TUMOR-TARGETING WITH NEW BORONATED PORPHYRINS

描述（由申请人提供）：该提案解决了开发适用于难治性脑肿瘤新治疗模式的分子的需求;这一需求源于高质量中子束的生产和可用性的进步。我们提出合成和表征新的无毒含硼卟啉，选择性地定位在肿瘤内，并可用于硼中子捕获治疗（BNCT）的癌症。具体目标是：1）合成新型无毒的硼化卟啉，2）研究它们的物理化学和生物学性质，3）选择最有前途的候选物用于进一步的动物研究，以及4）确定选择性肿瘤细胞摄取的机制和优化这些药代动力学参数的化学特征。卟啉类大环化合物已被证明可以选择性地定位于多种肿瘤组织中，并且这种性质为其在光动力学疗法（PDT）中的应用提供了基础。美国FDA已经批准了两种属于卟啉衍生物的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II期脑肿瘤试验。BNCT是一种基于核反应的新兴治疗方式，当位于肿瘤内的硼-10核捕获低能中子以产生高线性能量转移粒子时发生，其细胞毒性作用仅限于药物保留的细胞。1/11期BNCT临床试验正在美国进行，欧洲和日本，用于治疗胶质母细胞瘤和黑素瘤患者。我们建议进一步测试的假设，即含硼卟啉将保留低毒性和肿瘤定位性质的卟啉，因此可以有效地提供高浓度的硼-10到肿瘤细胞。以前的有限的测试，这一假设在文献中报道，但只有少数穷人的特点代理人进行了检查。然而，我们的初步结果确定，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，加上我们建议开发的新类似物，将为进一步开发更有效的药物提供平台。将在加州大学戴维斯麦克莱伦核辐射中心的2兆瓦TRIGA核反应堆中评估新的硼化卟啉用于BNCT的有效性。

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.