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PubMed1999

The radiation biology of boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a targeted radiation therapy that significantly increases the therapeutic ratio relative to conventional radiotherapeutic modalities. BNCT is a binary approach: A boron-10 (10B)-labeled compound is administered that delivers high concentrations of 10B to the target tumor relative to surrounding normal tissues. This is followed by irradiation with thermal neutrons or epithermal neutrons which become thermalized at depth in tissues. The short range (5-9 microm) of the alpha and 7Li particles released from the 10B(n,alpha)7Li neutron capture reaction make the microdistribution of 10B of critical importance in therapy. The radiation field in tissues during BNCT consists of a mixture of components with differing LET characteristics. Studies have been carried out in both normal and neoplastic tissues to characterize the relative biological effectiveness of each radiation component. The distribution patterns and radiobiological characteristics of the two 10B delivery agents in current clinical use, the amino acid p-boronophenylalanine (BPA) and the sulfhydryl borane (BSH), have been evaluated in a range of normal tissues and tumor types. Considered overall, BSH-mediated BNCT elicits proportionately less damage to normal tissue than does BNCT mediated with BPA. However, BPA exhibits superior in vivo tumor targeting and has proven much more effective in the treatment of brain tumors in rats. In terms of fractionation effects, boron neutron capture irradiation modalities are comparable with other high-LET radiation modalities such as fast-neutron therapy. There was no appreciable advantage in increasing the number of daily fractions of thermal neutrons beyond two with regard to sparing of normal tissue in the rat spinal cord model. The experimental studies described in this review constitute the radiobiological basis for the new BNCT clinical trials for glioblastoma at Brookhaven National Laboratory, at the Massachusetts Institute of Technology, and at the High Flux Reactor, Petten, The Netherlands. The radiobiology of experimental and clinical BNCT is discussed in detail.

Animals↗

PubMed2004

Delivery of (10)boron to oral squamous cell carcinoma using boronophenylalanine and borocaptate sodium for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a unique radiation therapy in which boron compounds are trapped into tumor cells. To determine the biodistribution of boronophenylalanine (BPA) in nude mice carrying oral squamous cell carcinoma (SCC), BPA was administered at a dose of 250 mg/kg body weight intraperitoneally. Two hours later, (10)B concentration in the tumor was 15.96 ppm and tumor/blood, tumor/tongue, tumor/skin and tumor/bone (10)B concentration ratios were 6.44, 4.19, 4.68 and 4.56, respectively. Two hours after the administration of borocaptate sodium (BSH) at a dose of 75 mg/kg body weight, (10)B concentration in the tumor was 3.61 ppm, and tumor/blood, tumor/tongue, tumor/skin and tumor/bone (10)B concentration ratios were 0.77, 1.05, 0.60 and 0.59, respectively. When cultured oral SCC cells were incubated with BPA or BSH for 2 h and then exposed to thermal neutrons, the proportion of survival cells that were capable of forming cell colonies decreased exponentially, depending on (10)B concentration. BPA-mediated BNCT was more efficient than BSH-mediated BNCT. Addition of boron compounds in the cell suspension during neutron irradiation enhanced the cell-killing effect of the neutrons. These results indicate that BPA is more selectively incorporated into human oral SCC as compared with normal oral tissues, and that both extra- and intra-cellular BPA contribute to the cell-killing effect of BNCT. BPA may be a useful boron carrier for BNCT in the treatment of advanced oral SCC.

Animals↗

PubMed1994

Cell survival measurements in an argon, aluminium and sulphur filtered neutron beam: a comparison with 24 keV neutrons and relevance to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) has been advanced as a suitable alternative therapy for the treatment of glioma. BNCT involves the selective uptake of a tumour with a boron-bearing substance and subsequent irradiation with a beam of neutrons. Previous attempts with BNCT have utilized thermal neutrons, but this involves resection of the scalp prior to treatment and is only possible with superficial tumours. An alternative is to use a beam of intermediate-energy neutrons which will produce a peak in the thermal neutron fluence at depth in tissue and so enable deep-seated tumours to be treated. A neutron beam with a mean energy of approximately 9 keV, obtained by filtering neutrons from a reactor with aluminium, argon and sulphur, has been used to explore the radiobiological advantage over thermal and 24 keV neutrons for BNCT. Irradiation of V79 and HeLa cells at various positions in a polythene phantom suggest that the beam is less cytotoxic for a given neutron fluence than the 24 keV neutron beam previously considered as an alternative to thermal neutrons for BNCT. However, optimization of boron distribution via the development of new compounds still appears to be necessary for BNCT to become a safe alternative option for the treatment of glioma.

