Targeted delivery of CXCR4-siRNA by scFv for HER2+ breast cancer therapy
Targeted delivery of CXCR4-siRNA by scFv for HER2+ breast cancer therapy
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通过 scFv 靶向递送 CXCR4-siRNA 用于 HER2( ) 乳腺癌治疗。
DOI：
10.1016/j.biomaterials.2015.04.030
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发表时间：
2015-08-01
期刊：
影响因子：
14
通讯作者：
Ma, Baoan
中科院分区：
文献类型：
--
作者：
Jiang, Kuo;Li, Jia;Ma, Baoan
基于短干扰RNA(SiRNAs)的治疗学在治疗人类疾病方面具有巨大的潜力。然而，siRNAs的细胞内摄取差、血清稳定性低、不能靶向特定细胞等因素限制了其临床应用。在这项研究中，我们通过使用HER2-scFv-精氨酸九聚体多肽融合蛋白(e23sFv-9R)作为siRNA载体，合成了用于治疗HER2(+)乳腺癌的分子靶向CXCR4-5iRNA(CXCR4si)，以解决这一缺乏特异性的问题。E23sFv-9R结合的siRNA能够特异性地将siRNA传递给HER2(+)乳腺癌细胞，并在HER2(+)乳腺癌原位移植瘤中浓缩并持续至少36h，e23sFv-9R携带的CXCR4si在体外抑制HER2(+)乳腺癌BT-474细胞系CXCR4基因的表达，减少增殖和转移，并诱导细胞凋亡。此外，通过e23sFv-9R系统递送CXCR4si能够抑制HER2(+)移植瘤小鼠的肿瘤生长，减少转移，延长生存期。这种方法不会引起全身毒性，也不会激活先天性免疫反应，这表明携带CXCR4si的融合蛋白在治疗HER2过表达的乳腺癌方面有希望。(C)2015爱思唯尔有限公司。保留所有权利。
Therapeutics based on short interfering RNAs (siRNAs) have great potential to treat human diseases. However, the clinical application of siRNAs has been limited by their poor intracellular uptake, low serum stability, and inability to target specific cells. In this study, we addressed this lack of specificity by synthesizing a molecularly targeted CXCR4-5iRNA (CXCR4si) for the treatment of HER2(+) breast cancers using a HER2-scFv-arginine nonamer peptide fusion protein (e23sFv-9R) as an siRNA carrier. The e23sFv-9R binding siRNA is able to specifically deliver the siRNA to HER2(+) breast cancer cells and concentrate and persist in orthotopic HER2(+) breast cancer xenografts for at least 36 h. CXCR4si delivered by e23sFv-9R inhibited CXCR4 gene expression, reduced proliferation and metastasis and induced apoptosis in the HER2(+) breast cancer BT-474 cell line in vitro. Moreover, the systemic delivery of CXCR4si by e23sFv-9R is able to suppress tumor growth, reduce metastasis and prolong survival in mice bearing HER2(+) xenografts. This approach causes no systemic toxicity and does not activate the innate immune response, suggesting that a fusion protein carrying CXCR4si shows promise in the treatment of HER2-overexpressing breast cancer. (C) 2015 Elsevier Ltd. All rights reserved.