硼中子俘获疗法的硼携带剂研究进展

硼中子俘获疗法（boron neutron capture therapy,BNCT）是一种新型的放疗方法,它是将与肿瘤有特异性亲合力的10B化合物（硼携带剂）注入人体,经中子束局部照射使聚集在肿瘤组织中的10B与热中子发生核反应,生成7Li与α粒子。这些粒子均属高传能线密度（linear energy transfer,LET）射线,具有能量高和射程短的特点,产生的α粒子能量可达1.7 Mev,平均LET为200 kev·μm-1（理论上几个α粒子释放的能量足以使瘤细胞致死）,射程分别为5μm和10μm（相当于一个肿瘤细胞的直径,该直径<10μm）。其相当空间内发生的电离反应可杀伤吸收硼化物的瘤细胞及与之相邻的细胞,而对正常的组织损害甚小。该疗法的基本特点是:①治疗靶向效应好,对正常组织损伤小,全身副作用轻;②肿瘤局部杀伤剂量大,可达2000cGy以上;③不需增氧效应（oxygenenhancement ratio,OER）,即α粒子不仅可以杀死富氧细胞,同时也能杀死乏氧细胞及未增殖的G0期细胞;④产生的亚致死损伤（sublethal damage,SLD）和潜在致死损伤（potentiallethal damage,PLD）不可修复;⑤使用的10B能与各种载体相结合,可通过生物结合或代谢途径进入靶组织,除可治疗脑内恶     

硼中子俘获疗法中硼携带剂的研究进展

硼中子俘获疗法（Boron Neutron Capture Therapy,BNCT）是一种新型的二元靶向放疗方法.BNCT是将与肿瘤有特异性亲合力的10B化合物注入人体,10B浓集于肿瘤细胞,经中子束局部照后肿瘤组织中的10B与热中子发生核反应,产生Li-7与α粒子,这些粒子能在细胞水平上杀灭肿瘤细胞,由于周围正常组织中10B的浓度很低,所以对正常组织损伤不大[1].进行BNCT治疗必须满足3个基本条件：一是建立用于BNCT的中子源,能提供BNCT所需的各种中子;二是建立精确的辐射剂量测算体系,以保证BNCT治疗的精确性和安全性;三是合成和肿瘤细胞具有高度亲和力的硼携带剂[2].其中能否研制出对肿瘤具有高度亲和力的硼携带剂对BNCT的疗效和安全性至关重要[3].近年来,用于BNCT治疗的硼携带剂的研究已取得了巨大进展,为肿瘤的BNCT治疗带来了新的希望,现就BNCT硼携带剂的研究现状和展望综述如下.关键词：放疗;肿瘤;硼中子俘获疗法;硼携带剂     

脑肿瘤的硼中子俘获疗法（综述）

放疗是脑肿瘤综合治疗中的一个重要组成部分,理想的放疗方法不但要求能杀伤肿瘤细胞,又不损害正常的脑组织结构与功能。目前,常用的~(60)CO、X—射线、加速器等放疗方法很难满足上述条件,虽然部分病人可以延长生命,但也会发生脑损害的并发症,如脑水肿、迟发性脑坏死、痴呆样的神经功能减退等,尤其治疗剂量超过50Gy 时更是如此。硼中子俘获疗法(Boron Neutron CaptureTherapy,BNCT)可选择性的杀伤肿瘤细胞,不     

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。     

硼中子俘获疗法诱导U87胶质瘤细胞凋亡

目的 探讨硼中子俘获疗法(BNCT)对人脑胶质瘤细胞株U87的增殖抑制和诱导凋亡的作用及可能机制.方法 实验分为未照射组(0 Gy)、γ射线对照组(4、8 Gy)、反应堆组(3.5 Gy)、BNCT组(4、8 Gy).采用形态观察、流式细胞仪Annexin V/PI荧光染色、四甲基偶氮唑蓝(MTT)法等方法观察BNCT对U87细胞的增殖抑制和诱导凋亡的作用,以免疫组织化学技术检测P53蛋白的表达,应用western blot检测BCL-2、BAX蛋白表达的变化.结果 硼中子照射后细胞出现典型的凋亡形态改变.BNCT 4、8 Gy组处理后48 h细胞的凋亡率分别为65.1%、85.9%.BNCT 4、8 Gy组细胞生长抑制作用显著高于同等剂量的γ射线照射组(P＜0.01).未照射的U87细胞P53蛋白表达阴性,BNCT4、8 Gy照射后P53蛋白表达阳性.BNCT4、8 Gy照射后BCL-2蛋白表达下降,BAX蛋白上升.结论 BNCT对U87细胞具有显著的增殖抑制作用,并有剂量、时间依赖性特点.     

