title: Silencing of miR-21 by locked nucleic acid-lipid nanocapsule complexes sensitize human glioblastoma cells to radiation-induced cell death.
abstract: The recent discovery of microRNA (miRNA) as major post-transcriptional repressors prompt the interest of developing novel approaches to target miRNA pathways to improve therapy. In this context, although the most significant barrier to their widespread clinical use remains delivery, nuclease-resistant locked nucleic acid (LNA) that bind specifically and irreversibly to miRNA represent interesting weapons. Thus, by focusing on oncongenic miR-21 miRNA, which participate to cancer cell resistance to apoptotic signals, the aim of the present study was to investigate the possibility of silencing miRNA by LNA conjugated to lipid nanocapsules (LNCs) as miRNA-targeted nanomedicines in U87MG glioblastoma (GBM) cells. After synthesis of an amphiphilic lipopeptide affine for nucleic acids, a post-insertion procedure during the LNC phase inversion formulation process allowed to construct peptide-conjugated LNCs. Peptide-conjugated LNCs were then incubated with LNAs to allow the formation of complexes characterized in gel retardation assays and by their physicochemical properties. U87MG cell treatment by LNA-LNC complexes resulted in a marked reduction of miR-21 expression as assessed by RTqPCR. In addition, exposure of U87MG cells to LNA-LNC complexes followed by external beam radiation demonstrated a significant improvement of cell sensitivity to treatment and emphasizes the interest to investigate further this miRNA-targeted strategy.
authors.affiliation: Inserm U1066, Micro et nanomédecines biomimétiques, F-49933 Angers, France.
authors.forename: A
authors.initials: A
authors.lastname: Griveau
authors.forename: J
authors.initials: J
authors.lastname: Bejaud
authors.forename: S
authors.initials: S
authors.lastname: Anthiya
authors.forename: S
authors.initials: S
authors.lastname: Avril
authors.forename: D
authors.initials: D
authors.lastname: Autret
authors.forename: E
authors.initials: E
authors.lastname: Garcion
mesh_terms: D016923:Cell Death; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000235:genetics* / Q000532:radiotherapy*; D006801:Humans; D054709:Lecithins / Q000737:chemistry; D055666:Lipopeptides / Q000737:chemistry; D035683:MicroRNAs / Q000235:genetics*; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034622:RNA Interference; D013229:Stearic Acids / Q000737:chemistry; D014280:Triglycerides / Q000737:chemistry
chemical_list: D054709:Lecithins; D055666:Lipopeptides; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D053769:Nanocapsules; D009841:Oligonucleotides; D013229:Stearic Acids; D014280:Triglycerides; C542236:labrafac WL 1349; C477371:locked nucleic acid; D011092:Polyethylene Glycols; C067028:Solutol HS 15
keywords: Glioblastoma; Lipid nanocapsules; Locked nucleic acid; MicroRNA; Radiotherapy