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PubMed2005

A novel 10B-enriched carboranyl-containing phthalocyanine as a radio- and photo-sensitising agent for boron neutron capture therapy and photodynamic therapy of tumours: in vitro and in vivo studies.

The synthesis of a Zn(ii)-phthalocyanine derivative bearing four 10B-enriched o-carboranyl units (10B-ZnB4Pc) and its natural isotopic abundance analogue (ZnB4Pc) in the peripheral positions of the tetraazaisoindole macrocycle is presented. The photophysical properties of ZnB4Pc, as tested against model biological systems, were found to be similar with those typical of other photodynamically active porphyrin-type photosensitisers, including a singlet oxygen quantum yield of 0.67. The carboranyl-carrying phthalocyanine was efficiently accumulated by B16F1 melanotic melanoma cells in vitro, appeared to be partitioned in at least some subcellular organelles and, upon red light irradiation, induced extensive cell mortality. Moreover, ZnB4Pc, once i.v.-injected to C57BL/6 mice bearing a subcutaneously transplanted pigmented melanoma, photosensitised an important tumour response, provided that the irradiation at 600-700 nm was performed 3 h after the phthalocyanine administration, when appreciable concentrations of ZnB4Pc were still present in the serum. Analogously, irradiation of the 10B-ZnB4Pc-loaded pigmented melanoma with thermal neutrons 24 h after injection led to a 4 day delay in tumour growth as compared with control untreated mice. These results open the possibility to use one chemical compound as both a photosensitising and a radiosensitising agent for the treatment of tumours by the combined application of photodynamic therapy and boron neutron capture therapy.

Animals↗
PubMed2006

Boron dipyrromethene dyes: a rational avenue for sensing and light emitting devices.

Boron dipyrromethene dyes bearing nitro, amino, isocyanate and isothiocyanate functions were readily prepared under mild conditions. Various combinations allow to produce urea, diurea, thiourea, dithiourea in the 3, 4 and 5-substitution positions of the appended phenyl group. Condensation of the 3,4-substituted diamino derivative with 1,10-phenanthroline-5,6-dione and 6-formyl-2-methylpyridine allow to prepare dipyridophenazine and indole derivatives. The 3,5-dinitro-substituted indacene dye was characterized by an X-ray molecular structure showing a pronounced tilt angle of the dinitrophenyl group relative to the indacene core (approximately 84 degrees) whereas one nitro groups is basically coplanar with the phenyl ring and the second titled by approximately 21 degrees. The optical properties of these dyes reveals on/off switching of the fluorescence from the nitro to the amino compounds and further to the urea likely understood in the framework of an photoinduced electron transfer process.

Boron↗
PubMed2006

The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented 10B conjugate compound, TX-2100, for boron neutron capture therapy.

PURPOSE: To evaluate the usefulness of a new 10B-compound (TX-2100) as a 10B-carrier in boron neutron capture therapy (BNCT), compared with the simultaneous use of its component drugs, sodium borocapate-10B (BSH) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (TX-402). Further, the usefulness of mild temperature hyperthermia (MTH, 40 degrees Celsius, 30 min) combined with TX-2100 was also examined compared with MTH combined with the concurrent administration with its component drugs. MATERIALS AND METHODS: TX-2100 is a hybrid compound that has both a hypoxic cytotoxin unit (TX-402) and a thermal neutron-sensitizing unit (BSH). TX-2100 or both TX-402 plus BSH in combination with MTH or not was administered to SCC VII tumour-bearing mice intra-peritoneally. Then, the 10B concentrations in the tumours and normal tissues were measured by gamma-ray spectrometry. Meanwhile, SCC VII tumour-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumours, then treated with TX-2100, TX-402 plus BSH or BSH only, in the same manner as in the biodistribution experiments, either with or without MTH. Right after thermal neutron irradiation during which intra-tumour 10B concentrations remained at similar levels, the tumours were excised, minced and trypsinized. The tumour cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker) and the micronucleus (MN) frequency in cells without BrdU labelling (=quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P + Q) tumour cell population was determined from the tumours that were not pre-treated with BrdU. The clonogenic cell survival was also determined in mice given no BrdU. RESULTS: 10B biodistribution analyses in tumours, brain, skin, muscles, blood and liver indicated that the administration of TX-2100 plus MTH is most favourable for concentrating a sufficient amount of 10B in tumours and maintaining a high enough 10B concentration during irradiation. In addition, MTH had a stronger sensitizing effect when combined with TX-2100 than with the concurrent administration of its components TX-402 and BSH on both the total and Q cell populations in solid tumours. CONCLUSION: MTH was very effective in combination with the newly-developed TX-2100. The sensitizing effect in combination with MTH should be examined when new 10B-carriers are designed.