Aluminum↗

PubMed2005

Capillary electrophoresis-electrospray mass spectrometry and HR-ICP-MS for the detection and quantification of 10B-boronophenylalanine (10B-BPA) used in boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a bimodal radiotherapeutic treatment based on the irradiation of neoplastic tissues with neutrons after the tissues have selectively accumulated molecules loaded with nuclides with large neutron capture cross-sections (such boron-10). Boron-10 carriers have been tested to a limited extent, and clinical trials have been conducted on sulfhydryl borane (10B-BSH) and boronophenylalanine (10B-BPA). However, precise and accurate measurements of boron-10 concentrations (0.1-100 microg/g) in specimens and samples of limited size (microg scale) are needed in order to be able to biologically characterise new compounds in predictive tissue dosimetry, toxicology and pharmacology studies as well as in clinical investigations. A new approach based on fast separation and detection of 10B-BPA performed by coupling capillary electrophoresis to electrospray mass spectrometry is reported. This method allows the quantitative analysis and characterisation of 10B-BPA in a short time with a high separation efficiency. Detection limits of 3 microM for 10B-BPA and 30 ng/mL for 10B were obtained with CE-ESI-MS. A quantification limit of 10 microM for 10B-BPA (100 ng/mL for 10B) was attained. The total boron-10 concentration was determined by high-resolution inductively coupled mass spectrometry in order to validate the method. Boron-10 isotope measurements were carried out by HR-ICP-MS at medium resolution (R=4000) due to the presence of an isobaric interference at mass 10. Good agreement was obtained between the values from CE-ESI-MS and those from HR-ICP-MS. The method has been successfully used to determine the 10B-BPA in two lines of cultured cells.

Animals↗

PubMed1994

Present status and perspectives of boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a mode of radiotherapy with great attractiveness, but also with a burden of past failure. In this review, the principles of BNCT, the reasons for its past failure, its present clinical application, and the on-going developmental work towards clinical trials are described.

Animals↗

PubMed2001

Carboranyl bisglycosides for the treatment of cancer by boron neutron capture therapy.

Boron neutron capture therapy is a special type of radiotherapy for the treatment of cancer by using boron compounds. Problems often arise from the low water solubility of these compounds, their unselective uptake into the cancer cells, and their toxicity. Here we describe the novel water-soluble ortho-carboranyl bisglycosides 7 and 10 containing either lactose or glucose and the mixed bisglycosides 1 and 28 containing glucose, mannose, and galactose. The carboranyl bisglycosides show almost no toxicity toward bronchial carcinoma cells of line A549 up to a concentration of 0.50 mM. As anticipated, these compounds exhibit nearly no uptake into C6 glioma cells; they can therefore be used for a selective delivery into malignant cells by using conjugates of glycohydrolases and monoclonal antibodies which bind to tumor-associated antigens, since by enzymatic hydrolysis the bisglycosides are transformed into lipophilic compounds.

Antineoplastic Agents↗

PubMed2002

Application of TEPC microdosimetry to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a bimodal radiation therapy used primarily for highly malignant gliomas. Tissue-equivalent proportional counter (TEPC) microdosimetry has proven an ideal dosimetry technique for BNCT, facilitating accurate separation of the photon and neutron absorbed dose components, assessment of radiation quality and measurement of the BNC dose. A miniature dual-TEPC system has been constructed to facilitate microdosimetry measurements with excellent spatial resolution in high-flux clinical neutron capture therapy beams. A 10B-loaded TEPC allows direct measurement of the secondary charged particle spectrum resulting from the BNC reaction. A matching TEPC fabricated from brain-tissue-equivalent plastic allows evaluation of secondary charged particle spectra from photon and neutron interactions in normal brain tissue. Microdosimetric measurements performed in clinical BNCT beams using these novel miniature TEPCs are presented, and the advantages of this technique for such applications are discussed.

Boron Neutron Capture Therapy↗

PubMedDate not supplied

Ligand liposomes and boron neutron capture therapy.

