Boron-containing nucleosides as tools for boron-neutron capture therapy

Despite the significant progress in cancer cure, the development of new approaches to cancer therapy is still of great importance since many deadly tumors remain untreatable. Boron neutron capture therapy (BNCT), proposed more than eighty years ago, is still considered a potentially advantageous approach. Irradiation of cells containing ¹⁰B isotopes with epithermal neutrons and the consequent decay of boron nuclei releases particles that deposit high energy along a very short path, inflicting heavy damage on the target cells but sparing the neighbouring tissue. Delivery and preferential accumulation of boron in cancer cells are the major obstacles that slow down the clinical use of BNCT. Since DNA damage caused by irradiation is the major reason for cell death, the incorporation of boron-containing nucleotides into the DNA of cancer cells may significantly increase the efficacy of BNCT. In this review, we discuss the current state of knowledge in the synthesis of boron-containing nucleosides and their application for BNCT with a special focus on their possible incorporation into genomic DNA.     

Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects

The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200 nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.     

45种食品中硼含量的测定及分析

目的测定常见食品中硼的含量,并分析食品中是否添加禁用防腐剂硼酸或硼砂。方法样品灰化后,用姜黄素分光光度法测定硼的含量。结果检测了3类45种样品中硼的含量,动物性食品硼含量范围0.26～0.75mg/kg;植物性食品硼含量范围较大0.31～21.83mg/kg;腌、炸类食品硼含量在0.61～5.29mg/kg之间。结论 45种食品均含有一定的硼,其中黄豆、葡萄干、绿豆等食品中硼含量较高,动物性食品硼含量较低。     

A histomorphometric study of alveolar bone modelling and remodelling in mice fed a boron-deficient diet

OBJECTIVE: Emerging evidence indicates that boron (B) plays a role in bone formation and maintenance. Thus, a study was performed to determine whether dietary B-deficiency affects periodontal alveolar bone modelling and remodelling. DESIGN: Weanling Swiss mice (n=30) were divided into three groups: control diet (GI, 3mg B/kg); B-deficient diet (GII, 0.07 mg B/kg); and pair-fed with GII (GIII). The animals were maintained on their respective diets for 9 weeks and then sacrificed. The guidelines of the NIH for the care and use of laboratory animals were observed. The mandibles were resected, fixed, decalcified in 10% EDTA and embedded in paraffin. Buccolingually oriented sections were obtained at the level of the mesial root of the first lower molar and stained with H-E. Histomorphometric studies were performed separately on the buccal and lingual sides of the periodontal alveolar bone. Percentages of osteoblast surfaces (ObSs), eroded surfaces (ESs), and quiescent surfaces (QSs) were determined. RESULTS: No statistically significant differences in food intake and body weight were observed between the groups. When compared with GI and GIII mice, GII mice (B-deficient) had 63% and 48% reductions in ObS and 58% and 73% increases in QS in buccal and lingual plates, respectively. ES were not affected by B nutriture. CONCLUSION: The results are evidence that dietary boron deprivation in mice alters periodontal alveolar bone modelling and remodelling by inhibiting bone formation.     

Induced radioactivity in the blood of cancer patients following Boron Neutron Capture Therapy

Since 1990, Boron Neutron Capture Therapy (BNCT) has been used for over 400 cancer patients at the Kyoto University Research Reactor Institute (KURRI). After BNCT, the patients are radioactive and their ²⁴Na and ³⁸Cl levels can be detected via a Na-I scintillation counter. This activity is predominantly due to ²⁴Na, which has a half-life of 14.96 h and thus remains in the body for extended time periods. Radioactive ²⁴Na is mainly generated from ²³Na in the target tissue that is exposed to the neutron beam in BNCT. The purpose of this study is to evaluate the relationship between the radioactivity of blood ²⁴Na following BNCT and the absorbed gamma ray dose in the irradiated field. To assess blood ²⁴Na, 1 ml of peripheral blood was collected from 30 patients immediately after the exposure, and the radioactivity of blood ²⁴Na was determined using a germanium counter. The activity of ²⁴Na in the blood correlated with the absorbed gamma ray doses in the irradiated field. For the same absorbed gamma ray dose in the irradiated field, the activity of blood ²⁴Na was higher in patients with neck or lung tumors than in patients with brain or skin tumors. The reasons for these findings are not readily apparent, but the difference in the blood volume and the ratio of bone to soft tissue in the irradiated field, as well as the dose that leaked through the clinical collimator, may be responsible.     