Animals↗
PubMed2006

Effects of boron neutron capture therapy on human oral squamous cell carcinoma in a nude mouse model.

PURPOSE: The effect of boronophenylalanine (BPA)-mediated boron neutron capture therapy (BNCT) on human oral squamous cell carcinoma (SCC) xenografts in nude mice was examined. MATERIALS AND METHODS: Tumor-bearing mice were given BPA at a dose of 250 mg/kg body weight. The tumor (10)B concentration 2 h after an injection of BPA was higher than those 1 or 3 h after the injection. Neutron irradiation was performed beginning 1, 2 or 3 h after an injection of BPA and the effects on body weight of the animals, tumor growth, survival of tumor-bearing animals, and histology of tumor and normal tissue were examined. Fragmented nuclear DNA, 5-bromo-2'-deoxyuridine (BrdU), and von Willebrand Factor (vWF) were detected by immunohistochemical staining. RESULTS: Tumor volumes of untreated control animals increased continuously, whereas those of BNCT-treated animals were markedly decreased. Animals given neutron irradiation 2 h after the injection of BPA survived for a longer period as compared with those given neutron irradiation 1 or 3 h after the injection. BNCT reduced the incorporation of BrdU into tumor cells, and induced the enlargement and vacuolation of tumor cells. Disintegration of blood vessels and dense inflammatory cell infiltration were also observed in the stroma of the tumor, but not surrounding normal tissues. CONCLUSION: These results indicate that BPA-mediated BNCT can exert a curative effect on human oral SCC xenografts in nude mice, if an optimal 10B concentration in tumors is achieved and that the disintegration of blood vessels in tumor stroma may contribute to tumor remission by BNCT.

Animals↗
PubMed2004

Tissue disposition of 5-o-carboranyluracil--a novel agent for the boron neutron capture therapy of prostate cancer.

The carboranyl nucleotides beta-D-5-o-carboranyl-2'-deoxyuridine (D-CDU), 1-(beta-L-arabinosyl)-5-o-carboranyluracil (D-ribo-CU) and the nucleotide base 5-o-carboranyluracil (CU), were developed as sensitizers for boron neutron capture therapy (BNCT). A structure activity study was initiated to determine the agent most suitable for targeting prostate tumors. Cellular accumulation studies were performed using LNCaP human prostate tumor cells, and the respective tumor disposition profiles were investigated in male nude mice bearing LNCaP and 9479 human prostate tumor xenografts in their flanks. D-CDU achieved high cellular concentrations in LNCaP cells and up to 2.5% of the total cellular compound was recovered in the 5'-monophosphorylated form. In vivo concentrations of D-CDU were similar in LNCaP and 9479 tumor xenografts. Studies in 9479 xenografted bearing mice indicated that increasing the number of hydroxyl groups in the sugar moeity of the carboranyl nucleosides corresponded with an increased rate and extent of renal elimination, shorter serum half-lives and an increased tissue specificity. Tumor/normal prostate ratios were greatest with the nucleoside base CU. These studies indicate that similar nucleoside analogues and bases may have different tissue affinities and retention properties, which should be considered when selecting agents for sensitizing specific tumors for eventual BNCT treatment. CU was found to be the most suitable compound for further development to treat prostate cancer.

Animals↗
PubMed2000

Phantom materials for boron neutron capture therapy.

The aim of this work was to establish which reference phantom material is most suited for dosimetry under reference conditions of neutron beams for boron neutron capture therapy (BNCT). For this purpose, phantoms of dimensions 15 x 15 x 15 cm3 and 30 x 30 x 30 cm3, composed of water, tissue-equivalent (TE) liquid, polyethylene (PE), polymethyl methacrylate (PMMA) and water containing 10 microg g(-1) and 30 microg g(-1) 10B were irradiated using the Petten BNCT beam. Activation foils and a diode detector were used for the determination of the thermal neutron fluence rate. The gamma-ray dose rate and the fast neutron dose rate were determined using paired ionization chambers. In water, PMMA and TE liquid the absolute dose and fluence values agreed within 3% at a reference depth of 2 cm, with the exception of the gamma-ray dose rate in PMMA, which was 12% lower than in water. Due to a higher hydrogen concentration in PE compared with water, the dose and fluence values in PE differed more than 30% from those in water. Only minor differences were observed between the percentage depth dose curves for the various dose components in water, PMMA and TE liquid. The addition of 10 microg g(-1) and 30 microg g(-1) 10B to water resulted in a decrease in the absolute thermal neutron fluence at 2 cm depth of about 2% and 8%, respectively, and a decreased penetration of thermal neutrons at depth for the 30 microg g(-1) 10B concentration. For reference dosimetry of an epithermal neutron beam for BNCT, both water and TE liquid are suitable phantom materials. For practical reasons, water is therefore proposed as reference phantom material. For measurements requiring a solid phantom, PMMA is proposed. The lower gamma-ray dose in PMMA compared to water, however, needs to be taken into account.

