title: Antisense oligonucleotide nanocapsules efficiently inhibit EWS-Fli1 expression in a Ewing's sarcoma model.
abstract: The cytogenetic abnormality of Ewing's sarcoma is related to the presence of a balanced t(11;22) translocation expressing the EWS-Fli1 chimeric fusion protein. Oligonucleotides (ODNs) are specific compounds that inhibit gene expression at the transcriptional level. They possess a poor bioavailability and are degraded by nucleases very rapidly. Therefore, there is a strong need for the development of ODN drug delivery systems. In the present study, polyisobutylcyanoacrylate nanocapsules entrapping ODNs in their aqueous core were prepared, with high encapsulation yield (99%). Previous studies have demonstrated that such complexes were able to inhibit tumor growth in mice. Nevertheless, no information was available about their mode of action at the cellular level. The aim of this study was to investigate the efficacy of these ODN nanocapsules on cultured tumor cells. We found that nanocapsules were capable of protecting ODN against degradation. Using confocal microscopy, we observed that cell uptake and nuclear accumulation of ODNs were importantly enhanced when ODNs were associated with these nanocapsules. Consequently, a specific cellular growth inhibition and suppression of EWSFli1 fusion gene expression was noticed. In conclusion, it was demonstrated that nanocapsules as nonviral vectors show great potential for the delivery of ODNs to cells.
authors.affiliation: Laboratoire de Physicochimie, Pharmacotechnie et Biopharmacie, UMR CNRS 8612, Faculté de Pharmacie, 92286 Châtenay-Malabry Cedex, France.
authors.forename: Nedjma
authors.initials: N
authors.lastname: Toub
authors.forename: Jean-Rémi
authors.initials: JR
authors.lastname: Bertrand
authors.forename: Claude
authors.initials: C
authors.lastname: Malvy
authors.forename: Elias
authors.initials: E
authors.lastname: Fattal
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics; D002214:Capsules / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D049329:Nanostructures / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000235:genetics
chemical_list: D002214:Capsules; C106031:EWS-FLI fusion protein; D016376:Oligonucleotides, Antisense; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS