Abstract：
Hepatocyte growth factor receptor (c-Met) is a suitable molecular target for the targeted therapy of cancer. Novel c-Met-targeting drugs need to be developed because conventional small-molecule inhibitors and antibodies of c-Met have some limitations. To synthesize such drugs, we developed a bispecific DNA nanoconnector (STPA) to inhibit c-Met function. STPA was constructed by using DNA triangular prism as a scaffold and aptamers as binding molecules. After c-Met-specific SL1 and nucleolin-specific AS1411 aptamers were integrated with STPA, STPA could bind to c-Met and nucleolin on the cell membrane. This led to the formation of the c-Met/STPA/nucleolin complex, which in turn blocked c-Met activation. In vitro experiments showed that STPA could not only inhibit the c-Met signaling pathways but also facilitate c-Met degradation through lysosomes. STPA also inhibited c-Met-promoted cell migration, invasion, and proliferation. The results of in vivo experiments showed that STPA could specifically target to tumor site in xenograft mouse model, and inhibit tumor growth with low toxicity by downregulating c-Met pathways. This study provided a novel and simple strategy to develop c-Met-targeting drugs for the targeted therapy of cancer.
摘要：
肝细胞生长因子受体(c-Met)是肿瘤靶向治疗的合适分子靶点。由于常规的c-Met小分子抑制剂和抗体具有一定的局限性,需要开发新的c-Met靶向药物。为了合成这些药物，我们开发了一种双特异性DNA纳米连接器（STPA）来抑制c-Met功能。STPA是通过使用DNA三角棱镜作为支架和适体作为结合分子来构建的。在c-Met特异性SL1和核仁素特异性AS1411适体与STPA整合后，STPA可以与细胞膜上的c-Met和核仁素结合。这导致了c-Met/STPA/核仁素复合物的形成，这反过来又阻止了c-Met激活。体外实验表明，STPA不仅可以抑制c-Met信号通路，而且可以通过溶酶体促进c-Met降解。STPA还抑制c-Met促进细胞迁移，入侵,和扩散。体内实验结果表明,在异种移植小鼠模型中,STPA能特异性靶向肿瘤部位,并通过下调c-Met途径以低毒性抑制肿瘤生长。本研究为开发用于癌症靶向治疗的c-Met靶向药物提供了一种新颖而简单的策略。