Boron↗
PubMed2005

Characteristics of boron-dose enhancer dependent on dose protocol and 10B concentration for BNCT using near-threshold 7Li(p,n)7Be direct neutrons.

The dependence of boron-dose enhancer (BDE) characteristics on dose protocol and 10B concentration was evaluated for BNCT using near-threshold 7Li(p,n)7Be direct neutrons. The treatable protocol depth (TPD) was utilized as an evaluation index. MCNP calculations were performed for near-threshold 7Li(p,n)7Be at a proton energy of 1.900 MeV and for a polyethylene BDE. The effect of dose protocol on BDE characteristics was reflected in terms of the optimum BDE thickness needed for maximum TPD which was found to be independent of the treatable dose but was observed to vary for different combinations of the tolerance doses for heavy charged particles and gamma rays. For the 10B concentration dependence, the TPD was increased by increasing the T/N ratio, i.e., the ratio of the 10B concentration in the tumour (10B(Tumour)) to that in the normal tissue (10B(Normal)), and by increasing 10B(Tumour) and 10B(Normal) at constant T/N ratio. It was found that the use of BDE becomes unnecessary from the viewpoint of increasing the TPD, when 10B(Tumour) is over a certain level which is decided by the conditions of the dose protocol.

Boron↗
PubMed1998

Effects of boron neutron capture therapy using borocaptate sodium in combination with a tumor-selective vasoactive agent in mice.

Boron neutron capture therapy (BNCT) destroys tumor cells by means of alpha particles and recoil protons emitted by 10B(n, alpha)7Li reaction. For BNCT to be effective, the tumor/normal tissue concentration ratio of 10B must be larger than 1.0, because neutron distribution is not selective. We examined the combination of 10B-enriched borocaptate sodium (BSH) with flavone acetic acid (FAA) as a model compound which causes vascular collapse in squamous cell carcinoma in mice (SCCVII tumors) and would increase the tumor/normal tissue concentration ratio of 10B. FAA (200 mg/kg, i.p.) was injected, and 5 min later BSH (75 mg/kg, i.v.) was administered, followed 15 to 180 min later by irradiation with thermal neutrons. The 10B concentrations were measured by prompt gamma ray spectrometry. Without FAA, tumor 10B concentrations were less than or equal to normal tissue concentrations at all time intervals, except that the concentrations were 1.7- to 2.7-fold greater in tumor than muscle at 15 and 180 min after injection of BSH. With FAA, 10B concentrations 2.1- to 6.9-fold greater in tumor than in muscle were achieved at all intervals tested. For blood and skin, significant differential accumulations were found in tumors at 120 and 180 min. Tumor/liver ratios were less than 1 at all times. Cell survival was determined by in vivo/in vitro colony assay, and increasing radiosensitization correlated with increasing tumor 10B concentrations, whether or not they were achieved with FAA. Tumor control rates, determined at 180 days after BNCT, similarly appeared to depend only on 10B levels at the time of irradiation. Because 10B levels correlate with the radiation response of tissues, a therapeutic gain would be expected whenever the tumor levels exceed normal tissue levels, such as in tumors located in muscle irradiated at 15-180 min after FAA + BSH, or in those in skin irradiated at 120 and 180 min.

Animals↗
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↗
PubMedDate not supplied

Liposomes containing boronophenylalanine for boron neutron capture therapy.

In the present work, liposomes loaded with Boronophenylalanine (BPA), with or without stabilization, were formulated for the application in boron neutron capture therapy. BPA was encapsulated into liposomes as a complex with fructose, but also as a free drug in two different pH buffers. The influence of critical variables (cholesterol content, drug:lipid molar ratio, osmotic stress of liposomes containing hyperosmotic drug solution) on liposome morphology and drug content was evaluated. The drug content and dissolution profile of different BPA loaded liposomes were also studied. The physical stability of liposomes in terms of changes in the size distribution in different osmotic pressure buffers and the chemical oxidation of phospholipids during storing conditions were investigated. The encapsulation efficiencies of all formulations were always satisfactory, being between 20-48%; even when the liposomes were exposed to high osmotic stress, the particle size was below 200 nm. The BPA-fructose complex loaded liposomes showed a slower drug release profile.

