Using Dendrimers to Design Multivalent Therapeutic Agents

使用树枝状聚合物设计多价治疗剂

• 批准号: 7939520
• 负责人: Mary J Cloninger
• 金额: $ 4.19万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939520
• 关键词: Affinity; Architecture; Binding; Binding Sites; Biochemistry; Biological Assay; Biological Models; Carbohydrates; Cell Aggregation; Cell surface; Dendrimers; Development; Distant; Exhibits; Funding; Galactosamine; Galectin 3; Goals; Knowledge; Lactose; Lectin; Malignant - descriptor; Malignant Neoplasms; Mediating; Neoplasm Metastasis; Polymers; Process; Protein-Carbohydrate Interaction; Proteins; Public Health; Reporting; Research; Role; Techniques; Therapeutic Agents; Work; adhesion process; base; cancer cell; design; metastatic process; nanoscale; novel therapeutics; programs; receptor; tool

We propose to study the roles of protein-carbohydrate and carbohydrate-carbohydrate interactions in cancer metastasis. We'll use dendrimers with clusters of carbohydrates, as well as heterogeneously-functionalized dendrimers synthesized using techniques developed in the last funding cycle, to study binding and adhesion processes associated with cancer metastasis. Specifically, the syntheses of N-acetyl galactosamine, lactose, and GM3-functionalized dendrimers are described. Binding assays to determine the affinity of the gal-NAc and lactose-functionalized dendrimers for galectin-3 and to determine the affinity of GM3- functionalized dendrimers for carbohydrate arrays are proposed. Carbohydrate-functionalized dendrimers that exhibit high affinity binding to their receptors will be further evaluated using cancer cell aggregation studies. Many reports suggest that cell surface carbohydrates serve a critical function in malignant transformation and metastasis, and so the development of artificial carbohydrate arrays such as those described in this proposal that can aptly mimic and interfere with cancer cell aggregation processes is critical. From the research proposed here, our goal is to advance fundamental knowledge regarding the role of protein- carbohydrate and carbohydrate-carbohydrateinteractions in the metastatic spread of cancer. Concurrently, new therapeutic agents to arrest cancer cell aggregation may emerge. Advancing the fundamental knowledge of the associations that mediate metastatic processes and developing multivalent, nanoscale therapeutic agents to arrest cancer metastasis clearly have enormous implications for public health.

我们建议研究蛋白质-碳水化合物和碳水化合物-碳水化合物相互作用在癌症中的作用 转移我们将使用带有碳水化合物簇的树枝状聚合物，以及异质功能化的 使用上一个资助周期开发的技术合成的树枝状聚合物，用于研究结合和粘附 与癌症转移相关的过程。具体而言，N-乙酰基半乳糖胺的合成， 乳糖和GM 3官能化的树枝状聚合物。结合测定以确定抗体的亲和力。 Gal-NAc和乳糖官能化的树枝状聚合物对半乳糖凝集素-3的亲和力，并测定GM 3- 提出了用于碳水化合物阵列的官能化树枝状聚合物。碳水化合物功能化树枝状大分子 将使用癌细胞聚集来进一步评价显示出与其受体的高亲和力结合的细胞 问题研究 许多报告表明，细胞表面碳水化合物在恶性转化中起着关键作用 和转移，因此人工碳水化合物阵列的发展，如本文所述的那些， 能够恰当地模拟和干扰癌细胞聚集过程的提议是至关重要的。从 在这里提出的研究中，我们的目标是推进关于蛋白质作用的基础知识， 碳水化合物和碳水化合物-碳水化合物在癌症转移扩散中的相互作用。与此同时， 可能出现阻止癌细胞聚集的新治疗剂。 推进介导转移过程的协会的基本知识， 开发多价纳米级治疗剂来阻止癌症转移显然具有巨大的 对公共卫生的影响。