Program for Development of BNCT Agents

靶向癌症治疗，在周围正常细胞存在的情况下选择性地破坏恶性细胞 细胞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 BNCT是一种靶向放射化疗，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 周围正常组织和脉管系统的发病率。该计划的重点是合成和测试 硼化卟啉作为潜在的BNCT剂，利用卟啉已知 局限于实体瘤。该计划的长期目标是产生足够的信息， 更多的候选化合物，为后续的BNCT临床试验提供良好的基础。这种平移 目的是通过定向合成的集成程序和体外合成的分层方案来实现 和体内生物学测试。为了实现我们的目标，提供至少一个合适的临床候选人， 在下一个资助周期，我们提出了四个具体目标，这些目标建立在我们从 本预算期。首先，我们将合成和测试硼化卟啉， 硼原子，这将告诉我们，有多少硼可以添加到卟啉，而不会破坏它的肿瘤。 定位能力。第二，我们将制备和测试新型的碳硼烷笼介孔卟啉 通过生理稳定和无毒的碳-碳键连接。第三，我们将调查 肽核定位序列选择性地将硼化化合物靶向至细胞核的用途， 癌细胞是对辐射最敏感的细胞靶点。第四，我们将建立和界定 成功应用硼化卟啉的对流增强输送（CED）的参数， 脑瘤迄今为止，CED研究在大鼠脑肿瘤中提供了高达520 ppm的硼， 倍于成功BNCT治疗的普遍接受的最小值。潜在的初步生物学试验 在正常大鼠中的候选物将建立最大耐受剂量、毒理学和组织病理学，并且将 随后在携带脑内人脑胶质瘤的无胸腺大鼠中通过全身或全身途径进行生物分布， CED化合物给药。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产生重大的健康影响，特别是对恶性脑肿瘤患者。

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.