Pilot clinical study of boron neutron capture therapy for recurrent hepatic cancer involving the intra-arterial injection of a 10BSH-containing WOW emulsion

A 63-year-old man with multiple HCC in his left liver lobe was enrolled as the first patient in a pilot study of boron neutron capture therapy (BNCT) involving the selective intra-arterial infusion of a ¹⁰BSH-containing water-in-oil-in-water emulsion (¹⁰BSH-WOW). The size of the tumorous region remained stable during the 3 months after the BNCT. No adverse effects of the BNCT were observed. The present results show that ¹⁰BSH-WOW can be used as novel intra-arterial boron carriers during BNCT for HCC.     

Boron concentration measurements by alpha spectrometry and quantitative neutron autoradiography in cells and tissues treated with different boronated formulations and administration protocols

The possibility to measure boron concentration with high precision in tissues that will be irradiated represents a fundamental step for a safe and effective BNCT treatment. In Pavia, two techniques have been used for this purpose, a quantitative method based on charged particles spectrometry and a boron biodistribution imaging based on neutron autoradiography. A quantitative method to determine boron concentration by neutron autoradiography has been recently set-up and calibrated for the measurement of biological samples, both solid and liquid, in the frame of the feasibility study of BNCT. This technique was calibrated and the obtained results were cross checked with those of α spectrometry, in order to validate them. The comparisons were performed using tissues taken form animals treated with different boron administration protocols. Subsequently the quantitative neutron autoradiography was employed to measure osteosarcoma cell samples treated with BPA and with new boronated formulations.     

Intracellular boron accumulation in CHO-K1 cells using amino acid transport control

BPA used in BNCT has a similar structure to some essential amino acids and is transported into tumor cells by amino acid transport systems. Previous study groups have tried various techniques of loading BPA to increase intracellular boron concentration. CHO-K1 cells demonstrate system L (LAT1) activity and are suitable for specifying the transport system of a neutral amino acid. In this study, we examined the intracellular accumulation of boron in CHO-K1 cells by amino acid transport control, which involves co-loading with L-type amino acid esters. Intracellular boron accumulation in CHO-K1 cells showed the greatest increased upon co-loading 1.0 mM BPA, with 1.0 mM l-Tyr-O-Et and incubating for 60 min. This increase is caused by activation of a system L amino acid exchanger between BPA and l-Tyr. The amino acid esters are metabolized to amino acids by intracellular hydrolytic enzymes that increase the concentrations of intracellular amino acids and stimulate exchange transportation. We expect that this amino acid transport control will be useful for enhancing intracellular boron accumulation.     

Boron’s neurophysiological effects and tumoricidal activity on glioblastoma cells with implications for clinical treatment

Abstract

Purpose: To define the actions of boron on normal neurophysiology and glioblastoma growth.

Materials and Methods: PubMed and other relevant databases were searched.

Results: Discovery of novel boron compounds in treatment of glioblastoma is being actively investigated, but the majority of such studies is focused on the synthesis of boron compounds as sensitizers to Boron Neutron Capture Therapy (BNCT). Nonetheless, the translational functionality of boron compounds is not limited to BNCT as many boron compounds possess direct tumoricidal activity and there is substantial evidence that certain boron compounds can cross the blood-brain barrier. Moreover, boron-containing compounds interfere with several tumorigenic pathways including intratumoral IGF-I levels, molybdenum Fe–S containing flavin hydroxylases, glycolysis, Transient Receptor Potential (TRP) and Store Operated Calcium Entry (SOCE) channels.

Conclusions: Boron compounds deserve to be studied further in treatment of systemic cancers and glioblastoma due to their versatile antineoplastic functions.     

Boron distribution in the normal rat brain after intravenous injection of boronophenylalanine-fructose

Boron neutron capture therapy (BNCT) is an experimental form of radiation therapy for malignant brain tumors and peripheral melanoma. The micro-distribution of the boron compound is critical to determine the radiation effects for both tumors and normal tissue. In the current dose calculation of BNCT, normal brain tissue is considered to have a homogeneous boron concentration. The purpose of this study was to examine the structure-specific boron concentration in normal rat neural tissue. At 10, 30 and 60 min after intravenous injection of 300 mg/kg boronophenylalanine-fructose to 10-week-old CD Fisher rats, neural tissue and blood were collected. Various neural structures were anatomically and histologically identified and specific boron concentrations were analyzed using high-resolution quantitative autoradiography. At 60 min after the injection, only the pituitary gland showed a higher boron concentration than that in blood, with the former being threefold higher. All other neural structures showed lower boron concentrations than that in blood. The present study thus demonstrated an extremely high boron concentration in the pituitary gland following intravenous injection of boronophenylalanine-fructose. In clinical trials of BNCT using an epithermal neutron beam, the radiation dose to the pituitary gland should be carefully evaluated.     

次氯酸钠窦腔滴注液的制备及其稳定性研究

目的对次氯酸钠窦腔滴注液的制备及其稳定性进行研究,拓宽次氯酸钠的用途,为临床提供新制剂.方法制备采取先配成2.5%次氯酸钠溶液和7.5%磷酸二氢钠溶液,临用时将上述两液各10ml加至0.9%氯化钠注射液500ml中作窦腔滴注,稳定性采用留样观察法.结果2.5%次氯酸钠液,pH=13时,t09为170d,加入氮化硼作为稳定剂,t0.9为306d,0.05%次氯酸钠窦腔滴注液,pH=7.2,含氮化硼0.015μg@ml-1时有效期为18d,临床试用疗效满意.结论次氯酸钠窦腔滴注液可作为治疗鼻窦炎常规制剂应用,其在碱性(pH=13)环境下稳定,加入氮化硼后稳定性显著增高.     

