Yoshihide Hattori

Biological Evaluation of Dodecaborate-Containing l-Amino Acids for Boron Neutron Capture Therapy

To develop a boron carrier for practical purposes, new boron-containing amino acids with an undecahydro-closo-dodecaboranylthio ([(10)B(12)H(11)S](2-)-) unit in the side chain of the α-amino acid have already been designed and synthesized. In the present paper, cytotoxicity, the incorporation amounts into tumor cells, and the tumor cell killing effects of these compounds were elucidated to evaluate their usefulness as boron carriers. Furthermore, the microdistribution of the amino acids in tumor cells was established.

Synthesis of optically active dodecaborate-containing L-amino acids for BNCT.

A convenient and simple synthetic method of dodecaboratethio-L-amino acid, a new class of tumor-seeking boron carrier for BNCT, was accomplished from S-cyanoethylthioundecahydro-closo-dodecaborate (S-cyanoethyl-(10)BSH, [(10)B(12)H(11)](2-)SCH(2)CH(2)CN) and bromo-L-α-amino acids by nearly one step S-alkylation. An improved synthesis of S-cyanoethyl-(10)BSH, a key starting compound for S-alkylation, was also performed by Michael addition of (10)BSH with acryronitrile in high yield. Four kinds of new dodecaboratethio-L-amino acids were obtained in optically pure form without the need for any optical resolution.

Comparison of the pharmacokinetics between L-BPA and L-FBPA using the same administration dose and protocol: A validation study for the theranostic approach using [18F]-L-FBPA positron emission tomography in boron neutron capture therapy

BackgroundBoron neutron capture therapy (BNCT) is a cellular-level particle radiation therapy that combines the selective delivery of boron compounds to tumour tissue with neutron irradiation. L-p-Boronophenylalanine (L-BPA) is a boron compound now widely used in clinical situations. Determination of the boron distribution is required for successful BNCT prior to neutron irradiation. Thus, positron emission tomography with [18F]-L-FBPA, an 18F-labelled radiopharmaceutical analogue of L-BPA, was developed. However, several differences between L-BPA and [18F]-L-FBPA have been highlighted, including the different injection doses and administration protocols. The purpose of this study was to clarify the equivalence between L-BPA and [19F]-L-FBPA as alternatives to [18F]-L-FBPA.MethodsSCC-VII was subcutaneously inoculated into the legs of C3H/He mice. The same dose of L-BPA or [19F]-L-FBPA was subcutaneously injected. The time courses of the boron concentrations in blood, tumour tissue, and normal tissue were compared between the groups. Next, we administered the therapeutic dose of L-BPA or the same dose of [19F]-L-FBPA by continuous infusion and compared the effects of the administration protocol on boron accumulation in tissues.ResultsThere were no differences between L-BPA and [19F]-L-FBPA in the transition of boron concentrations in blood, tumour tissue, and normal tissue using the same administration protocol. However, the normal tissue to blood ratio of the boron concentrations in the continuous-infusion group was lower than that in the subcutaneous injection group.ConclusionsNo difference was noted in the time course of the boron concentrations in tumour tissue and normal tissues between L-BPA and [19F]-L-FBPA. However, the administration protocol had effects on the normal tissue to blood ratio of the boron concentration. In estimating the BNCT dose in normal tissue by positron emission tomography (PET), we should consider the possible overestimation of the normal tissue to blood ratio of the boron concentrations derived from the values measured by PET on dose calculation.

Synthesis and in vitro evaluation of thiododecaborated α, α- cycloalkylamino acids for the treatment of malignant brain tumors by boron neutron capture therapy

Boron-neutron capture therapy (BNCT) is an attractive technique for cancer treatment. As such, α, α-cycloalkyl amino acids containing thiododecaborate ([B12H11]2−-S-) units were designed and synthesized as novel boron delivery agents for BNCT. In the present study, new thiododecaborate α, α-cycloalkyl amino acids were synthesized, and biological evaluation of the boron compounds as boron carrier for BNCT was carried out.

Biological evaluation of fluorinated p-boronophenylalanine derivatives as a boron carrier.

Boron neutron capture therapy (BNCT) and magnetic resonance imaging (MRI) are quite attractive techniques for treatment and diagnosis of cancer, respectively. In order to develop practical materials utilizing both for BNCT and MRI, fluorinated p-boronophenylalanines and their alcohol derivatives had already been designed and synthesized. In the present paper the cytotoxicity, the incorporated amount into cancer cells, and the tumor cell killing effects of these compounds were elucidated to evaluate their usefulness as a boron carrier.

Evaluation of a novel sodium borocaptate-containing unnatural amino acid as a boron delivery agent for neutron capture therapy of the F98 rat glioma

BackgroundBoron neutron capture therapy (BNCT) is a unique particle radiation therapy based on the nuclear capture reactions in boron-10. We developed a novel boron-10 containing sodium borocaptate (BSH) derivative, 1-amino-3-fluorocyclobutane-1-carboxylic acid (ACBC)-BSH. ACBC is a tumor selective synthetic amino acid. The purpose of this study was to assess the biodistribution of ACBC-BSH and its therapeutic efficacy following Boron Neutron Capture Therapy (BNCT) of the F98 rat glioma.MethodsWe evaluated the biodistribution of three boron-10 compounds, ACBC-BSH, BSH and boronophenylalanine (BPA), in vitro and in vivo, following intravenous (i.v.) administration and intratumoral (i.t.) convection-enhanced delivery (CED) in F98 rat glioma bearing rats. For BNCT studies, rats were stratified into five groups: untreated controls, neutron-irradiation controls, BNCT with BPA/i.v., BNCT with ACBC-BSH/CED, and BNCT concomitantly using BPA/i.v. and ACBC-BSH/CED.ResultsIn vitro, ACBC-BSH attained higher cellular uptake F98 rat glioma cells compared with BSH. In vivo biodistribution studies following i.v. administration and i.t. CED of ACBC-BSH attained significantly higher boron concentrations than that of BSH, but much lower than that of BPA. However, following convection enhanced delivery (CED), ACBC-BSH attained significantly higher tumor concentrations than BPA. The i.t. boron-10 concentrations were almost equal between the ACBC-BSH/CED group and BPA/i.v. group of rats. The tumor/brain boron-10 concentration ratio was higher with ACBC-BSH/CED than that of BPA/i.v. group. Based on these data, BNCT studies were carried out in F98 glioma bearing rats using BPA/i.v. and ACBC-BSH/CED as the delivery agents. The corresponding mean survival times were 37.4 ± 2.6d and 44.3 ± 8.0d, respectively, and although modest, these differences were statistically significant.ConclusionsOur findings suggest that further studies are warranted to evaluate ACBC-BSH/CED as a boron delivery agent.

Development and Elucidation of a Novel Fluorescent Boron-Sensor for the Analysis of Boronic Acid-Containing Compounds

Novel boron-containing drugs have recently been suggested as a new class of pharmaceuticals. However, the majority of current boron-detection techniques require expensive facilities and/or tedious pretreatment methods. Thus, to develop a novel and convenient detection method for boron-based pharmaceuticals, imine-type boron-chelating-ligands were previously synthesized for use in a fluorescent sensor for boronic acid containing compounds. However, the fluorescence quantum yield of the imine-type sensor was particularly low, and the sensor was easily decomposed in aqueous media. Thus, in this paper, we report the development of a novel, convenient, and stable fluorescent boron-sensor based on O- and N-chelation (i.e., 2-(pyridine-2yl)phenol), and a corresponding method for the quantitative and qualitative detection of boronic acid-containing compounds using this commercially available sensor is presented.