Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China.
Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
Biomaterials. 2015 Aug;59:77-87. doi: 10.1016/j.biomaterials.2015.04.030. Epub 2015 May 15.
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-siRNA (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.
基于短干扰 RNA（siRNA）的治疗方法在治疗人类疾病方面具有巨大的潜力。然而，siRNA 的临床应用受到其细胞内摄取不良、血清稳定性低和无法靶向特定细胞等因素的限制。在这项研究中，我们通过使用 HER2-scFv-精氨酸九肽融合蛋白（e23sFv-9R）作为 siRNA 载体，合成了一种针对 CXCR4 的靶向 siRNA（CXCR4si），用于治疗 HER2（+）乳腺癌，从而解决了这种特异性缺乏的问题。e23sFv-9R 结合的 siRNA 能够特异性地将 siRNA 递送至 HER2（+）乳腺癌细胞，并在同源性 HER2（+）乳腺癌异种移植瘤中至少聚集和持续 36 小时。e23sFv-9R 递呈的 CXCR4si 抑制了 CXCR4 基因表达，降低了体外 HER2（+）乳腺癌 BT-474 细胞系的增殖和转移，并诱导了细胞凋亡。此外，e23sFv-9R 系统递送的 CXCR4si 能够抑制携带 HER2（+）异种移植瘤的小鼠的肿瘤生长、减少转移并延长其生存时间。这种方法不会引起全身毒性，也不会激活先天免疫反应，这表明携带 CXCR4si 的融合蛋白在治疗 HER2 过表达的乳腺癌方面具有广阔的前景。
