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The toxicity and binding of the three new carborane based compounds: 2 (1,2-dicarba-closo-dodecaborane (12)-1(-yl-methoxy)-2-(3-amino-propyl))-1,3-propanediol, called DAC-1; 7-(3-amino-propyl)-7,8-dicarba-nido-undecarborate (-1) called ANC-1; and rac-1-(9-o-carboranyl)-nonyl-2-methyl-glycero-3- phosphocholine, called B-Et-11-OMe, were analyzed with cultured human glioma cells, U-343MGa, and mouse melanoma cells, B16, as biological models. The previously developed compound di-sodium undecahydro-mercapto-closo-dodecarborate (BSH), which is tested for therapy of malignant gliomas, was analyzed for comparison. In the toxicity tests the cells were exposed to the substances at cell culture medium concentrations in the range 0-50 ppm boron for 1 or 20 h and thereafter analyzed regarding growth. Growth-disturbing effects were seen for the two compounds DAC-1 and B-Et-11-OMe at the concentrations corresponding to 15 and 50 ppm boron, respectively. The compounds ANC-1 and BSH showed no growth-disturbing effects at the tested concentrations. In the binding tests, the cells were incubated for 20 h at about the highest compound concentrations that did not cause growth disturbances. The boron content in the cells was then determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES) and in some cases ICP-mass spectrometry (ICP-MS). The most extensive binding was seen for DAC-1 and B-Et-11-OMe, which accumulated boron to about 100 and 60 times, respectively, compared with the concentration in the culture medium. The compound ANC-1 also accumulated boron in the cells but the boron could be easily washed out indicating no or only a weak binding. BSH did not accumulate. Further analysis should be made regarding biological properties such as intracellular compartmentalization, metabolic interference and tumor specificity of the compounds DAC-1 and B-Et-11-OMe.
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PMID:New carborane-based compounds for boron neutron capture therapy: binding and toxicity of ANC-1, DAC-1 and B-Et-11-OMe in cultured human glioma and mouse melanoma cells. 818 29

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.
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PMID:Preparation of sulfhydrylborane-dextran conjugates for boron neutron capture therapy. 830 28

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.
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PMID: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. 1637 82

New anti-cancer therapy with boron neutron capture therapy (BNCT) is based on the nuclear reaction of boron-10 with neutron irradiation. The median survival of BNCT patients with glioblastoma was almost twice as long as those receiving standard therapy in a Japanese BNCT clinical trial. In this clinical trial, two boron compounds, BPA (boronophenylalanine) and BSH (sodium borocaptate), were used for BNCT. BPA is taken up into cells through amino acid transporters that are expressed highly in almost all malignant cells, but BSH cannot pass through the cell membrane and remains outside the cell. We simulated the energy transfer against the nucleus at different locations of boron from outside the cell to the nuclear region with neutron irradiation and concluded that there was a marked difference between inside and outside the cell in boron localization. To overcome this disadvantage of BSH in BNCT, we used a cell-penetrating peptide system for transduction of BSH. CPP (cell-membrane penetrating peptide) is very common peptide domains that transduce many physiologically active substances into cells in vitro and in vivo. BSH-fused CPPs can penetrate the cell membrane and localize inside a cell. To increase the boron ratio in one BSH-peptide molecule, 8BSH fused to 11R with a dendritic lysine structure was synthesized and administrated to malignant glioma cells and a brain tumor mouse model. 8BSH-11R localized at the cell nucleus and showed a very high boron value in ICP results. With neutron irradiation, the 8BSH-11R administrated group showed a significant cancer killing effect compared to the 100 times higher concentration of BSH-administrated group. We concluded that BSH-fused CPPs were one of the most improved and potential boron compounds in the next-stage BNCT trial and 8BSH-11R may be applied in the clinical setting.
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PMID:The acceleration of boron neutron capture therapy using multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating peptide. 2445 95