Changed delivery of boron to tumours using electroporation for boron neutron capture therapy with BSH

For effective boron neutron capture therapy (BNCT) it is important that a sufficient concentration of boron (10B) is present in the tumour during irradiation. This requirement represents a specific problem. The aim of this study was to test whether electroporation can be used as a non-specific drug delivery system to increase the delivery of sodium borocaptate-10B (BSH) into MCF7 (breast carcinoma) and B16F1 (melanoma) tumour cells in vitro and in B16F1 tumours in vivo. For the in vitro determination of 10B uptake, the cells were incubated in medium containing BSH and exposed to electric pulses. Boron levels were determined by inductively coupled plasma atomic emission spectrometry. In vivo, tumours were exposed to electric pulses 3 min after intravenous BSH injection. At different times after exposure the 10B concentration was determined in tumours and in blood. A difference in the 10B accumulation in the two cell lines was observed after continuous incubation of cells with BSH. No accumulation of 10B was observed in MCF7 cells, whereas in B16F1 cells, 10B accumulated well and reached a plateau within 30 min. Electroporation of these cells resulted in an accumulation of 10B into MCF7 cells up to the level of 10B in B16F1 cells. In vivo, the application of electric pulses increased and prolonged the entrapment of 10B (BSH) in the B16F1 melanoma tumours. A sufficient concentration of 10B was present in the tumour exposed to electric pulses for up to 24 h. Boron was quickly washed out from the blood and the level was below the concentrations in the tumours exposed to electric pulses at 2 h. The results of this study show that electroporation may provide a tool to increase boron concentration in the cells that have impaired transport of BSH through the plasma membrane. Furthermore, prolonged entrapment of BSH in tumours in vivo may, in addition to electroporation, be caused by the modifying effect of electric pulses on blood flow.     

Treatment results of boron neutron capture therapy using intra-arterial administration of boron compounds for recurrent head and neck cancer

The effect of boron neutron capture therapy (BNCT) is correlated with the density of boron in the tumour. BNCT using intra-arterial administration of boron compounds was performed for recurrent head and neck cancer. Of the five patients treated, one achieved a complete response and four achieved a partial response. There was one case of transient headache but no severe adverse effects were observed. The advantages of using an intra-arterial administration route for BNCT, which causes the selective killing of tumour cells, might offer a new option in the treatment of recurrent head and neck malignancies. These promising results require further verification and optimization of the BNCT schedule; however, dose escalation would appear to be justified because the toxicity appears to be very low.     

Synthesis of conjugates of polyhedral boron compounds with tumor-seeking molecules for neutron capture therapy

Recent achievements in design and synthesis of boronated acids, amino acids, glycerols as well as conjugates of polyhedral boron hydrides (ortho-carborane, closo-dodecaborate and cobalt bis(dicarbollide)) with natural porphyrins, carbohydrates and nucleosides are described.     

Tolerance of normal human brain to boron neutron capture therapy.

Data from the Harvard-MIT and the BNL Phase I and Phase I/II clinical trials, conducted between 1994 and 1999, have been analyzed and combined, providing the most complete data set yet available on the tolerance of the normal human brain to BPA-mediated boron neutron capture therapy. Both peak (1cm(3)) dose and average whole-brain dose show a steep dose-response relationship using somnolence syndrome as the clinical endpoint. Probit analysis indicates that the doses associated with a 50% incidence for somnolence (ED(50)+/-SE) were 6.2+/-1.0 Gy(w) for average whole-brain dose and 14.1+/-1.8 Gy(w) for peak brain dose.     

Development of real-time thermal neutron monitor using boron-loaded plastic scintillator with optical fiber for boron neutron capture therapy.

