Two-step synthesis of multivalent cancer-targeting constructs.
Two-step synthesis of multivalent cancer-targeting constructs.
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DOI：
10.1021/bm9010276
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发表时间：
2010-01
影响因子：
6.2
通讯作者：
Jill M. Stukel;R. C. Li;H. Maynard;M. Caplan
中科院分区：
文献类型：
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作者：
Jill M. Stukel;R. C. Li;H. Maynard;M. Caplan
已提出通过连接一个或多个过表达受体的一个或多个配体来选择性地将构建物靶向病理细胞，以增强对特定感兴趣细胞的治疗药物的传递和成像。我们实验室以前的工作已经证明了以α(6)β(1)整合素为靶向的多价生物大分子构建物靶向胶质母细胞瘤细胞的有效性。然而，固相合成这种结构在成本和步骤数量方面效率低下。在这里，我们展示了两步合成的概念证明，该合成可用于创建针对胶质母细胞瘤细胞的类似结构。具体地说，合成了一种定义明确的醛侧链聚合物，并利用肟化化学连接了α(6)β(1)-整合素的特异性配体。这些构建物随后在竞争结合、荧光结合和毒性分析中进行了测试，通过这些测试，我们证明了构建体是多价的，优先针对胶质母细胞瘤细胞，并且是无毒的。靶向结构的快速、潜在的低成本合成将使它们能够在临床和个性化药物中使用。
Selective targeting of constructs to pathological cells by conjugating one or more ligands for an overexpressed receptor has been proposed to enhance the delivery of therapeutics to and imaging of specific cells of interest. Previous work in our lab has demonstrated the efficacy of targeting glioblastoma cells with a multivalent, biomacromolecular construct targeted to the alpha(6)beta(1)-integrin. However, solid-phase synthesis of this construct was inefficient in terms of cost and number of steps. Here we show proof-of-concept of a two-step synthesis that can be used to create similar constructs targeted to glioblastoma cells. Specifically, a well-defined aldehyde side chain polymer was synthesized and oxime chemistry was employed to conjugate ligands specific for the alpha(6)beta(1)-integrin. These constructs were then tested in competitive binding, fluorescence binding, and toxicity assays, through which we demonstrate that constructs are multivalent, preferentially target glioblastoma cells, and are nontoxic. Rapid, potentially low-cost synthesis of targeting constructs will enable their use in the clinic and for personalized medicine.