Biological evaluation of dopamine analogues containing phenylboronic acid group as new boron carriers

As new BNCT reagents, we designed and synthesized dopamine analogues containing phenylboronic acid group, N-3,4-dihydroxyphenethyl-4-dihydroxyborylbenzamide (dopamine–PCBA) and N-[2-(3,4-dihydroxyphenetyl)ethyl]-3-(4-dihydroxyborylphenyl)promionamide (dopamine–CEBA). The efficacies of these compounds have not been investigated for biological samples. Therefore we have carried out experiments with cultured tumor cells and tumor-bearing mice, and evaluated possibility of these compounds as boron carriers. Dopamine–PCBA and dopamine–CEBA were synthesized by coupling between p-carboxyphenylboronic acid (PCBA) or 4-(2-carboxyethyl)benzeneboronic acid (CEBA) and 3,4-(dibenzyloxy)phenethylamine hydrochloride (DBPA-HCl) followed by catalytic hydrogenation using Pd catalyst. The effect of compounds on cell vitality was determined by MTT assay in various cells. In vivo biodistribution of compounds was determined in Balb/c and DDY mice in bearing implanted CT26 cells. These results have demonstrated that dopamine–CEBA was less toxic.     

Development of a prompt gamma neutron activation analysis facility for B concentration measurements at RA-3: Design stage

A PGNAA facility is being developed for ¹⁰B concentration measurements at RA-3 reactor. Its design targets detection limits better than tenths of a microgram and irradiation times on the order of minutes. Computational models were developed, which estimated thermal neutron fluxes in irradiation position to be larger than 10⁹ n cm⁻² s⁻¹. Calculated amounts of photons and fast neutrons make necessary for filter/moderator arrangements. An irradiation device was designed and numerically tested, which is being built and is to be used for performing characterizing measurements.     

Susceptibility to radiation-induced leukaemia/lymphoma is genetically separable from sensitivity to radiation-induced genomic instability

Purpose : To determine whether there is a relationship between the genetics underlying the susceptibility to radiation-induced leukaemia in CBA/H (acute myeloid leukaemia, AML) and C57BL/6 (thymic lymphoma, TL) mice, and the genetics underlying the sensitivity of CBA/H (sensitive) and C57BL/6 (resistant) mice to radiation-induced chromosomal instability. Materials and methods : CBA/H, (CBA/H ×C57BL/6)F 1, F 1 ×CBA/H, F 1 ×C57BL/6 and F 1 ×F 1 mice were exposed to a single acute dose of 3.0 Gy X-rays. AML and TL were diagnosed over the subsequent 30 months. Results : There was no statistically significant difference in the incidence of AML in F 1, F 1 ×F 1, F 1 ×CBA/H and F 1 ×C57BL/6 mice, which was ~50% that in CBA/H mice. AML susceptibility is therefore a dominant polygenic trait, and both susceptibility and resistance (variable penetrance) CBA/H and C57BL/6 loci are involved. The incidence of TL in the F 1 and F 1 ×CBA/H mice was negligible, indicating that TL susceptibility is a recessive trait. As the TL incidence in the F 1 ×C57BL/6 mice was about half that in C57BL/6 mice, one recessive locus is probably involved. Conclusions : AML susceptibility in CBA/H mice is a dominant trait in contrast to the recessive inheritance of CBA/H sensitivity to radiation-induced chromosomal instability. TL-susceptibility in C57BL/6 is a recessive trait in contrast to the dominant inheritance of C57BL/6 resistance to radiation-induced chromosomal instability.     

Pharmacokinetics of Na2B12H11SH (BSH) in patients with malignant brain tumours as prerequisite for a phase I clinical trial of boron neutron capture

Summary The disposition of Na₂B₁₂H₁₁SH (BSH) in patients with malignant glioma has been investigated, in preparation for a Phase I clinical trial of boron neutron capture therapy. BSH was found to possess a linear disposition over the dosage interval investigated (up to 75 mg/kg). A bi-phasic blood pharmacokinetics was observed. Tumour-to-blood ratios showed variations between patients between 0.08 and 5.1. The data allow the definition of amount of BSH and timing of infusion for a Phase I clinical trial protocol.     

树枝状高分子在生物医学领域的应用研究进展

树枝状大分子 (dendrim ers)是近年来出现的一类新型合成高分子 ,具有高度支化、结构规整、单分散等特性。这些特点使其在许多领域有潜在的重要应用价值 ,成为相关领域的研究热点。本文介绍了树枝状大分子的基本结构和合成路线 ,并对近年来国际上关于树枝状大分子在药物运载、DNA传递、特殊造影剂、肿瘤治疗新技术等生物医学领域的研究及应用探索进行了综述。     

Boron’s journey: advances in the study and application of pharmacokinetics

Introduction: Boron-containing compounds (BCCs) are attractive chemical entities in drug development. Some of these compounds have been used in the treatment of human disease, and studies on their pharmacodynamics suggest that they employ multiple forms of activity. However, less is known about the pharmacokinetic profile of these molecules.

Areas covered: The herein compiled reported data is presented in accordance with the classical ‘ADME’ system for identifying the scope of BCCs in the respective fields. Our analysis suggests that these compounds have several distinct ways to move within the human body, and that the specific structural features of each molecule account for its distinct pharmacokinetic profile. These insights should be useful for designing BCCs with a desired effect.