A new thermal neutron monitor for boron neutron capture therapy was developed in this study. We called this monitor equipped boron-loaded plastic scintillator that uses optical fiber for signal transmission as an [scintillator with optical fiber] SOF detector. A water phantom experiment was performed to verify how the SOF detector compared with conventional method of measuring thermal neutron fluence. Measurements with a single SOF detector yielded indistinguishable signals for thermal neutrons and gamma rays. To account for the gamma ray contribution in the signal recorded by the SOF detector, a paired SOF detector system was employed. This was composed of an SOF detector with boron-loaded scintillator and an SOF detector with a boron-free scintillator. The difference between the recorded counts of these paired SOF detectors was used as the measure of the gamma ray contribution in the measured neutron fluence. The paired SOF detectors were ascertained to be effective in measuring thermal neutron flux in the range above 10(6)(n/cm(2)/s). Clinical trials using paired SOF to measure thermal neutron flux during therapy confirmed that paired SOF detectors were effective as a real-time thermal neutron flux monitor.     

Radiation injury of boron neutron capture therapy using mixed epithermal- and thermal neutron beams in patients with malignant glioma.

The purpose of this study was to clarify the radiation injury in acute or delayed stage after boron neutron capture therapy (BNCT) using mixed epithermal- and thermal neutron beams in patients with malignant glioma. Eighteen patients with malignant glioma underwent mixed epithermal- and thermal neutron beam and sodium borocaptate between 1998 and 2004. The radiation dose (i.e. physical dose of boron n-alpha reaction) in the protocol used between 1998 and 2000 (Protocol A, n = 8) prescribed a maximum tumor volume dose of 15 Gy. In 2001, a new dose-escalated protocol was introduced (Protocol B, n = 4); it prescribes a minimum tumor volume dose of 18 Gy or, alternatively, a minimum target volume dose of 15 Gy. Since 2002, the radiation dose was reduced to 80-90% dose of Protocol B because of acute radiation injury. A new Protocol was applied to 6 glioblastoma patients (Protocol C, n = 6). The average values of the maximum vascular dose of brain surface in Protocol A, B and C were 11.4+/-4.2 Gy, 15.7+/-1.2 and 13.9+/-3.6 Gy, respectively. Acute radiation injury such as a generalized convulsion within 1 week after BNCT was recognized in three patients of Protocol B. Delayed radiation injury such as a neurological deterioration appeared 3-6 months after BNCT, and it was recognized in 1 patient in Protocol A, 5 patients in Protocol B. According to acute radiation injury, the maximum vascular dose was 15.8+/-1.3 Gy in positive and was 12.6+/-4.3 Gy in negative. There was no significant difference between them. According to the delayed radiation injury, the maximum vascular dose was 13.8+/-3.8 Gy in positive and was 13.6+/-4.9 Gy in negative. There was no significant difference between them. The dose escalation is limited because most patients in Protocol B suffered from acute radiation injury. We conclude that the maximum vascular dose does not exceed over 12 Gy to avoid the delayed radiation injury, especially, it should be limited under 10 Gy in the case that tumor exists in speech center.     

GE PETtrace cyclotron as a neutron source for boron neutron capture therapy.

This paper discusses the use of a General Electric PETtrace cyclotron as a neutron source for boron neutron capture therapy. In particular, the standard PETtrace (18)O target is considered. The resulting dose from the neutrons emitted from the target is evaluated using the Monte Carlo radiation transport code MCNP at different depths in a brain phantom. MCNP-simulated results are presented at 1, 2, 3, 4, 5, 6, 7, and 8 cm depth inside this brain phantom. Results showed that using a PETtrace cyclotron in the current configuration allows treating tumors at a depth of up to 4 cm with reasonable treatment times. Further increase of a beam current should significantly improve the treatment time and allow treating tumors at greater depths.     

Potential of using boric acid as a boron drug for boron neutron capture therapy for osteosarcoma

Osteosarcoma is a malignant tumor commonly found in human and animals. The ability of boric acid (BA) to accumulate in osteosarcoma due to the mechanism of the bone formation of cancer cells would make boron neutron capture therapy (BNCT) an alternative therapy for osteosarcoma. This study evaluated the feasibility of using BA as the boron drug for BNCT of bone cancer. The cytotoxicity of BA to L929 cells exceeded that of UMR-106 cells. With 25 μg ¹⁰B/mL medium of BA treatment, the boron concentration in UMR-106 cells was higher than that in L929 cells. The biodistribution and pharmacokinetics of BA in Sprague–Dawley (SD) rats were studied by administrating 25 mg ¹⁰B/kg body weight to SD rats. Blood boron level decreased rapidly within one hour after BA injection. Boron concentration in the long bone was 4–6 time higher than that of blood. Results of this study suggest that BA may be a potential drug for BNCT for osteosarcoma.     

