Using Dendrimers to Design Multivalent Therapeutic Agents

描述（申请人提供）：我们拟研究蛋白质-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。我们将使用带有碳水化合物簇的树状大分子，以及使用上一个资助周期开发的技术合成的异质功能化树状大分子，来研究与癌症转移相关的结合和粘附过程。具体来说，n -乙酰半乳糖胺、乳糖和gm3功能化树状大分子的合成进行了描述。为了确定半乳糖凝集素-3和乳糖功能化树状大分子的亲和力以及gm3功能化树状大分子对碳水化合物阵列的亲和力，提出了结合实验。碳水化合物功能化的树状大分子与其受体具有高亲和力结合，将通过癌细胞聚集研究进一步评估。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，开发像本提案中描述的那样能够适当地模拟和干扰癌细胞聚集过程的人工碳水化合物阵列是至关重要的。从这里提出的研究，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，可能会出现新的治疗药物来阻止癌细胞聚集。推进介导转移过程关联的基础知识，开发多价纳米级治疗药物来阻止癌症转移，显然对公共卫生具有巨大意义。

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.