Targeted Delivery of PLK1-siRNA by ScFv Suppresses Her2+ Breast Cancer Growth and Metastasis
Targeted Delivery of PLK1-siRNA by ScFv Suppresses Her2+ Breast Cancer Growth and Metastasis
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ScFv 靶向递送 PLK1-siRNA 可抑制 Her2 乳腺癌生长和转移
DOI：
10.1126/scitranslmed.3003601
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发表时间：
2012-04-18
影响因子：
17.1
通讯作者：
Song, Erwei
中科院分区：
文献类型：
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作者：
Yao, Yan-dan;Sun, Tian-meng;Song, Erwei
将小干扰RNA（siRNAs）开发为癌症药物的一个主要障碍是它们向扩散的癌细胞的细胞内递送。单链抗体片段（ScFvs）和带正电荷的肽的融合蛋白可将siRNAs递送到特定的靶细胞中。然而，ScFv介导的siRNA递送的治疗潜力尚未在癌症中得到评估。在此，我们测试了与Her2 - ScFv - 鱼精蛋白肽融合蛋白（F5 - P）复合的Polo样激酶1（PLK1）siRNAs是否能在原位乳腺癌模型中抑制Her2（+）乳腺癌细胞系和原发性人类癌症。由F5 - P转运的PLK1 - siRNAs在体外抑制了靶基因表达，减少了增殖，并诱导了Her2（+）乳腺癌细胞系和原发性人类癌细胞的凋亡，且未引发干扰素反应。静脉注射的F5 - P/PLK1 - siRNA复合物在原位Her2（+）乳腺癌异种移植物中富集，并持续至少72小时，导致PLK1基因表达受抑和肿瘤细胞凋亡。静脉注射的siRNA复合物延缓了Her2（+）乳腺肿瘤的生长，减少了转移，并延长了生存期，且无明显毒性。F5 - P介导的PLK1、CCND1和AKT siRNAs混合物的递送比同等剂量的单一PLK1 - siRNAs更有效。这些数据表明，F5 - P可用于递送siRNAs来治疗Her2（+）乳腺癌。
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.