硼中子俘获疗法促人黑色素瘤细胞凋亡

目的 研究硼中子俘获疗法(BNCT)体外杀伤人黑色素瘤细胞的效应及机制.方法 首先检测黑色素瘤细胞A375吸收含硼化合物二羟基苯丙氨酸硼(BPA)的情况,然后采用医院中子照射器(IHNI-1)对含硼(10B)细胞进行照射.克隆存活实验检测细胞的放射敏感性,MTT法检测细胞增殖率,流式细胞术检测凋亡,Western blot检测胞质内细胞色素C表达和caspase-9的激活.结果 BPA孵育24 h,A375细胞10B浓度为(2.884±0.148)μg/107个细胞,达到了BNCT杀伤细胞的要求.富含10B的细胞经中子照射2.1 min后存活分数降低为对照组的58％(t=2.964,P＜0.05),细胞经中子照射后24 h增殖率下降为对照组的83％(t=3.286,P＜0.05),BNCT组细胞凋亡率达(55.2±7.9)％,明显高于对照组(t =9.754,P＜0.05),胞质内细胞色素C水平上升且caspase-9激活程度增加(t=7.625、8.307,P＜0.05).结论 BNCT能够杀伤黑色素瘤细胞,其机制可能通过线粒体途径诱导细胞凋亡.     

H and B NMR and MRI investigation of boron- and gadolinium–boron compounds in boron neutron capture therapy

¹⁰B molecular compounds suitable for Boron Neutron Capture Therapy (BNCT) are tagged with a Gd(III) paramagnetic ion. The newly synthesized molecule, Gd-BPA, is investigated as contrast agent in Magnetic Resonance Imaging (MRI) with the final aim of mapping the boron distribution in tissues. Preliminary Nuclear Magnetic Resonance (NMR) measurements, which include ¹H and ¹⁰B relaxometry in animal tissues, proton relaxivity of the paramagnetic Gd-BPA molecule in water and its absorption in tumoral living cells, are reported.     

A shielding design for an accelerator-based neutron source for boron neutron capture therapy.

Research in boron neutron capture therapy (BNCT) at The Ohio State University Nuclear Engineering Department has been primarily focused on delivering a high quality neutron field for use in BNCT using an accelerator-based neutron source (ABNS). An ABNS for BNCT is composed of a proton accelerator, a high-energy beam transport system, a (7)Li target, a target heat removal system (HRS), a moderator assembly, and a treatment room. The intent of this paper is to demonstrate the advantages of a shielded moderator assembly design, in terms of material requirements necessary to adequately protect radiation personnel located outside a treatment room for BNCT, over an unshielded moderator assembly design.     

Targeting liposomes to tumor endothelial cells for neutron capture therapy.

The aim of our work is to target (10)B to the tumor vasculature for neutron capture therapy (NCT). Alpha (v)-integrin specific RGD-peptides were coupled to liposomes that encapsulated dodecahydrododecaborate. These RGD-liposomes strongly associated with human umbilical vein endothelial cells (HUVEC) expressing this integrin and were internalized. Proliferating HUVEC proved sensitive to treatment with gamma-irradiation resulting in decreased cell viability and pronounced inhibition of DNA-synthesis with increasing dose. Irradiation of RGD-(10)B-liposome incubated HUVEC with neutrons strongly inhibited endothelial cell viability. These results suggest that efficient NCT can be achieved by targeting (10)B-liposomes to angiogenic endothelium in tumors.     

