microRNA 21 silencing using targeted nanoparticles: a promising therapy for glioma

A research team from the Center for Neuroscience and Cell Biology, University of Coimbra, developed a targeted lipid-based nanosystem for specific nucleic acid delivery to glioma cells. The exposure of glioma cells to nanoparticles encapsulating anti-microRNA-21 oligonucleotides enhanced the anti-tumoral effect of the anti-angiogenic drug sunitinib. Moreover, increased particle accumulation was found after therapeutic intravenous administration, in a mouse model of glioma. The results obtained in this study show that the developed therapeutic approach has potential for future clinical application.

Auhors and affiliations:
Pedro M. Costa, Ana L. Cardoso, Liliana S. Mendonça, Angelo Serani, Carlos Custódia, Mariana Conceição, Sérgio Simões, João N Moreira, Luís P. de Almeida and Maria C. Pedroso de Lima

CNC - Centro de Neurociências e Biologia Celular, Universidade de Coimbra

Abstract:
The 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 (<180nm) 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.

Journal:
Molecular Therapy - Nucleic Acids

Link:

http://www.nature.com/mtna/journal/v2/n6/pdf/mtna201330a.pdf