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题目:: Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis.
作者:: Yao(Yan-dan),Sun(Tian-meng),Huang(Song-yin),Dou(Shuang),Lin(Ling),Chen(Jia-ning),Ruan(Jian-bin),Mao(Cheng-qiong),Yu(Feng-yan),Zeng(Mu-sheng),Zang(Jian-ye),Liu(Qiang),Su(Feng-xi),Zhang(Peter),Lieberman(Judy),Wang(Jun),Song(Erwei)
状态:: 发布时间2012-04-20 , 更新时间 2014-11-20
期刊:: Sci Transl Med
摘要:: A major obstacle to developing small interfering RNAs (siRNAs) as cancer drugs is their intracellular delivery to disseminated cancer cells. Fusion proteins of single-chain fragmented antibodies (ScFvs) and positively charged peptides deliver siRNAs into specific target cells. However, the therapeutic potential of ScFv-mediated siRNA delivery has not been evaluated in cancer. Here, we tested whether Polo-like kinase 1 (PLK1) siRNAs complexed with a Her2-ScFv-protamine peptide fusion protein (F5-P) could suppress Her2(+) breast cancer cell lines and primary human cancers in orthotopic breast cancer models. PLK1-siRNAs transferred by F5-P inhibited target gene expression, reduced proliferation, and induced apoptosis of Her2(+) breast cancer cell lines and primary human cancer cells in vitro without triggering an interferon response. Intravenously injected F5-P/PLK1-siRNA complexes concentrated in orthotopic Her2(+) breast cancer xenografts and persisted for at least 72 hours, leading to suppressed PLK1 gene expression and tumor cell apoptosis. The intravenously injected siRNA complexes retarded Her2(+) breast tumor growth, reduced metastasis, and prolonged survival without evident toxicity. F5-P-mediated delivery of a cocktail of PLK1, CCND1, and AKT siRNAs was more effective than an equivalent dose of PLK1-siRNAs alone. These data suggest that F5-P could be used to deliver siRNAs to treat Her2(+) breast cancer.
语言:: eng
DOI:: 10.1126/scitranslmed.3003601

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