Boronated Metalloporphyrins: A novel approach to the diagnosis and treatment of cancer using contrast-enhanced MR imaging and neutron capture therapy

Porphyrins are a unique class of metal chelating agents that have shown specific affinity for neoplasms. The water-soluble free-base derivative, tetrakiscarborane carboxylate ester of 2,4-(α,β-dihydroxyethyl) deuteroporphyrin IX (BOPP), an agent designed for neutron capture therapy, has previously demonstrated selective localization and retention in a C6 murine glioma. In the present work, the authors demonstrate that the manganese chelate of BOPP also selectively localizes in a rat 9L gliosarcoma and preferentially enhances the tumor-normal brain contrast of T1-weighted images for at least 92 hours. The data indicate a maximal enhancement of contrast between tumor and normal brain at 24 hours after injection, compared with 5 minutes for manganese (III) tetraphenylporphine sulfonate (TPPS₄). The results also indicate that Mn-BOPP may have a slower uptake in the 9L glioma than Mn-TPPS₄ but a longer retention in the tumor. Mn-BOPP is unique in that it represents, to the authors' knowledge, the first example of a single agent that can enhance contrast between tumor and normal tissue and be potentially effective as an agent for boron neutron capture therapy.     

Comparison of cardioprotective effects of labeled and unlabeled oleanoic acids with new BOPIM dye on primary neonatal rat cardiomyocytes following hypoxia/reoxygenation injury

BackgroundIt is well known that fluorescent labeling has recently become a major research tool in molecular and cellular biology for demonstrating therapeutic mechanisms and metabolic pathways. However, few studies have reported the use of fluorescent labeling of natural products.MethodsWe recently explored the boron 2-(2′-pyridyl) imidazole (BOPIM) derivative analogs, which are highly fluorescent, non-aggregated, and nontoxic. In the present study, the natural product oleanolic acid (OA) was functionalized and labeled with BOPIM, thus yielding a highly fluorescent probe, the comparison of cardioprotective effects of labeled and unlabeled OAs with BOPIM on primary neonatal rat cardiomyocytes with hypoxia/reoxygenation (H/R) injury were investigated.ResultsPretreatment with OA and BOPIM-OA significantly prevented the H/R induced cell death in primary neonatal rat cardiomyocytes. However, BOPIM exhibited no improvements on the H/R injury cardiomyocytes, and which were similar to those of the H/R group. The results of comparison of cardioprotective effects between labeled and unlabeled OAs with BOPIM showed that introducing the BOPIM chromophore did not make a difference with H/R injury cardiomyocytes.ConclusionBOPIM chromophore is a suitable probe for investigating the pharmacological mechanisms of natural products.     

Boron neutron capture therapy as a novel modality of radiotherapy for oral cancer: Principle and antitumor effect

Radiotherapy is essential for the treatment of oral cancer, especially in advanced cases. There has been marked progress in this field due to the prevalence of intensity-modified radiation therapy and introduction of particle radiotherapy using protons and carbon-ions. However, these treatments are still non-selective. Boron neutron capture therapy (BNCT) is a unique modality in which neutron beams destroy only boron compound-bearing tumor cells while leaving the surrounding normal tissues intact. Thus, BNCT is a selective form of radiotherapy, if high tumor/normal tissue ratio in boron concentration could be achieved. The principle of BNCT, and the basic study of the mechanism by which BNCT exerts antitumor effects using oral squamous cell carcinoma (SCC) cells and oral SCC xenografts in mice are described.     

硼中子俘获疗法治疗小鼠颅内G422胶质细胞瘤

目的探讨硼中子俘获疗法（BNCT）治疗G422胶质细胞瘤的效果。方法建立小鼠颅内G422胶质细胞瘤模型，以ICP—AES法测定荷瘤小鼠不同组织中的10^B浓度。将荷瘤小鼠随机分为未照射组（0Gy）、γ射线对照组（5、10Gy）、反应堆组（5、10Gy）、BNCT组（5、10Gy）。采用生存时间的中位数、平均生存时间、生存时间延长率作为评价指标，观察各组的治疗效果。结果荷瘤小鼠腹腔注射对二羟苯丙氨酸硼溶液后1．5h，瘤组织内的10^B浓度达到峰值[（43．78±3．02）μg/g]。BNCT5、10Gy照射后，移植G422胶质细胞瘤小鼠的生存时间延长率分别为235％（233％）、329％（342％）。BNCT5Gy组的生存率与未照射组、γ射线5Gy组和反应堆5Gy组相比差异有统计学意义（P〈0．05）。BNCT10Gy组的生存率与未照射组、γ射线5Gy组、γ射线10Gy组、反应堆5Gy组、反应堆10Gy组、BNCT5Gy组相比差异有统计学意义（P〈0．05）。结论BNCT可以显著提高荷G422胶质细胞瘤小鼠的生存率，并具有剂量依赖性的特点；同时BNCT具有较高的相对生物学效应，优于同剂量γ射线的治疗效果。