School of Biological and Health Systems Engineering, Center for Interventional Biomaterials, Arizona State University, Tempe, Arizona, USA.
Biomacromolecules. 2010 Jan 11;11(1):160-7. doi: 10.1021/bm9010276.
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.
通过将一个或多个针对过表达受体的配体与构建体连接，选择性地将构建体靶向病理细胞，已被提议用于增强治疗剂向特定靶细胞的递送和成像。我们实验室之前的工作已经证明，使用针对α(6)β(1)-整联蛋白的多价生物大分子构建体靶向神经胶质瘤细胞是有效的。然而，从成本和步骤数量的角度来看，这种构建体的固相合成效率不高。在这里，我们展示了两步合成的概念验证，该合成可用于构建针对神经胶质瘤细胞的类似构建体。具体来说，合成了一种具有明确醛侧链的聚合物，并采用肟化学将针对α(6)β(1)-整联蛋白的配体连接起来。然后通过竞争性结合、荧光结合和毒性测定来测试这些构建体，通过这些测试，我们证明了这些构建体是多价的，优先靶向神经胶质瘤细胞，并且无毒。针对构建体的快速、潜在低成本合成将使它们能够在临床和个性化医疗中得到应用。
