Using Dendrimers to Design Multivalent Therapeutic Agents

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。我们将使用具有碳水化合物簇的树枝状大分子，以及多官能化的 使用上一个资助周期中开发的技术合成的树枝状大分子，以研究结合和粘合 与癌症转移相关的过程。具体地，N-乙酰半乳糖胺的合成， 描述了乳糖和GM3官能化树枝状大分子。结合分析，以确定亲和力 Gal-NAC和乳糖功能化树状大分子对Galectin-3的作用，并测定GM3-的亲和力 提出了用于碳水化合物阵列的官能化树枝状大分子。碳水化合物功能化树枝状大分子 表现出与其受体高亲和力结合的将使用癌细胞聚集来进一步评估 学习。 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，如本文件中描述的 能够恰当地模仿和干扰癌细胞聚集过程的提议至关重要。从 在这里提出的研究，我们的目标是推进关于蛋白质的作用的基础知识- 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。同时， 可能会出现阻止癌细胞聚集的新治疗剂。 促进对调节转移过程和 开发多价、纳米级的治疗药物来阻止癌症转移显然具有巨大的 对公共卫生的影响。

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.