Boron neutron capture therapy (BNCT) has been used both experimentally and clinically for the treatment of gliomas and melanomas, with varying results. However, the therapeutic effects on micro-invasive tumor cells are not clear. The two drugs that have been used clinically, p-boronophenylalanine, (BPA), and the sulfhydryl borane, (BSH), seem to be taken up preferentially in solid tumor areas but it is uncertain whether enough boron is taken up by micro-invasive tumor cells. To increase the selective uptake of boron by such cells, would be to exploit tumor transformation related cellular changes such as over-expression of growth factor receptors. However, the number of receptors varies from small to large and the uptake of large amounts of boron for each receptor interaction is necessary in order to deliver sufficient amounts of boron. Therefore, each targeting moiety must deliver large number of boron atoms. One possible way to meet these requirements would be to use receptor-targeting ligand liposomes, containing large number of boron atoms. This will be the subject of this review and studies of boron containing liposomes, with or without ligand, will be discussed. Two recent examples from the literature are ligand liposomes targeting either folate or epidermal growth factor (EGF) receptors on tumor cells. Other potential receptors on gliomas include PDGFR and EGFRvIII. Besides the appropriate choice of target receptor, it is also important to consider delivery of the ligand liposomes, their pharmacodynamics and pharmacokinetics and cellular processing, subjects that also will be discussed in this review.

Animals↗

PubMed1996

Ion microscopy imaging of 10B from p-boronophenylalanine in a brain tumor model for boron neutron capture therapy.

Boron neutron capture therapy (BNCT), a binary treatment modality that can potentially irradiate tumor tissue within cellular dimensions, is critically dependent on the preferential delivery of 10B to individual neoplastic cells. In this study, ion microscopy was used to quantitatively evaluate the selectivity of p-boronophenylalanine-fructose (BPA-F) in the rat 9L gliosarcoma brain tumor model. With a spatial resolution of approximately 0.5 microm, ion microscopy images show that BPA-F delivers 3.5 times more boron to the main tumor mass [99 +/- 36 microg/g tissue (mean +/- SD)] than to the contiguous normal brain (27 +/- 12 microg/g tissue). A similar, but lower, accumulation was observed away from the main tumor mass in small clusters of neoplastic cells (47 +/- 15 microg/g tissue) invading the surrounding brain (16 +/- 8 microg/g tissue). These findings establish for the first time the selectivity of BPA-F to the neoplastic cells invading the normal brain and provide a much-needed baseline measurement of the distribution of a clinically approved BNCT drug. Given the propensity for malignant brain tumors to infiltrate the surrounding normal brain, these observations have particular significance for clinical trials of BNCT for human glioblastoma multiforme using the drug BPA-F.

Animals↗

PubMedDate not supplied

A critical assessment of boron target compounds for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) has undergone dramatic developments since its inception by Locher in 1936 and the development of nuclear energy during World War II. The ensuing Cold War spawned the entirely new field of polyhedral borane chemistry, rapid advances in nuclear reactor technology and a corresponding increase in the number to reactors potentially available for BNCT. This effort has been largely oriented toward the eradication of glioblastoma multiforme (GBM) and melanoma with reduced interest in other types of malignancies. The design and synthesis of boron-10 target compounds needed for BNCT was not channeled to those types of compounds specifically required for GBM or melanoma. Consequently, a number of potentially useful boron agents are known which have not been biologically evaluated beyond a cursory examination and only three boron-10 enriched target species are approved for human use following their Investigational New Drug classification by the US Food and Drug Administration; BSH, BPA and GB-10. All ongoing clinical trials with GBM and melanoma are necessarily conducted with one of these three species and most often with BPA. The further development of BNCT is presently stalled by the absence of strong support for advanced compound evaluation and compound discovery driven by recent advances in biology and chemistry. A rigorous demonstration of BNCT efficacy surpassing that of currently available protocols has yet to be achieved. This article discusses the past history of compound development, contemporary problems such as compound classification and those problems which impede future advances. The latter include means for biological evaluation of new (and existing) boron target candidates at all stages of their development and the large-scale synthesis of boron target species for clinical trials and beyond. The future of BNCT is bright if latitude is given to the choice of clinical disease to be treated and if a recognized study demonstrating improved efficacy is completed. Eventually, BNCT in some form will be commercialized.

Animals↗

PubMed1994

Radiation dose heterogeneity in receptor and antigen mediated boron neutron capture therapy.

