PROGRAM FOR DEVELOPMENT OF BNCT AGENTS

描述（改编自申请人的摘要）：本项目的长期目标 该计划是开发肿瘤寻求硼化合物作为 用于癌症的硼捕获疗法（BNCT）的放射化学治疗剂。BNCT 依赖于肿瘤对无毒物质的选择性吸收和保留 含硼药物，然后用光束照射肿瘤区域 非常低能量的中子。中子被（10）B核俘获， 一种快速的裂变反应，其中硼原子核分裂形成α原子 一个锂原子核和一个伽马射线这些裂变产物存款 它们的大部分实质性能量在一个细胞直径内，并且被认为是 高线性能量（LET）碎片。二元疗法，如BNCT， 通过增加辐射剂量提高局部癌症控制的潜力 同时减少辐射引起的发病率， 周围的正常组织和脉管系统这项建议的目的是 在其五年期内提供一种或多种硼化卟啉， BNCT的临床应用这一高度转化的目标是 通过定向合成和分层的综合方案来完成 生物学和放射生物学临床前测试方案。为了 满足这一目标，三个具体目标，涉及结构-活性/毒性 这些化合物之间的关系有待解决。校长 研究人员和他的团队将1）检查几种连锁化学， 2）紧密连接碳硼烷以降低毒性; 多面体硼烷阴离子以优化敏化剂药代动力学;以及3） 评估每个分子连接超过40个硼原子的方法， 肿瘤硼浓度在头2-3年的综合努力将 重点介绍了硼化卟啉的合成和表征， 五个基本的结构图案。潜在的初步生物学试验 正常大鼠中的候选物将建立最大耐受剂量， 组织学特征，并随后在无胸腺裸小鼠中进行生物分布 带有脑内胶质瘤的大鼠。成功的候选人将进一步 在体外和BNCT协议中使用加速器产生的超热 劳伦斯伯克利国家实验室的光束。建议的合成 在过去的两年中，将集中在化合物具有最 有希望的结构基序。

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.