Using Dendrimers to Design Multivalent Therapeutic Agents

描述（由申请人提供）：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转移中的作用。我们将使用具有碳水化合物簇的树枝状聚合物，以及使用上一个资助周期中开发的技术合成的异质功能化树枝状聚合物，来研究与癌症转移相关的结合和粘附过程。具体地，描述了N-乙酰基半乳糖胺、乳糖和GM 3官能化树枝状聚合物的合成。提出了确定半乳糖-NAc和乳糖官能化的树枝状聚合物对半乳糖凝集素-3的亲和力和确定GM 3官能化的树枝状聚合物对碳水化合物阵列的亲和力的结合测定。碳水化合物官能化的树枝状聚合物，表现出高亲和力结合其受体将进一步评估使用癌细胞聚集研究。许多报告表明，细胞表面碳水化合物在恶性转化和转移中起着关键作用，因此开发人工碳水化合物阵列（如本提案中描述的那些）可以适当地模拟和干扰癌细胞聚集过程是至关重要的。从这里提出的研究中，我们的目标是推进关于蛋白质-碳水化合物和碳水化合物-碳水化合物相互作用在癌症转移扩散中的作用的基础知识。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础知识和开发多价纳米级治疗剂以阻止癌症转移显然对公共卫生具有巨大的影响。

DESCRIPTION (provided by applicant): 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-carbohydrate interactions 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.