Expert opinion: Increasing knowledge about the pharmacokinetics of BCCs is providing a broader understanding about the design of new release systems and potential drugs, as well as probable protein transporters that could be related to key roles in physiological processes. These transporters may be involved in sodium transport, hormone release and regulation of the cell cycle. The shared features among groups of BCCs are being identified in order to apply these insights to the design of advantageous compounds.     

Acute in vitro and in vivo toxicity of a commercial grade boron nitride nanotube mixture

Boron nitride nanotubes (BNNTs) are an emerging engineered nanomaterial attracting significant attention due to superior electrical, chemical and thermal properties. Currently, the toxicity profile of this material is largely unknown. Commercial grade BNNTs are composed of a mixture (BNNT-M) of ～50–60% BNNTs, and ～40–50% impurities of boron and hexagonal boron nitride. We performed acute in vitro and in vivo studies with commercial grade BNNT-M, dispersed by sonication in vehicle, in comparison to the extensively studied multiwalled carbon nanotube-7 (MWCNT-7). THP-1 wild-type and NLRP3-deficient human monocytic cells were exposed to 0–100?µg/ml and C57BL/6?J male mice were treated with 40?µg of BNNT-M for in vitro and in vivo studies, respectively. In vitro, BNNT-M induced a dose-dependent increase in cytotoxicity and oxidative stress. This was confirmed in vivo following acute exposure increase in bronchoalveolar lavage levels of lactate dehydrogenase, pulmonary polymorphonuclear cell influx, loss in mitochondrial membrane potential and augmented levels of 4-hydroxynonenal. Uptake of this material caused lysosomal destabilization, pyroptosis and inflammasome activation, corroborated by an increase in cathepsin B, caspase 1, increased protein levels of IL-1β and IL-18 both in vitro and in vivo. Attenuation of these effects in NLRP3-deficient THP-1 cells confirmed NLRP3-dependent inflammasome activation by BNNT-M. BNNT-M induced a similar profile of inflammatory pulmonary protein production when compared to MWCNT-7. Functionally, pretreatment with BNNT-M caused suppression in bacterial uptake by THP-1 cells, an effect that was mirrored in challenged alveolar macrophages collected from exposed mice and attenuated with NLRP3 deficiency. Analysis of cytokines secreted by LPS-challenged alveolar macrophages collected after in vivo exposure to dispersions of BNNT-M showed a differential macrophage response. The observed results demonstrated acute inflammation and toxicity in vitro and in vivo following exposure to sonicated BNNT-M was in part due to NLRP3 inflammasome activation.     

面食中硼的测定

采用添加碳酸锂来固定样品中的硼,高温灰化去除有机物,提高样品的灰化温度,用ICP-AES对样品进行快速检测,提高了检测速度和精度。     

硼作业工人精子质量的初步分析

目的研究硼暴露对男性精子质量的影响。方法于2002年在辽宁省某硼矿区及硼加工厂选择硼暴露组(60人)和对照组(9人)男性研究对象,进行体格检查和精液分析。精液分析使用综合光学可视精子分析仪和光学生物显微镜。结果对照组的精子密度、精子前向运动百分率、a级精子完全符合WHO标准,而暴露组各项指标均有不符合WHO标准的样本,高达44.8%的样本精子前向运动百分率低于WHO标准(≥50%)。暴露组和对照组的精子存活率、精子前向运动百分率、a级精子、精子的曲线运动速度和直线运动速度差异有统计学意义(P<0.01),并且暴露组精子各项指标的均值除精子密度外均低于对照组。结论硼暴露的工人精子质量有所下降。     

Translational boron neutron capture therapy (BNCT) studies for the treatment of tumors in lung

Abstract

Purpose: Boron neutron capture therapy (BNCT) combines selective accumulation of ¹⁰B carriers in tumor tissue with subsequent neutron irradiation. BNCT has been proposed for the treatment of multiple, non-resectable, diffuse tumors in lung. The aim of the present study was to evaluate the therapeutic efficacy and toxicity of BNCT in an experimental model of lung metastases of colon carcinoma in BDIX rats and perform complementary survival studies.

Materials and methods: We evaluated tumor control and toxicity in lung 2?weeks post-BNCT at 2 dose levels, including 5 experimental groups per dose level: T0 (euthanized pre-treatment), Boronophenylalanine-BNCT (BPA-BNCT), BPA?+?Sodium decahydrodecaborate-BNCT ((BPA?+?GB-10)-BNCT), Beam only (BO) and Sham (no treatment, same manipulation). Tumor response was assessed employing macroscopic and microscopic end-points. An additional experiment was performed to evaluate survival and oxygen saturation in blood.

Results and conclusions: No dose-limiting signs of short/medium-term toxicity were observed in lung. All end-points revealed statistically significant BNCT-induced tumor control vs Sham at both dose levels. The survival experiment showed a statistically significant 45% increase in post-treatment survival time in the BNCT group (48?days) versus Sham (33?days). These data consistently revealed growth suppression of lung metastases by BNCT with no manifest lung toxicity.

• Highlights

• Boron Neutron Capture Therapy suppresses growth of experimental lung metastases

• No BNCT-induced short/medium-term toxicity in lung is associated with tumor control

• Boron Neutron Capture Therapy increased post-treatment survival time by 45%