Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer.
Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer.
复制标题
DOI：
10.1038/srep30346
复制
发表时间：
2016-07-26
影响因子：
4.6
通讯作者：
She JX
中科院分区：
文献类型：
--
作者：
Liu HY;Yu X;Liu H;Wu D;She JX
目前使用小激酶抑制剂和抗体的靶向疗法在治疗前列腺癌（PCa）方面效果有限，前列腺癌是美国男性癌症死亡的主要原因。我们已经开发了一种新的策略，通过工程改造的RNA为基础的适配子-siRNA嵌合体，其中二价适配子特异性结合前列腺特异性膜抗原（PSMA）通过抗体样结构，以促进siRNA的内化在PCa细胞，和两个siRNA特异性EGFR和生存素之间融合的两个适配子。该嵌合体能够同时抑制EGFR和Survivin，并在体内外有效诱导细胞凋亡。在C4-2 PCa异种移植模型中，用嵌合体治疗显著抑制肿瘤生长和血管生成。血管生成的抑制是由EGFR-HIF 1 α-VEGF依赖性机制介导的。我们的结果支持二价适体驱动的两种siRNA的递送可能是一种新的组合治疗策略，以有效地抑制多个和常规的“不可用药”的靶点。
Current targeted therapies using small kinase inhibitors and antibodies have limited efficacy in treating prostate cancer (PCa), a leading cause of cancer death in American men. We have developed a novel strategy by engineering an RNA-based aptamer-siRNA chimera, in which a bivalent aptamer specifically binds prostate-specific membrane antigen (PSMA) via an antibody-like structure to promote siRNA internalization in PCa cells, and two siRNAs specific to EGFR and survivin are fused between two aptamers. The chimera is able to inhibit EGFR and survivin simultaneously and induce apoptosis effectively in vitro and in vivo. In the C4-2 PCa xenograft model, the treatment with the chimera significantly suppresses tumor growth and angiogenesis. The inhibition of angiogenesis is mediated by an EGFR-HIF1α-VEGF-dependent mechanism. Our results support that the bivalent aptamer-driven delivery of two siRNAs could be a new combination therapeutic strategy to effectively inhibit multiple and conventionally “undruggable” targets.