Program for Development of BNCT Agents

描述（由申请人提供）：在周围正常细胞存在的情况下选择性地破坏恶性细胞的靶向癌症治疗是药物化学家和肿瘤学家最梦寐以求的目标之一。硼中子俘获治疗（BNCT）是一种靶向放化疗形式，通过增加对癌细胞的辐射剂量，同时减少辐射引起的对周围正常组织和血管的发病率，有可能增加对癌症的局部控制。该项目利用卟啉在实体肿瘤中具有局限性的事实，重点研究硼化卟啉作为潜在的BNCT药物的合成和测试。该项目的长期目标是产生一种或多种候选化合物的足够信息，为后续的BNCT临床试验提供坚实的基础。这个翻译的目标是通过一个综合程序的定向合成和一层协议的体外和体内的生物测试来完成。为了实现我们在下一个拨款周期内为BNCT提供至少一名合适的临床候选人的目标，我们提出了四个具体目标，这些目标建立在我们当前预算期现有工作的基础上。首先，我们将合成并测试含有数百个硼原子的硼化卟啉，这将告诉我们在不破坏其肿瘤定位能力的情况下，可以向卟啉中添加多少硼。二是制备新型碳硼烷笼型中邻卟啉并进行测试，碳硼烷笼通过生理稳定、无毒的碳-碳键连接。第三，我们将研究利用肽核定位序列选择性地将硼化化合物靶向到癌细胞的细胞核，这是对辐射最敏感的细胞靶标。第四，我们将建立和定义硼化卟啉对流增强输送（CED）成功应用于脑肿瘤的参数。迄今为止，CED研究已在大鼠脑肿瘤中提供高达520ppm的硼，这一数字约为BNCT成功治疗的公认最低值的15倍。在正常大鼠中进行潜在候选药物的初步生物学试验将确定最大耐受剂量、毒理学和组织病理学，然后通过全身或CED化合物给药在患有脑内胶质瘤的胸腺大鼠中的生物分布。成功的候选人将在体外和BNCT方案中进一步研究。一个成功的结果可能会对健康产生重大影响，特别是对恶性脑肿瘤患者。

DESCRIPTION (provided by applicant): 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 propose four 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.