Boron neutron capture therapy, BNCT, might be a valuable tumour therapeutical modality for the treatment of cells that are difficult to handle with conventional methods such as surgery or external radiotherapy. The principle is that tumour associated 10B atoms capture thermal neutrons and thereby forms high-LET helium and lithium ions as reaction products. An interesting development is to conjugate 10B atoms to macromolecules that bind to tumour cells with over-expressed receptors or specific antigens. The targeting macromolecules might be receptor-ligands, antibodies or antibody-fragments containing 10B. The present study deals with the limitations of such an approach. One problem is the background dose from capture of neutrons in physiologically occurring elements, especially nitrogen. We showed, with computer simulations, that the background specific energy (the stochastic analogy of dose) in the cell nuclei, due to captures in nitrogen, had a wide spread and could be rather high, up to 3 Gy in some cells, when relevant neutron fluencies were applied. The maximal amount of 10B that can be delivered to single tumour cells due to receptor-ligand, receptor-antibody or antigen-antibody mediated binding is probably in the range 10(8)-10(10) atoms/cell. Our calculations showed that the tumour cells had to contain about 10(9) 10B/cell to give a therapeutically interesting dose to the nuclei of the targeted cells. The doses were highest when the boron was in the cell nucleus. There was also a wide spread of specific energy absorbed by the nuclei after neutron capture in 10B. When, for example, 10(8) 10(10)B/nucleus were applied the specific energy to the analysed nuclei varied from 0 Gy up to about 7 Gy. These variations were due to the stochastic nature of the capture processes. Some helium or lithium ion tracks passed through the centre of the cell nuclei delivering a lot of energy, some passed through only a smaller part delivering small amounts of energy and sometimes the nuclei escaped without any hits at all. The results were obtained when relevant neutron fluencies (2-5 x 10(12) n/cm2) were applied. Increased neutron fluencies gave higher doses both due to capture in boron and in nitrogen but in order to improve the ratio between the dose to targeted tumour cells and the dose to normal cells, the number of 10B atoms in the targeted cells had to be increased and/or the boron placed in the cell nuclei.

Boron↗

PubMed1998

Selective delivery of 10B to soft tissue sarcoma using 10B-L-borophenylalanine for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) may improve the locoregional control of radio/chemoresistant tumours like soft tissues sarcomas (STS). This technique uses the 10B(n,alpha)7Li nuclear reaction to destroy tumour cells, provided that a sufficient amount of 10B may be carried selectively into them. In order to evaluate the targeting potential of 10B-L-borophenylalanine (BPA) a 10B biodistribution study was carried out in 24 Wistar rats bearing Yoshida sarcoma. Six animals received increasing intraperitoneal doses of BPA (300, 600 and 1200 mg kg-1), while the remainder received a BPA dose of 600 mg kg-1 but with a sacrifice at six different time points: 1, 2, 4, 6, 9 and 12 h. The 10B concentrations in the tumours, normal tissues and blood were analysed with neutron capture radiography (NCR). The analysis shows that 36 micrograms g-1 (+/- 4 SD) of 10B may be incorporated into the tumour, with a ratio of 13 (+/- 4 SD) versus the muscle and a ratio of 15 (+/- 3 SD) versus the blood, 6 h after an intraperitoneal injection of 600 mg kg-1 of BPA. The BPA appears to be abundantly incorporated in the tumour, and the kidney proximal tubule area. These data suggest that BNCT using BPA may provide an improved therapeutic ratio for the treatment of STS.

Animals↗

PubMed2001

A new approach for the synthesis of isonitrile carborane derivatives. Ligands for metal based boron neutron capture therapy (BNCT) and boron neutron capture synovectomy (BNCS) agents.

A new approach for the synthesis of carborane isonitrile derivatives was developed. This approach involved the dehydration of both boron and carbon derived formamides using the Burgess reagent. The products, some of which were characterized by X-ray crystallography, can now be used as ligands for the synthesis of transition metal based boron neutron capture therapy and synovectomy agents and targeted radiopharmaceuticals.

Journal Article↗

PubMed1994

Boron neutron capture therapy: boron biodistribution and pharmacokinetics of Na2B12H11SH in patients with glioblastoma.

Data on biodistribution and pharmacokinetics of Na2B12H11SH are few and lack in standardization. This study comprises a uniform series of 10 patients with glioblastoma administered Na2B12H11SH i.v. 24 h before surgery at a dose level used in earlier therapeutical trials (75 mg/kg body weight). Boron concentrations in tumor, normal brain, peritumoral edematous brain, blood, and urine were determined by inductively coupled plasma-atomic emission spectroscopy 24 h after Na2B12H11SH administration; boron uptake in tumor (mean, 12.2 micrograms/g) was sufficiently selective compared to concentrations in normal and edematous brain (1.2 and 2.3 micrograms/g, respectively). Mean concentration ratio of tumor:blood was slightly above unity. Boron concentration in blood decreased according to an open two-compartment model, mean excretion in urine over 24 h was 81.9%. The only side effect was an inconstant facial flush. Among efforts aiming at an optimized treatment protocol a dose escalation study seems to be justified.

