PROGRAM FOR DEVELOPMENT OF BNCT AGENTS

BNCT 制剂开发计划

• 批准号: 6706305
• 负责人: STEPHEN B KAHL
• 金额: $ 29.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6706305
• 关键词: boron; chemical structure function; glioma; laboratory rat; neoplasm /cancer radionuclide therapy; neutron radiation; nonhuman therapy evaluation; pharmacokinetics; porphyrins; radiosensitizer

DESCRIPTION (adapted from applicant's abstract): The long-term goal of this program is the development of tumor seeking boron compounds for use as radiochemotherapeutic agents for boron capture therapy (BNCT) of cancer. BNCT relies on the selective tumor uptake and retention of a non-toxic boron-containing drug followed by irradiation of the rumor region with a beam of very low energy neutrons. Capture of a neutron by a (10)B nucleus causes a prompt fission reaction in which the boron nucleus splits to form an alpha particle, a lithium nucleus and a gamma ray. These fission products deposit most of their substantial energies within one cell diameter and are considered high linear energy (LET) fragments. Binary therapies such as BNCT have the potential to increase local control of cancer by increasing the radiation dose to cancer cells and simultaneously reducing radiation-induced morbidity to surrounding normal tissue and vasculature. The objective of this proposal is to provide over its five year length one or more boronated porphyrins suitable for clinical BNCT application. This highly translational objective is to be accomplished through an integrated program of directed synthesis and a tier protocol of biological and radiobiological pre-clinical testing. In order to meet this goal, three specific aims, relating to structure-activity/toxicity relationships in these compounds are to be addressed. The Principal Investigator and his team will 1) examine several linkage chemistries for attaching closo carboranes in order to reduce toxicity; 2) attach closo polyhedral borane anions to optimize sensitizer pharmacokinetics; and 3) evaluate methods of attaching more than 40 boron atoms per molecule to maximize tumor boron concentration. Synthetic efforts during the first 2-3 years will focus on the synthesis and characterization of boronated porphyrins from each of five basic structural motifs. Initial biological testing of potential candidates in normal rats will establish maximum tolerated dose and histological profiles and will be followed by biodistribution in athymic nude rats bearing an intracerebral glioma. Successful candidates will be further studied in vitro and in BNCT protocols using an accelerator-produced epithermal beam at the Lawrence Berkeley National Laboratory. The proposed syntheses during the last two years will concentrate on compounds having the most promising structural motif.

描述(改编自申请人的摘要)：该项目的长期目标 该计划是开发用于治疗肿瘤的硼化合物 用于癌症的硼捕获治疗(BNCT)的放化疗药物。BNCT 依赖于肿瘤的选择性摄取和保留无毒的 含硼药物后用束流照射肿瘤区域 极低能量的中子。中子被(10)B核俘获会引起 一种快速裂变反应，其中硼原子核分裂形成阿尔法原子核 粒子、锂原子核和伽马射线。这些裂变产物存放在 它们的大部分实质性能量都在一个细胞直径内，并被认为 高线能量(LET)碎片。像BNCT这样的二元疗法有 通过增加辐射剂量来提高癌症局部控制的潜力 同时将辐射引起的发病率降低到 环绕正常组织和血管系统。这项建议的目的是 在其五年内提供一种或多种适合于 BNCT的临床应用。这个高度翻译的目标是 通过定向合成和分层的集成计划完成 生物和放射生物学临床前检测方案。为了 实现这一目标，与结构-活性/毒性有关的三个具体目标 这些化合物中的关系是需要解决的。《校长》 研究人员和他的团队将检查几种连锁化学 为了减少毒性而附着闭合碳硼烷；2)附着闭合 优化增敏剂药代动力学的多面体硼烷阴离子； 评估每个分子连接40个以上硼原子的方法，以最大限度地提高 肿瘤硼浓度。头2-3年内的综合努力将 重点研究了含硼卟啉的合成与表征 五个基本的结构主题。潜力的初步生物测试 正常大鼠的候选者将建立最大耐受量和 无性系裸鼠的组织学特征和生物分布 携带脑内胶质瘤的大鼠。成功的应聘者将进一步 在体外和BNCT方案中使用加速器产生的超热进行研究 在劳伦斯伯克利国家实验室。建议的合成 在过去的两年里将集中在具有最多 前景看好的结构主题。