硼中子俘获疗法诱导U251胶质瘤细胞凋亡

目的研究硼中子俘获疗法（BNCT）能否诱导体外培养的U251细胞发生凋亡，并探讨其诱导细胞凋亡的机制。方法采用四甲基偶氮唑蓝（MTT）法绘制细胞生长曲线，应用光镜、荧光显微镜、透射电子显微镜观察BNCT后细胞形态改变；使用流式细胞仪检测细胞凋亡率；利用细胞克隆形成实验分析细胞存活分数；用免疫组织化学方法检测相关蛋白表达的变化。结果在体外试验中BNCT对U251细胞的杀伤力强，并观察到了典型的细胞凋亡改变，4、8Gy照射后48h流式细胞仪检测，细胞凋亡率分别为60．2％、80．6％。在凋亡过程中，p53蛋白表达明显增高，而bcl-2蛋白表达下调。结论BNCT可诱导U251细胞发生凋亡，其机制可能与p53基因表达上调及bcl-2基因表达下调有关。     

硼中子俘获治疗中硼的转运方法研究进展

脑胶质瘤是一种死亡率较高的病变,用目前的常规治疗方法很难治愈,而硼中子俘获治疗(BNCT)是一种很有希望治愈胶质瘤的方法,但由于血脑屏障(BBB)的存在,阻止了很多含硼药物进入脑内,因此如何向瘤组织中转运足够剂量的10B,是BNCT成功应用的关键。借助肿瘤比正常组织代谢快的特点,利用针对肿瘤细胞表面特异性抗原的抗体,采取脂溶性较好的微粒包裹药物,通过电通透作用,药物破坏或者选择性开放BBB,直接颅内或者瘤内注射等方法单独或联合运用转运含硼药物,可以在瘤组织中获得理想的10B剂量,为BNCT在胶质瘤治疗中发挥重要作用奠定基础。     

硼中子俘获治疗脑胶质瘤的研究进展

脑胶质瘤是呈浸润性生长的恶性肿瘤,与正常脑组织间无明显边界,手术难以全部切除,术后常需辅以放射治疗和化学药物治疗。目前常用的放疗方法有普通~(60)Co、立体定向放射治疗(X-刀和γ-刀),前者常伴有正常脑组织的水肿反应、放射性脑坏死等并发症;后者虽然可直接针对靶点治疗,但因胶质瘤生长的特性,照射范围仍常难以确定。理想的放射治疗方法要求能选择性地杀死肿瘤细胞,而不损伤脑组织的     

硼中子俘获治疗脑脑质瘤的研究进展

硼中子俘获疗法治疗脑胶质瘤是基于硼-10在热中子的辐射下能产生放射性作用的原理,硼化合物/硼携带剂和热中子源是治疗成功的两个关键因素。本文对此疗法的作用原理、硼化合物/硼携带剂和热中子源的研究作一综述。     

硼中子俘获治疗脑胶质瘤超热中子束的品质参数研究

目的 研究硼中子俘获治疗肿瘤所需超热中子束的品质参数,得到无损治疗脑胶质瘤的较佳能量中子束.方法 建立人体头颅等效模型内中子、γ的通量和剂量计算模型,分析西安脉冲堆超热中子源在人体头颅等效模型内所产生的剂量成分,采用蒙特卡罗程序(MCNP/4B)模拟计算单能理想中子束和脉冲堆超热中子束的优化深度、优化深度剂量率、优化比等品质参数.结果 束孔直径为20 cm、平均能量为11.5815 keV的西安脉冲堆超热中子源的相对生物等效因子(RBE)优化深度为9.78 cm、RBE优化比大于3.5.结论 在不进行外科手术情况下,理论设计的西安脉冲堆超热中子源是治疗脑胶质瘤的较佳能量中子束.     

