Systemic Delivery of Aptamer-Conjugated XBP1 siRNA Nanoparticles for Efficient Suppression of HER2+Breast Cancer
Systemic Delivery of Aptamer-Conjugated XBP1 siRNA Nanoparticles for Efficient Suppression of HER2+Breast Cancer
复制标题
DOI：
10.1021/acsami.0c07353
复制
发表时间：
2020-07-22
影响因子：
9.5
通讯作者：
Li, Huaqiong
中科院分区：
文献类型：
--
作者：
Zhang, Long;Mu, Chaofeng;Li, Huaqiong
SiRNA治疗作为一种新兴的药物开发类别，正在成功地进入临床应用。基于RNA的治疗被广泛用于探索机制和治疗各种基因特异性疾病。肿瘤是一种由癌基因驱动的疾病，许多基因与肿瘤进展和化疗耐药有关。虽然以人表皮生长因子受体2(HER2)为靶点的单抗治疗显著提高了生存率，但化疗对HER2阳性(HER2+)乳腺癌患者仍然是必不可少的。最近，X-box结合蛋白1(XBP1)参与了三阴性乳腺癌(TNBC)的化疗耐药和进展，但其在HER2+乳腺癌中的作用尚不清楚。在这里，我们使用核糖核酸酶抗性RNA纳米颗粒(NPs)来沉默XBP1的表达。静脉注射带有HER2特异性适配子的RNA NPs导致与肿瘤的强结合，但不与健康组织结合。在HER2+乳腺癌小鼠模型中，RNANPs缺失XBP1可抑制血管生成和抑制细胞增殖，显著抑制乳腺癌生长，并促进化疗增敏。总体而言，这些结果揭示了XBPI在HER2+乳腺癌发生和化疗耐药中的作用，并暗示通过RNA NPs靶向XBP1可能为未来乳腺癌的联合治疗提供一种简单且有前景的策略。
siRNA therapeutics as an emerging class of drug development is successfully coming to clinical utilization. The RNA-based therapy is widely utilized to explore the mechanism and cure a variety of gene-specific diseases. Tumor is an oncogene-driven disease; many genes are related to tumor progression and chemoresistance. Although human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody therapy has dramatically improved the survival rate, chemotherapy remains essential to HER2-positive (HER2+) breast cancer patients. Recently, X-box binding protein 1 (XBP1) has been involved in triple-negative breast cancer (TNBC) chemoresistance and progression, but its function in HER2+ breast cancer is poorly explored. Here, we silenced XBP1 expression using RNase-resistant RNA nanoparticles (NPs). Intravenous injection of RNA NPs with HER2-specific aptamers resulted in strong binding to tumors but not to healthy tissues. XBP1 deletion by RNA NPs impaired angiogenesis and inhibited cell proliferation, significantly suppressed breast cancer growth, and promoted the sensitization of chemotherapy in an HER2+ breast cancer mouse model. Overall, these results reveal the function of XBPI in HER2+ breast cancer development and chemoresistance and imply that targeting XBP1 by RNA NPs may offer an easy and promising strategy for a combination treatment of breast cancer in the future.