TUMOR-TARGETING WITH NEW BORONATED PORPHYRINS

描述（由申请人提供）：本提案解决了开发适用于难治性脑肿瘤新治疗方式的合适分子的需求；这种需求源于高质量中子束的生产和可用性的进步。我们拟合成并表征一种新的无毒含硼卟啉，该卟啉可选择性地定位于肿瘤内，并可用于癌症的硼中子俘获治疗（BNCT）。具体目标是：1)合成新型无毒硼化卟啉；2)研究其物理化学和生物学特性；3)选择最有希望的候选药物进行进一步的动物研究；4)确定肿瘤细胞选择性摄取的机制和优化这些药代动力学参数的化学特征。卟啉样大环已被证明在多种肿瘤组织中选择性定位，这一特性为其在光动力治疗（PDT）中的应用提供了基础。美国FDA已经批准了两种卟啉衍生物PDT敏化剂：Photofrin和Visudyne。迄今为止，Photofrin已成功用于治疗全球数千名癌症患者，目前正在进行二期脑肿瘤试验。BNCT是一种基于核反应的新兴治疗方式，当肿瘤内的硼-10核捕获低能中子产生高线性能量转移粒子时，其细胞毒性作用仅限于保留药物的细胞。bnct 1/11期临床试验正在美国、欧洲和日本进行，用于治疗胶质母细胞瘤和黑色素瘤患者。我们建议进一步验证含硼卟啉是否保留了卟啉的低毒性和肿瘤定位特性，从而可以有效地将高浓度的硼-10输送到肿瘤细胞。文献中报道了先前对这一假设的有限测试，但只检查了少数特征较差的药物。然而，我们的初步结果表明，许多硼化卟啉是无毒的肿瘤定位剂。我们相信，对我们第一代化合物的持续生物学研究，加上我们打算开发的新类似物，将为进一步开发更有效的药物提供一个平台。新型硼化卟啉用于BNCT的有效性将在加州大学戴维斯麦克莱伦核辐射中心的2兆瓦TRIGA核反应堆上进行评估。

DESCRIPTION (provided by applicant): This proposal addresses the need for the development of suitable molecules for application in a new treatment modality for intractable brain tumors; this need arises from advances in the production and availability of high quality neutron beams. We propose to synthesize and characterize new non-toxic boron containing porphyrins that selectively localize within tumors and which may be used for boron neutron capture therapy (BNCT) of cancer. Specific aims are: 1) to synthesize novel non-toxic boronated porphyrins, 2) to study their physicochemical and biological properties, 3) to select the most promising candidates for further animal studies, and 4) to determine the mechanisms of selective tumor cell uptake and the chemical features that optimize these pharmacokinetic parameters. Porphyrin-like macrocycles have been shown to selectively localize in a variety of neoplastic tissues, and this property provides the basis for their use in photodynamic therapy (PDT). The U.S. FDA has approved two PDT sensitizers that are porphyrin derivatives: Photofrin and Visudyne. To date, Photofrin has successfully been used to treat thousands of cancer patients worldwide, and is currently being investigated in a Phase II brain tumor trial. BNCT is an emerging therapeutic modality based on a nuclear reaction, which occurs when boron-10 nuclei localized within tumors capture low-energy neutrons to produce high linear energy transfer particles whose cytotoxic effects are confined to the cells in which the drug is retained. Phase 1/11BNCT clinical trials are being pursued in the U.S., Europe, and Japan, for the treatment of patients with glioblastomas and melanomas. We propose to further test the hypothesis that boron-containing porphyrins will retain the low toxicity and tumor localizing properties of porphyrins, and therefore can efficaciously deliver high concentrations of boron-10 to tumor cells. Previous limited tests of this hypothesis were reported in the literature, but only a few poor characterized agents were examined. Our preliminary results however establish that numerous boronated porphyrins are non-toxic tumor localizing agents. We are confident that continued biological studies of our first generation compounds, coupled to new analogues we propose to develop, would provide a platform for further development of even more efficacious drugs. The effectiveness of the new boronated porphyrins for BNCT will be evaluated at the 2 MW TRIGA nuclear reactor at the University of California, Davis McClellan Nuclear Radiation Center.