Boron Compounds↗
PubMedDate not supplied

Applicability of the 2-nitroimidazole-sodium borocaptate-10B conjugate, TX-2060, as a 10B-carrier in boron neutron capture therapy.

BACKGROUND: It is difficult to deliver a therapeutic amount of 10B from conventional 10B-carriers for boron neutron capture therapy (BNCT) throughout the target tumors, especially into the intratumor hypoxic cells which have low uptake capacities. We evaluated the usefulness of 5 new 10B-compounds (TX-2041, TX-2042, TX-2058, TX-2059 and TX-2060) as 10B-carriers in BNCT. They are 2-nitroimidazole-sodium borocaptate-10B (BSH) conjugates, that is, hybrid compounds that have both a hypoxic tumor cell sensitizing unit under gamma-ray irradiation, 2-nitroimidazoles and a thermal neutron-sensitizing unit, BSH. MATERIALS AND METHODS: The 5 new compounds were administered to SCC VII tumor-bearing mice intraperitoneally. As a control, BSH was also administered in the same manner. Then, the 10B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Based on the data of the pharmacokinetics analyses, TX-2060 was chosen for a subsequent tumor-irradiation study. SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2060 or BSH in the same manner as in the pharmacokinetics analyses. To obtain similar intratumor 10B concentrations during radiation exposure, irradiation with thermal neutrons or gamma-rays was started from 60 min after administration of the 10B-carrier. Right after irradiation, the tumors were excised, minced and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU-labelling (= quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU. The clonogenic cell survival was also determined in mice given no BrdU. RESULTS: 10B distribution analyses in tumors, muscles, blood and liver indicated that TX-2060 has the most favorable characteristics for concentrating a sufficient amount of 10B in tumors and maintaining a high enough 10B concentration during irradiation. In addition, TX-2060 had a significantly stronger radio-sensitization effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2060 clearly exhibited a radio-sensitization effect with gamma-rays, not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH. CONCLUSION: 10B-carrier, with a gamma-ray-sensitizing effect on tumor cells as well as the potential to keep 10B in tumors and sensitize tumor cells more markedly than conventional 10B-carriers, such as TX-2060, is a promising candidate for use in BNCT.

Animals↗
PubMedDate not supplied

Synthesis and biological behavior of a boronated analogue of the antiestrogen U 23,469-M.

A boronated analogue of the antiestrogen U 23,469-M (D. Lednicer, D. W. Emmert, S. C. Lyster, and G. W. Duncan, J. Med. Chem. 12, 881 (1969] was prepared, for possible use in neutron capture therapy of estrogen receptor-positive tumors. In this analogue, the terminal OH group was replaced by a B-decachloro-o-carboranyl residue. This compound showed a large, non-specific uptake in ZR 75-1 breast cancer-derived cells. It could partially inhibit the uptake of estradiol in these cells. Accumulation in the cells at physiologically obtainable concentrations was, however, too low to envisage a therapeutic effect following thermal neutron irradiation.

Boron↗
PubMed1994

Boron neutron capture therapy of malignant melanoma using 10B-paraboronophenylalanine with special reference to evaluation of radiation dose and damage to the normal skin.

A treatment regimen for boron neutron capture therapy of malignant melanomas is described using 10B-paraboronophenylalanine as the tumor-targeting compound. As a therapeutic dose, we adopted the maximum tolerable dose for the skin regardless of tumor 10B concentration. In practice, the maximum neutron fluence should be decided prior to starting irradiation. For this purpose, the kinetics of the concentration of 10B in the blood and skin and the skin-to-blood ratios were analyzed in the six patients who received 170 mg/kg of the compound intravenously, and skin concentrations during irradiation were predicted using a standard skin factor curve. This yields a skin concentration at time T based on the blood concentration at time 0. We calculated the maximum tolerable fluence yielding but not exceeding 18 RBE-Gy by assuming that the RBE of 14N(n,p)14C and 10B(n, alpha)7Li reaction for skin damage is 2.5. Actual skin reactions in three of five patients treated with the therapy were, as predicted, within tolerable limits, and we were able to obtain complete tumor regression in four cases. The results indicate that application of our logical approach will be useful for subsequent cases and further development of this therapy.

