Tumor-targeted Chlorotoxin-coupled Nanoparticles for Nucleic Acid Delivery to Glioblastoma Cells: A Promising System for Glioblastoma Treatment

被引:84
作者
Costa, Pedro M. [1 ,2 ]
Cardoso, Ana L. [1 ]
Mendonca, Liliana S. [1 ]
Serani, Angelo [1 ]
Custodia, Carlos [2 ]
Conceicao, Mariana [1 ,3 ]
Simoes, Sergio [1 ,3 ]
Moreira, Joao N. [1 ,3 ]
de Almeida, Luis Pereira [1 ,3 ]
Pedroso de Lima, Maria C. [1 ,2 ]
机构
[1] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3001401 Coimbra, Portugal
[2] Univ Coimbra, Dept Life Sci, Fac Sci & Technol, P-3001401 Coimbra, Portugal
[3] Univ Coimbra, Fac Pharm, P-3001401 Coimbra, Portugal
来源
MOLECULAR THERAPY-NUCLEIC ACIDS | 2013年 / 2卷
关键词
chlorotoxin; glioblastoma; liposome; miR-21; stable nucleic acid lipid particle; IN-VIVO; SYNERGISTIC INHIBITION; STEALTH LIPOSOMES; DOWN-REGULATION; CANCER-CELLS; GENE; GLIOMA; SIRNA; MIR-21; SUPPRESSOR;
D O I
10.1038/mtna.2013.30
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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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页数:13
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