TUMOR-TARGETING WITH NEW BORONATED PORPHYRINS

使用新型硼卟啉靶向肿瘤

• 批准号: 6777782
• 负责人: MARIA DA GRACA HENRIQUES VICENTE
• 金额: $ 19.85万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-10 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777782
• 关键词: amphiphilicity; boranes; boron; brain neoplasms; cell line; chemical property; chemical structure; chemical synthesis; cytotoxicity; hydropathy; laboratory mouse; laboratory rat; neoplasm /cancer photoradiation therapy; neoplastic growth; neutron radiation; nonhuman therapy evaluation; pharmacokinetics; physical property; porphyrins; radionuclide therapy; spectrometry

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.

描述(由申请人提供)：本提案针对开发适用于难治性脑瘤的新治疗方法的合适分子的需求；这一需求源于高质量中子束的生产和可获得性的进步。我们建议合成和表征新的无毒的含硼卟啉，它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)合成新的无毒的硼化卟啉；2)研究它们的物理化学和生物学性质；3)选择最有希望用于进一步动物研究的候选化合物；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。类似卟啉的大环已被证明选择性地定位于各种肿瘤组织中，这一特性为它们在光动力疗法(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增敏剂：PHOTOFRIN和Visudyne。到目前为止，Photofrin已经成功地用于治疗世界各地数以千计的癌症患者，目前正在进行二期脑瘤试验。BNCT是一种基于核反应的新兴治疗方法，当位于肿瘤内的B-10原子核捕获低能中子产生高线性能量转移粒子时，其细胞毒作用仅限于药物所在的细胞。美国、欧洲和日本正在进行1/11BNCT阶段的临床试验，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这一假设，即含硼的卟啉将保留卟啉的低毒和肿瘤定位特性，因此可以有效地将高浓度的硼-10输送到肿瘤细胞。以前的文献报道了对这一假说的有限测试，但只检查了几个特征不佳的试剂。然而，我们的初步结果证实，许多硼化的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。用于BNCT的新的硼化卟啉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核反应堆进行评估。