Borohydrides↗

PubMed2001

Toward clinical application of prompt gamma spectroscopy for in vivo monitoring of boron uptake in boron neutron capture therapy.

In boron neutron capture therapy (BNCT) the absorbed dose to the tumor cells and healthy tissues depends critically on the boron uptake. Pronounced individual variations in the uptake patterns have been observed for two boron compounds currently used in clinical trials. This implies a high uncertainty in the determination of the boron dose component. In the present work a technique known as prompt gamma spectroscopy (PGS) is studied that potentially can be used for in vivo and noninvasive boron concentration determination at the time of the treatment. The technique is based upon measurement of gamma rays promptly emitted in the 10B(n,alpha)7Li and 1H(n,gamma)2D reactions. The aim of this work is to prepare the present setup for clinical application as a monitor of boron uptake in BNCT patients. Therefore, a full calibration and a set of phantom experiments were performed in a clinical setting. Specifically, a nonuniform boron distribution was studied; a skin/ dura, a larger blood vessel, and tumor within a head phantom was simulated. The results show that it is possible to determine a homogeneous boron concentration of 5 microg/g within +/-3% (1 standard deviation). In the nonuniform case, this work shows that the boron concentration can be determined through a multistep measurement procedure, however, with a somewhat higher uncertainty (approximately 10%). The present work forms the basis for a subsequent clinical application of the PGS setup aimed at in vivo monitoring of boron uptake.

Blood Vessels↗

PubMed1996

Targeted drug delivery for boron neutron capture therapy.

PURPOSE: Boron neutron capture therapy (BNCT) is a form of radiochemotherapy that is becoming increasingly important for the treatment of malignant gliomas, malignant melanomas and other forms of cancer. Targeted delivery of boron to tumors is a critical prerequisite for successful BNCT. METHODS: Strategies that involve synthetic chemical approaches and biochemical and biophysical approaches are employed to meet this requirement. Compounds developed for targeting to tumors include borocaptate sodium (BSH) and p-boronophenylalanine (BPA) which are currently in clinical use. RESULTS: Boronated porphyrins, nucleosides, nucleotides and other boronated compounds show potentials as targeting molecules. Conjugation of boron compounds to macromolecules such as monoclonal antibodies, epidermal growth factor and dextran is also employed for active or passive tumor targeting. CONCLUSIONS: Boron delivery via microparticulate carriers such as liposomes, high density lipoproteins and microcapsules is also attractive for its potential application in BNCT.

Animals↗

PubMed1987

Preliminary study for application of anti-alpha-fetoprotein monoclonal antibody to boron-neutron capture therapy.

Boron-neutron capture therapy (BNCT) has been applied clinically, especially in brain-neuro surgery. We intended to expand the application of BNCT for the treatment of abdominal cancers and tried to determine whether MoAb (monoclonal antibody) against AFP (alpha-fetoprotein) could be useful tool to deliver boron-10 (10B) to AH-66 hepatoma cells for BNCT. Firstly, MoAb was boronated by mixing with 10B-compound (Cs2 10B12H11SH) by using N-succinimidyl 3(2-pyridyldithio)propionate (SPDP). Numbers of 10B atoms bound to an antibody molecule were in proportion to the dose of 10B-compound added, and maximum number of 10B atoms conjugated to an antibody molecule was approximately 1240. Secondly, using this boronated MoAb, 10B was delivered to AH-66 cells, and 11 X 10(9) 10B atoms were estimated to be on and/or in an AH-66 cell. After the irradiation with thermal neutron, boronated AH-66 cells showed decreasing uptake of [3H]TdR in proportion to the number of 10B atoms bound to and/or incorporated into the tumor cells. These results indicate that 10B atoms delivered by MoAb exert cytotoxic effect on AH-66 cells in a dose dependent manner by thermal neutron irradiation.

Animals↗

PubMed1997

The role of boron MRI in boron neutron capture therapy.

Boron magnetic resonance imaging (MRI) and spectroscopy (MRS) are being developed for use in boron neutron capture therapy (BNCT). With continued development, boron MRI may be used to locate BNCT agents in vivo, evaluate the pharmacokinetics of BNCT agents, and aid in treatment planning.

Animals↗