Boron neutron capture therapy of primary and metastatic brain tumors

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated with low energy (0.025 eV) thermal neutrons (n _th) to yield alpha (⁴He) particles and,⁷Li nuclei (¹⁰B+n _th→[¹¹B]→⁴He+⁷Li+2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of¹⁰B andn _th to individual cancer cells to sustain a lethal¹⁰B(n, α)⁷Li reaction. Boron delivery agents include a variety of compounds, such as the sulfhydryl containing polyhedral borane sodium borocaptate (Na₂B₁₂H₁₁SH, [BSH]), boronoporphyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The present review will focus on three delivery systems that currently are under investigation in our laboratories, boronated monoclonal antibodies, carboranyl uridines, and boronophenylalanine. Methodology has been developed to heavily boronate MAb using a precision macromolecule, a “starburst” dendrimer, which can be linked to MAb by means of heterobifunctional reagents. Although the resulting immunoconjugates retain their in vitro immunoreactivity, they lose their in vivo tumor localizing properties and accumulate in the liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can simultaneously recognize a tumor-associated antigen and a boronated macromolecule. Boron containing, nucleosides are potential vehicles for incorporating boron compounds into nucleic acids of neoplastic cells. For this purpose, carboranyl uridines have been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides currently are being synthesized that may have better tumor localizing properties. The potential use of boronophenylalanine as a capture agent for the treatment of melanoma metastatic to the brain also is under investigation. A nude rat model has been developed using human melanoma cells that are stereotactically implanted into the brain. BNCT-treated animals have either had prolonged survival times or continue to live compared to control rats that invariably died of their tumors, thereby suggesting therapeutic efficacy.     

Boron neutron capture therapy of primary and metastatic brain tumors

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated with low energy (0.025 eV) thermal neutrons (n _th) to yield alpha (⁴He) particles and,⁷Li nuclei (¹⁰B+n _th→[¹¹B]→⁴He+⁷Li+2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of¹⁰B andn _th to individual cancer cells to sustain a lethal¹⁰B(n, α)⁷Li reaction. Boron delivery agents include a variety of compounds, such as the sulfhydryl containing polyhedral borane sodium borocaptate (Na₂B₁₂H₁₁SH, [BSH]), boronoporphyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The present review will focus on three delivery systems that currently are under investigation in our laboratories, boronated monoclonal antibodies, carboranyl uridines, and boronophenylalanine. Methodology has been developed to heavily boronate MAb using a precision macromolecule, a “starburst” dendrimer, which can be linked to MAb by means of heterobifunctional reagents. Although the resulting immunoconjugates retain their in vitro immunoreactivity, they lose their in vivo tumor localizing properties and accumulate in the liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can simultaneously recognize a tumor-associated antigen and a boronated macromolecule. Boron containing, nucleosides are potential vehicles for incorporating boron compounds into nucleic acids of neoplastic cells. For this purpose, carboranyl uridines have been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides currently are being synthesized that may have better tumor localizing properties. The potential use of boronophenylalanine as a capture agent for the treatment of melanoma metastatic to the brain also is under investigation. A nude rat model has been developed using human melanoma cells that are stereotactically implanted into the brain. BNCT-treated animals have either had prolonged survival times or continue to live compared to control rats that invariably died of their tumors, thereby suggesting therapeutic efficacy.     

An investigation of boron neutron capture therapy for recurrent glioblastoma multiforme

Objectives –  To explore the use of boron neutron capture therapy (BNCT) for patients with glioblastoma multiforme (GBM), recurring after surgery and conventional radiotherapy (photon radiotherapy).
Materials and methods –  Boron uptake in recurrent GBM was measured for four patients. Twelve patients were subsequently treated by BNCT with boronophenylalanine-fructose (900 mg/kg body weight), administered by intravenous infusion for 6 h.
Results –  Median survival time from initial diagnosis was 22.2 months. Comparison with other BNCT studies indicates a clinical advantage of the prolonged infusion. BNCT was well tolerated and quality of life remained stable until tumor progression for all 12 patients. No correlation was found between survival times and minimum tumor dose and number of radiation fields.
Conclusions –  Boron neutron capture therapy, with the prolonged procedure for infusion, is at least as effective as other radiation therapies for recurrent GBM and is delivered in one treatment session, with low radiation dose to the healthy brain. Survival from diagnosis compares favorably with that obtained with conventional radiotherapy plus concomitant and adjuvant temozolomide (TMZ) and survival from recurrence compares favorably with that obtained with TMZ at first relapse. The results of the present investigation are encouraging and should be confirmed in a randomized trial.