Aged↗
PubMedDate not supplied

Evaluation of in vitro cytotoxicity of carboranyl amino acids, their chemical precursors and nido carboranyl amino acids for boron neutron capture therapy.

The purpose of the present study was to define the in vitro cellular toxicity of three carborane-containing amino acids: p-(o-carboran-yl)-phenylalanine (CBPA), O-(o-carboran-1-ylmethyl)-tyrosine (CBT), and o-carboranylalanine (CBA), which are analogues of phenylalanine, tyrosine, and alanine respectively. In addition, two of their chemical precursors: CBACN (B10H11C2-CH2CHNH2CN) and CBTCN (B10H11C2-CH2OC6H4CH2CHNH2CN) and nido CBA were evaluated for their toxicity on human MRA 27 melanoma cells. Hydroxypropyl-beta-cyclodextrin (beta-CD) initially was used to solubilize all the compounds except nido CBA in the toxicity assays Cells were incubated with the test compounds at varying concentrations for 24 hrs, following which the proliferative activity of surviving cells was determined by pulsing with tritiated thymidine ([3H]-TdR) for an additional 18 hrs. CBT at a concentration of 280 micrograms/ml was non-toxic when solubilized with beta-CD. CBA at a concentration of 350 micrograms/ml was non-toxic when solubilized with beta-CD, but when solubilized with DMSO produced a 50% reduction in uptake of [3H]-TdR at a concentration of 75 micrograms/ml. CBPA, solubilized with beta-CD, was nontoxic at a concentration of 400 micrograms/ml, while CBTCN and CBACN at concentrations of 50 micrograms/ml and 40 micrograms/ml, respectively, were both toxic, even when solubilized with beta-CD. Nido CBA at a concentration of 400 micrograms/ml in medium was non-toxic. Although the toxicity of these boron compounds precludes their use as capture agents for Neutron Capture Therapy, they may have some potential for cytoreductive chemotherapy of cancer, and further evaluation may be warranted.

Amino Acids↗
PubMed1996

Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascular-mediated pathogenesis.

A histopathological study was carried out on the spinal cord of rats after boron neutron capture (BNC) irradiation. Rats were irradiated with thermal neutrons alone or in combination with borocaptate sodium (BSH) or p-boronophenylalanine (BPA). Spinal cords were examined 1 year after irradiation, or at earlier times in rats developing myelopathy. Considered overall, the pathology of the spinal cord after BNC irradiation was comparable with that reported previously after X irradiation of the spinal cord in the identical strain of rat. When BSH was used as the neutron capture agent, the biologically effective dose of radiation delivered to the CNS parenchyma was a factor of -2.7 lower than that delivered to the vascular endothelium. In effect, the blood vessels were selectively irradiated using this BNC modality. The resultant pathology was similar to that observed after irradiation with thermal neutrons alone or in the presence of BPA, situations in which the CNS vasculature was not selectively irradiated. This points to the vascular endothelium as being the critical target cell population, damage to which results in the development of the lesions seen in the spinal cord after BNC irradiation and, by inference, after irradiation with more conventional modalities.

Alpha Particles↗
PubMed1998

Structural evolution in boron nitrides during the hexagonal-cubic phase transition under high pressure at high temperature.

Structural evolution during the phase transition from h (hexagonal)- to c (cubic)-boron nitrides (BN) under high pressure (6.5-7.7 GPa) at high temperature (1,700-2,150 degrees C) was examined by using high-resolution transmission electron microscopy (HRTEM) and electron energy loss spectroscopy (EELS). At the initial stage of the evolution, some starting h-BN plates were strongly folded, while others were slightly bent. As a result, a strong texture was formed. HRTEM revealed that the interplanar distance between sp2 sheets became slightly shortened and they were slightly sheared to each other during the folding and bending. As a result, m (monoclinic)-BN was formed near the folding plane with lattice parameters; a = 0.433 nm, b = 0.250 nm, c = 0.32-0.33 nm, and beta = 90-92 degrees. In a succeeding stage, the value of beta increased to 92-95 degrees. c-BN grains appeared with nano-scale twins and sometimes partly included wurtzite-type BN. They started to grow with secondary twins at higher temperature. EELS analysis revealed that the band structure of sp2 sheets changed during the transition from h-BN to m-BN; the density of state for the pi* bond became prominently high in m-BN as compared to that in h-BN.

Animals↗