Author(s):
Costa, Pedro M. 
; Cardoso, Ana L. ; Mendonça, Liliana S. ; Serani, Angelo ; Custódia, Carlos ; Conceição, Mariana ; Simões, Sérgio ; Moreira, João N. ; Almeida, Luis Pereira de ; de Lima, M. C. P.
Date: 2013
Persistent ID: http://hdl.handle.net/10316/25539
Origin: Estudo Geral - Universidade de Coimbra
Subject(s): chlorotoxin; glioblastoma; liposome; miR-21; stable nucleic acid lipid particle
Description
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. This work was supported
by the Portuguese Foundation for Science and Technology
(grants PTDC/DTP-FTO/0265/2012, PTDC/SAUFAR/
116535/2010 and PEst-C/SAU/LA0001/20119). The
drug sunitinib was kindly provided by Pfizer. P.M.C. is recipient
of a fellowship from the Portuguese Foundation for Science
and Technology (SFRH/BD/45902/2008).
