Program for Development of BNCT Agents

有针对性的癌症治疗，在周围正常细胞存在的情况下选择性地摧毁癌细胞 细胞是药物化学家和肿瘤学家梦寐以求的目标之一。硼中子俘获 治疗(BNCT)是一种靶向放化疗，有可能增加局部控制 通过增加对癌细胞的辐射剂量，同时减少辐射诱导的癌症 对周围正常组织和血管系统的发病率。本程序侧重于综合和测试 将硼化卟啉作为潜在的BNCT试剂，利用卟啉已知的事实 定位于实体瘤。该计划的长期目标是生成关于一个或多个项目的足够信息 更多的候选化合物，为后续的BNCT临床试验提供良好的基础。此翻译 目标是通过定向合成的综合计划和体外实验的分层方案来实现 和活体生物测试。为了实现我们的目标，即至少提供一名合适的临床候选人 在下一个赠款周期，我们提出了我们的具体目标，这些目标建立在我们现有工作的基础上 本预算期。首先，我们将合成和测试高达数百个的硼化卟啉 硼原子，它将告诉我们在不破坏其肿瘤的情况下，在卟啉中添加多少硼 本地化能力。第二，我们将制备和测试新的碳硼烷基中位卟啉和碳硼环 通过生理稳定和无毒的碳-碳键连接。第三，我们将调查 利用多肽核定位序列选择性地将含硼化合物靶向 癌细胞，最高辐射敏感的细胞靶点。第四，我们将建立和定义 硼化卟啉对流强化输送(CED)成功应用的工艺参数 脑瘤。到目前为止，CED的研究已经在大鼠脑瘤中提供了高达520ppm的硼，数字~15 是普遍接受的成功BNCT治疗的最低要求的倍。潜力的初步生物测试 候选的正常大鼠将建立最大耐受剂量、毒理学和组织病理学，并将 其次是携带人脑胶质瘤的裸鼠体内的生物分布，无论是通过全身还是通过 CED复方给药。成功的候选者将在体外和BNCT方案中进行进一步研究。 一个成功的结果可能会对健康产生重大影响，特别是对患有恶性脑瘤的患者。

Targeted cancer therapies that selectively destroy malignant cells in the presence of surrounding normal cells are among the most coveted goals of medicinal chemists and oncologists. Boron neutron capture therapy (BNCT) is a form of targeted radiochemotherapy that has the potential to increase local control of cancer by increasing the radiation dose to cancer cells while simultaneously reducing radiation-induced morbidity to surrounding normal tissue and vasculature. This program focuses on the synthesis and testing of boronated porphyrins as potential BNCT agents, making use of the fact that porphyrins are known to localize in solid tumors. The long term goal of the program is to generate sufficient information on one or more candidate compounds to provide a sound basis for a subsequent BNCT clinical trial. This translational objective is to be accomplished by an integrated program of directed synthesis and a tier protocol of in vitro and in vivo biological testing. To achieve our goal of providing at least one suitable clinical candidate for BNCT during the next grant cycle, we proposefour specific aims that build on our exisiting work from the current budget period. First, we will synthesize and test boronated porphyrins bearing up to several hundred boron atoms, which willtell us how much boron can be added to a porphyrin without destroying its tumor localizing ability. Second, we will prepare and test new carboranyl meso-porphyrins with carborane cages attached through physiologically stable and non-toxic carbon-carbon bonds. Third, we will investigate the use of peptide nuclear localization sequences to selectively target boronated compounds to the nucleus of cancer cells, the most highly radiation sensitive cellular target. Fourth, we will establish and define the parameters for successful application of convection enhanced delivery (CED) of boronated porphyrins to brain tumors. CED studies to date have provided up to 520 ppm boron in rat brain tumors, a figure ~15 times the generally accepted minimum for successful BNCT therapy. Initial biological testing of potential candidates in normal rats will establish maximum tolerated dose, toxicology and histopathology, and will be followed by biodistribution in athymic rats bearing an intracerebral human glioma, either through systemic or CED compound administration. Successful candidates will be further studied in vitro and in BNCT protocols. A successful outcome could have a major health impact, especially for patients with malignant brain tumors.