Tumor-targeted Chlorotoxin-coupled Nanoparticles for Nucleic Acid Delivery to Glioblastoma Cells: A Promising System for Glioblastoma Treatment.
Tumor-targeted Chlorotoxin-coupled Nanoparticles for Nucleic Acid Delivery to Glioblastoma Cells: A Promising System for Glioblastoma Treatment.
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DOI：
10.1038/mtna.2013.30
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发表时间：
2013-06-18
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本工作旨在开发和应用基于脂质的纳米载体，用于向胶质母细胞瘤（GBM）靶向递送核酸。为此目的，氯毒素（CTX），一种肽报道选择性结合神经胶质瘤细胞，而不显示非肿瘤细胞的亲和力，共价偶联到脂质体封装反义寡核苷酸（asO）或小干扰RNA（siRNA）。所得到的靶向纳米颗粒，称为CTX偶联的稳定核酸脂质颗粒（SNALP），表现出用于体内应用的优异特征，即小尺寸（<180 nm）和中性表面电荷。细胞缔合和内化研究表明，CTX到脂质体表面的附件增强颗粒内化到胶质瘤细胞，而在非癌细胞中没有观察到显着的内化。此外，在U87人GBM和GL 261小鼠胶质瘤细胞中纳米颗粒介导的miR-21沉默导致肿瘤抑制因子PTEN和PDCD 4、半胱天冬酶3/7活化水平升高，并降低肿瘤细胞增殖。初步的体内研究表明，CTX增强颗粒内化到已建立的颅内肿瘤。总的来说，我们的研究结果表明，开发的靶向纳米粒子代表了一种有价值的工具，用于靶向核酸递送到癌细胞。与基于药物的治疗相结合，纳米颗粒介导的miR-21沉默构成了针对GBM的有希望的多模式治疗方法。
The present work aimed at the development and application of a lipid-based nanocarrier for targeted delivery of nucleic acids to glioblastoma (GBM). For this purpose, chlorotoxin (CTX), a peptide reported to bind selectively to glioma cells while showing no affinity for non-neoplastic cells, was covalently coupled to liposomes encapsulating antisense oligonucleotides (asOs) or small interfering RNAs (siRNAs). The resulting targeted nanoparticles, designated CTX-coupled stable nucleic acid lipid particles (SNALPs), exhibited excellent features for in vivo application, namely small size (<180 nm) and neutral surface charge. Cellular association and internalization studies revealed that attachment of CTX onto the liposomal surface enhanced particle internalization into glioma cells, whereas no significant internalization was observed in noncancer cells. Moreover, nanoparticle-mediated miR-21 silencing in U87 human GBM and GL261 mouse glioma cells resulted in increased levels of the tumor suppressors PTEN and PDCD4, caspase 3/7 activation and decreased tumor cell proliferation. Preliminary in vivo studies revealed that CTX enhances particle internalization into established intracranial tumors. Overall, our results indicate that the developed targeted nanoparticles represent a valuable tool for targeted nucleic acid delivery to cancer cells. Combined with a drug-based therapy, nanoparticle-mediated miR-21 silencing constitutes a promising multimodal therapeutic approach towards GBM.
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