用于硼中子俘获治疗的超热中子束理论设计

目的 设计用于硼中子俘获治疗(BNCT)的超热中子束理论方案。方法 基于清华大学试验核反应堆,以其1号孔道为材料布放孔道,设计了由慢化材料、热中子吸收材料、γ屏蔽材料组成,但材料布放位置具有差异的5种理论方案;利用蒙特卡罗(MC)模拟方法,分别计算5种方案束出口处的中子注量率、剂量率及γ剂量率值,通过与BNCT技术指标对比,从5种方案中选择一种合适的方案。结果 得到了一个符合BNCT各项技术指标的超热中子束理论方案,其慢化材料厚度为53.5 cm、热中子吸收材料厚度为2 mm、γ屏蔽材料厚度为9 cm。结论 本研究给出的超热中子束理论方案为基于反应堆实现BNCT提供一定的理论参考。     

Gamma/neutron dose evaluation using Fricke gel and alanine gel dosimeters to be applied in boron neutron capture therapy

Gel dosimetry has been studied mainly for medical applications. The radiation induced ferric ions concentration can be measured by different techniques to be related with the absorbed dose. Aiming to assess gamma/thermal neutrons dose from research reactors, Fricke gel and alanine gel solutions produced at IPEN using 300 bloom gelatin were mixed with Na₂B₄O₇ salt, and the mixtures were irradiated at the beam hole #3 of the IEA-R1 research reactor, (BH#3) adapted to BNCT studies, and the dose-response was evaluated using spectrophotometry technique.     

Long-survivors of glioblatoma treated with boron neutron capture therapy (BNCT)

The purpose of this study was to compare the radiation dose between long-survivors and non-long-survivors in patients with glioblatoma (GBM) treated with boron neutron capture therapy (BNCT). Among 23 GBM patients treated with BNCT, there were five patients who survived more than three years after diagnosis. The physical and weighted dose of the minimum gross tumor volume (GTV) of long-survivors was much higher than that of non-long survivors with significant statistical differences.     

Effects of boron neutron capture irradiation on the normal lung of rats.

The whole lung of rats was irradiated with X-rays, thermal neutrons, or thermal neutrons in the presence of p-boronophenylalanine (BPA). A >/= 20% increase in breathing rate, in the period 40-80 days after irradiation, was indicative of radiation-induced pneumonitis. The ED(50) (+/-SE) for a >/= 20% increase in breathing rate, relative to age-matched controls, was 11.6 +/- 0.13 Gy for X-rays and 9.6 +/- 0.08 Gy for neutrons only. This indicated a thermal neutron beam RBE of 1.2 and an RBE of 2.2 for the high-LET components of the dose, assuming a dose reduction factor of 1.0 for gamma rays. Preliminary data indicate the compound biological effectiveness factor for BPA in the lung is approximately 1.5.     

Moderated 252Cf neutron energy spectra in brain tissue and calculated boron neutron capture dose.

While there is significant clinical experience using both low- and high-dose (252)Cf brachytherapy, combination therapy using (10)B for neutron capture therapy-enhanced (252)Cf brachytherapy has not been performed. Monte Carlo calculations were performed in a brain phantom (ICRU 44 brain tissue) to evaluate the dose enhancement predicted for a range of (10)B concentrations over a range of distances from a clinical (252)Cf source. These results were compared to experimental measurements and calculations published in the literature. For (10)B concentrations 相似文献   

硼中子俘获治疗剂量验证方法进展

硼中子俘获治疗(BNCT)利用中子与肿瘤细胞中富集的硼发生特异性俘获反应, 可以定向杀死癌细胞。为了验证中子放疗计划的准确性, 保障患者的治疗效果, 需要在治疗前进行剂量验证, 即对比分析实验照射剂量与计划剂量。目前, BNCT剂量测量方法主要包括电离室法、热释光法、活化法等点剂量测量方法, 基于胶片的二维剂量测量方法, 以及基于凝胶剂量仪的三维剂量测量方法。本文总结了国际上BNCT剂量验证方法的进展, 讨论了这些方法的发展前景。     

Dose response of the AIA rabbit stifle joint to boron neutron capture synovectomy

This study assessed the treatment with boron neutron capture synovectomy of synovitis in the antigen-induced arthritis (AIA) model. A boron compound, potassium dodecahydrododeca-borate (K(2)B(12)H(12)), was injected into stifle joints of 24 AIA and 12 normal rabbits and activated by neutron bombardment of the joint to achieve doses from 800 to 81,000 RBE-cGy. Synovial ablation in the AIA joint was accomplished at doses of 6,000 to 7,000 RBE-cGy with no adverse effects to skin or extracapsular tissues.