Biodistribution of a carborane-containing porphyrin as a targeting agent for Boron Neutron Capture Therapy of oral cancer in the hamster cheek pouch

Boron Neutron Capture Therapy (BNCT) is a bimodal cancer treatment based on the selective accumulation of 10B in tumors and concurrent irradiation with thermalized neutrons. The short-range, high-LET radiation produced by the capture of neutrons by 10B could potentially control tumor while sparing normal tissue if the boron compound targets tumor selectively within the treatment volume. In previous studies, we proposed and validated the hamster cheek pouch model of oral cancer for BNCT studies, proved that absolute and relative uptake of the clinically employed boron compound boronophenylalanine (BPA) would be potentially therapeutic in this model and provided evidence of the efficacy of in vivo BPA-mediated BNCT to control hamster oral mucosa tumors with virtually no damage to normal tissue. We herein present the biodistribution and pharmacokinetics of a lipophilic, carborane-containing tetraphenylporphyrin (CuTCPH) in the hamster oral cancer model. CuTCPH is a novel, non-toxic compound that may be advantageous in terms of selective and absolute delivery of boron to tumor tissues. For potentially effective BNCT, tumor boron concentrations from a new agent should be greater than 30 ppm and tumor/blood and tumor/normal tissue boron concentration ratios should be greater than 5/1 without causing significant toxicity. We administered CuTCPH intraperitoneally (i.p.) as a single dose of 32 microg/g body weight (b.w.) (10 microg B/g b.w.) or as four doses of 32 microg/g b.w. over 2 days. Blood (Bl) and tissues were sampled at 3, 6, 12, 24, 48, and 72 h in the single-dose protocol and at 1-4 days after the last injection in the multidose protocol. The tissues sampled were tumor (T), precancerous tissue surrounding tumor, normal pouch (N), skin, tongue, cheek and palate mucosa, liver, spleen, parotid gland and brain. The maximum mean B ratios for the single-dose protocol were T/N: 9.2/1 (12h) and T/Bl: 18.1/1 (72 h). The B value peaked to 20.7+/-18.5 ppm in tumor at 24h. The multidose protocol maximum mean ratios were T/N: 11.9/1 (3 days) and T/Bl: 235/1 (4 days). Absolute boron concentration in tumor reached a maximum value of 116 ppm and a mean value of 71.5+/-48.3 ppm at 3 days. The fact that absolute and relative B values markedly exceeded the BNCT therapeutic threshold with no apparent toxicity may confer on this compound a therapeutic advantage. CuTCPH-mediated BNCT would be potentially useful for the treatment of oral cancer in an experimental model.     

Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography

It is important to measure the microdistribution of ¹⁰B in a cell to predict the cell-killing effect of new boron compounds in the field of boron neutron capture therapy. Alpha autoradiography has generally been used to detect the microdistribution of ¹⁰B in a cell. Although it has been performed using a reactor-based neutron source, the realization of an accelerator-based thermal neutron irradiation field is anticipated because of its easy installation at any location and stable operation. Therefore, we propose a method using a cyclotron-based epithermal neutron source in combination with a water phantom to produce a thermal neutron irradiation field for alpha autoradiography. This system can supply a uniform thermal neutron field with an intensity of 1.7×10⁹ (cm⁻² s⁻¹) and an area of 40 mm in diameter. In this paper, we give an overview of our proposed system and describe a demonstration test using a mouse liver sample injected with 500 mg/kg of boronophenyl-alanine.     

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.