Porphyrin-mediated boron neutron capture therapy: evaluation of the reactions of skin and central nervous system

Purpose: Recently, various boronated porphyrins have been shown to preferentially target a variety of tumour types. Of the different porphyrins evaluated, copper tetra-phenyl-carboranyl porphyrin (CuTCPH) is a strong candidate for future preclinical evaluation. In the present study, the responses of two critical normal tissues, skin and central nervous system (CNS), to boron neutron capture (BNC) irradiation in the presence of this porphyrin were evaluated.

Materials and methods: Standard models for the skin and spinal cord of adult male Fischer 344 rats were used. CuTCPH was administered by intravenous infusion at a dose of 200 mg kg^{m 1} body weight, over 48 h. The thermal beam at the Brookhaven Medical Research Reactor was used for the BNC irradiations. The 20-mm diameter irradiation field, for both the skin and the spinal cord, was located on the mid-dorsal line of the neck. Dose-response data were fitted using probit analysis and the doses required to produce a 50% incidence rate of early and late skin changes or myeloparesis (ED 50 - SE) were calculated from these curves.

Results: Biodistribution studies indicated very low levels of boron (<3 µ;g g^{m 1}) in the blood 3 days after the administration of CuTCPH. This was the time point selected for radiation exposure in the radiobiological studies. Levels of boron in the CNS were also low (2.8 - 0.6 µ;g g^{m 1}) after 3 days. However, the concentration of boron in the skin was considerably higher at 22.7 - 2.6 µ;g g^{m 1}. Single radiation exposures were carried out using a thermal neutron beam. The impact of CuTCPH-mediated BNC irradiation on the normal skin and CNS at therapeutically effective exposure times was minimal. This was primarily due to the very low blood boron levels (from CuTCPH) at the time of irradiation. Analysis of the relevant dose-effect data gave compound biological effectiveness factors of about 1.8 for skin (moist desquamation) and about 4.4 for spinal cord (myeloparesis) for CuTCPH. These values were based on the BNC radiation doses to tissues calculated using the blood boron levels at the time of irradiation.

Conclusions: CuTCPH-mediated BNC irradiation will not cause significant damage to skin and CNS at clinically relevant radiation doses provided that blood boron levels are low at the time of radiation exposure.     

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。     

Drug delivery system design and development for boron neutron capture therapy on cancer treatment

We have already synthesized a boron-containing polymeric micellar drug delivery system for boron neutron capture therapy (BNCT). The synthesized diblock copolymer, boron-terminated copolymers (Bpin-PLA-PEOz), consisted of biodegradable poly(D,l-lactide) (PLA) block and water-soluble polyelectrolyte poly(2-ethyl-2-oxazoline) (PEOz) block, and a cap of pinacol boronate ester (Bpin). In this study, we have demonstrated that synthesized Bpin-PLA-PEOz micelle has great potential to be boron drug delivery system with preliminary evaluation of biocompatibility and boron content.     

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。     

硼中子俘获治疗的生物学机制及临床研究进展

硼中子俘获治疗(boron neutron capture therapy,BNCT)是一种新型且高度精准的肿瘤放疗手段。BNCT可依赖高效靶向的含硼药物,在细胞级别同时实现对肿瘤细胞的精准打击和对正常细胞的精准防护。含硼药物研发正在深入进行,新型高效的制剂层出不穷,这为充分发挥BNCT优势和疗效带来新的曙光。由于BNCT过程中产生复合射线,其对肿瘤细胞的杀伤机制较为复杂,相关研究仍相对匮乏,具体分子机制有待阐明和完善。世界范围内,BNCT已用于恶性脑瘤、头颈部肿瘤、恶性黑色素瘤等临床治疗,并取得良好疗效。本文主要针对BNCT药物研究、生物学机制、潜在优势、临床应用进行综述。     

Feasibility study of SPECT system for online dosimetry imaging in boron neutron capture therapy

A single collimator version of a proposed PG-SPECT system was manufactured and experimentally tested. Combining this experimental data with Monte Carlo simulation, the viability of Ge and CdTe semiconductors detectors was calculated. It was determined that the best detector of the ones compared would be a CdTe detector of 2–3 mm, aided by the benefit of adding a Compton-suppression anti-coincidence timing detector.     

The radiobiological principles of boron neutron capture therapy: A critical review

The radiobiology of the dose components in a BNCT exposure is examined. The effect of exposure time in determining the biological effectiveness of γ-rays, due to the repair of sublethal damage, has been largely overlooked in the application of BNCT. Recoil protons from fast neutrons vary in their relative biological effectiveness (RBE) as a function of energy and tissue endpoint. Thus the energy spectrum of a beam will influence the RBE of this dose component. Protons from the neutron capture reaction in nitrogen have not been studied but in practice protons from nitrogen capture have been combined with the recoil proton contribution into a total proton dose. The relative biological effectiveness of the products of the neutron capture reaction in boron is derived from two factors, the RBE of the short range particles and the bio-distribution of boron, referred to collectively as the compound biological effectiveness factor. Caution is needed in the application of these factors for different normal tissues and tumors.     

High-power liquid-lithium target prototype for accelerator-based boron neutron capture therapy

A prototype of a compact Liquid-Lithium Target (LiLiT), which will possibly constitute an accelerator-based intense neutron source for Boron Neutron Capture Therapy (BNCT) in hospitals, was built. The LiLiT setup is presently being commissioned at Soreq Nuclear Research Center (SNRC). The liquid-lithium target will produce neutrons through the ⁷Li(p,n)⁷Be reaction and it will overcome the major problem of removing the thermal power generated using a high-intensity proton beam (>10 kW), necessary for sufficient neutron flux. In off-line circulation tests, the liquid-lithium loop generated a stable lithium jet at high velocity, on a concave supporting wall; the concept will first be tested using a high-power electron beam impinging on the lithium jet. High intensity proton beam irradiation (1.91–2.5 MeV, 2–4 mA) will take place at Soreq Applied Research Accelerator Facility (SARAF) superconducting linear accelerator currently in construction at SNRC. Radiological risks due to the ⁷Be produced in the reaction were studied and will be handled through a proper design, including a cold trap and appropriate shielding. A moderator/reflector assembly is planned according to a Monte Carlo simulation, to create a neutron spectrum and intensity maximally effective to the treatment and to reduce prompt gamma radiation dose risks.     

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.     

硼中子俘获治疗的微剂量学研究现状

微剂量学研究在临床硼中子俘获治疗(BNCT)的计划设计和疗效评价中起着重要作用。设计一套既能准确描述10B化合物及其反应产生的次级粒子在细胞、亚细胞水平的剂量不均匀分布,又适合于临床上使用的微剂量估算模式,一直是此领域的研究重点。为此,着重介绍了BNCT的微剂量估算方法及其最近发现显著影响其精确度的因素。     

Physics of epi-thermal boron neutron capture therapy (epi-thermal BNCT)

The physics of epi-thermal neutrons in the human body is discussed in the effort to clarify the nature of the unique radiologic properties of boron neutron capture therapy (BNCT). This discussion leads to the computational method of Monte Carlo simulation in BNCT. The method is discussed through two examples based on model phantoms. The physics is kept at an introductory level in the discussion in this tutorial review.     

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.     

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.     

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.     

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.     

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.