Chen Yijie, Wang Xinran, Liu Ting, Zhang Ding Sheng-Zi, Wang Yunfei, Gu Hongchen, Di Wen
State Key Laboratory of Oncogenes and Related Genes, Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China ; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China ; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, People's Republic of China.
Int J Nanomedicine. 2015 Mar 31;10:2579-94. doi: 10.2147/IJN.S78774. eCollection 2015.
Therapeutic antiangiogenesis strategies have demonstrated significant antitumor efficacy in ovarian cancer. Recently, RNA interference (RNAi) has come to be regarded as a promising technology for treatment of disease, especially cancer. In this study, vascular endothelial growth factor (VEGF)-small interfering RNA (siRNA) was encapsulated into a magnetic mesoporous silica nanoparticle (M-MSN)-based, polyethylenimine (PEI)-capped, polyethylene glycol (PEG)-grafted, fusogenic peptide (KALA)-functionalized siRNA delivery system, termed M-MSN_VEGF siRNA@PEI-PEG-KALA, which showed significant effectiveness with regard to VEGF gene silencing in vitro and in vivo. The prepared siRNA delivery system readily exhibited cellular internalization and ease of endosomal escape, resulting in excellent RNAi efficacy without associated cytotoxicity in SKOV3 cells. In in vivo experiments, notable retardation of tumor growth was observed in orthotopic ovarian tumor-bearing mice, which was attributed to significant inhibition of angiogenesis by systemic administration of this nanocarrier. No obvious toxic drug responses were detected in major organs. Further, the magnetic core of M-MSN_VEGF siRNA@PEI-PEG-KALA proved capable of probing the site and size of the ovarian cancer in mice on magnetic resonance imaging. Collectively, the results demonstrate that an M-MSN-based delivery system has potential to serve as a carrier of siRNA therapeutics in ovarian cancer.
治疗性抗血管生成策略已在卵巢癌中显示出显著的抗肿瘤疗效。最近，RNA干扰（RNAi）已成为一种有前途的疾病治疗技术，尤其是癌症治疗。在本研究中，血管内皮生长因子（VEGF）小干扰RNA（siRNA）被封装到一种基于磁性介孔二氧化硅纳米颗粒（M-MSN）、聚乙二胺（PEI）封端、聚乙二醇（PEG）接枝、融合肽（KALA）功能化的siRNA递送系统中，称为M-MSN_VEGF siRNA@PEI-PEG-KALA，该系统在体外和体内对VEGF基因沉默均显示出显著效果。所制备的siRNA递送系统易于实现细胞内化并易于从内体逃逸，在SKOV3细胞中产生了优异的RNAi效果且无相关细胞毒性。在体内实验中，原位荷卵巢肿瘤小鼠的肿瘤生长明显迟缓，这归因于全身给药该纳米载体对血管生成的显著抑制。在主要器官中未检测到明显的药物毒性反应。此外，M-MSN_VEGF siRNA@PEI-PEG-KALA的磁性核心在磁共振成像中能够探测小鼠卵巢癌的部位和大小。总体而言，结果表明基于M-MSN的递送系统有潜力作为卵巢癌中siRNA治疗药物的载体。
