Anti-Her2 single-chain antibody mediated DNMTs-siRNA delivery for targeted breast cancer therapy
Anti-Her2 single-chain antibody mediated DNMTs-siRNA delivery for targeted breast cancer therapy
复制标题
DOI：
10.1016/j.jconrel.2012.05.015
复制
发表时间：
2012-08-10
影响因子：
10.8
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Dou, Shuang;Yao, Yan-Dan;Wang, Jun
针对特定的肿瘤组织和肿瘤细胞的小干扰RNA(SiRNA)的靶向传递仍然是RNA干扰作为治疗应用发展的关键挑战之一。为了针对乳腺癌，我们开发了一种治疗性递送系统，使用抗Her2单链抗体片段与带正电的鱼精蛋白的融合蛋白，即F5-P作为载体，将针对DNA甲基转移酶1和/或3b基因的siRNA特异性地递送到表达Her2的乳腺肿瘤细胞中。在大肠杆菌系统中表达的载体F5-P能够结合siRNA分子并特异性地将siRNA传递到表达Her2的BT474乳腺癌细胞，而不是不表达Her2的MDA-MB-231乳腺癌细胞，而siDNMTs成功地沉默了靶向DNA甲基转移酶(DNMTs)的表达，促进了RASSF1A抑癌基因启动子的去甲基化，从而抑制了肿瘤细胞的增殖。此外，在BT474异种移植小鼠模型中，F5-P成功地将siRNA转移到表达Her2的乳腺肿瘤中，静脉注射F5-P/siDNMTs复合体通过下调DNMTs的表达和恢复肿瘤抑制基因的表达来介导肿瘤生长抑制。这些数据表明，F5-P介导的siDNMTs可用于治疗表达Her2的乳腺癌。(C)2012爱思唯尔B.V.保留所有权利。
The targeted delivery of small interfering RNA (siRNA) to specific tumor tissues and tumor cells remains as one of the key challenges in the development of RNA interference as a therapeutic application. To target breast cancer, we developed a therapeutic delivery system using a fusion protein of an anti-Her2 single-chain antibody fragment with a positively charged protamine, namely F5-P, as the carrier to specifically deliver siRNA-targeting DNA methyltransferases 1 and/or 3b genes (siDNMTs) into Her2-expressing breast tumor cells. The carrier F5-P, expressed by the Escherichia coli system, was able to bind siRNA molecules and specifically deliver the siRNA to Her2-expressing BT474 breast cancer cells but not Her2-nonexpressing MDA-MB-231 breast cancer cells, while delivery of siDNMTs to BT474 cells successfully silenced the expression of targeted DNA methyltransferases (DNMTs) and facilitated the de-methylation of the RASSF1A tumor suppressor gene promoter, leading to the suppression of tumor cell proliferation. Moreover, as demonstrated in the BT474 xenograft murine model, F5-P successfully delivered siRNA into a Her2-expressing breast tumor, and tumor growth inhibition was mediated by an intravenous injection of F5-P/siDNMTs complex by down-regulating the expression of DNMTs and restoring tumor suppressor gene expression. These data suggest that the delivery of siDNMTs by F5-P could be used to treat Her2-expressing breast cancer. (c) 2012 Elsevier B.V. All rights reserved.