4-1.8 x . Implementation of the code under clinical conditions is demonstrated. CONCLUSION: The NCTPLAN code has been shown to be well suited to treatment-planning applications in BNCT. Comparison of computationally derived dose distributions in a phantom compared with experimental measurements demonstrates good agreement. Automatic superposition of isodose contours with corresponding CT image data provides the ability to evaluate BNCT doses to tumor and to normal structures. Calculation of gain factors suggests that for the M67 epithermal neutron beam, more advantage is gained from increasing boron concentrations in tumor than from increasing the boron tumor-to-normal brain ratio.

Boron Neutron Capture Therapy↗
PubMed1991

In vivo boron-11 MRI and MRS using (B24H22S2)4- in the rat.

In vivo boron-11 magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were performed on a rat that had been infused with a potential boron neutron capture therapy agent, Na4B24H22S2, using methods for detecting nuclei with a short T2 relaxation time. MRI and MRS were also performed on a euthanized rat that had been similarly infused in vivo. Boron-11 spectral intensities decreased in the living rat over a 25-h period. The results demonstrate the capability of MRI and MRS to noninvasively monitor the distribution and excretion of boron agents in vivo.

Animals↗