In vivo potentialities of EWS-Fli-1 targeted antisense oligonucleotides-nanospheres complexes.
The EWS/FLI-1 fusion gene, resulting from a t(11;22) translocation, plays a key role in the pathogenesis of Ewing sarcoma. Previously, we have shown that antisense oligonucleotides designed against EWS-Fli-1 inhibited tumor growth in nude mice provided they were delivered intratumorally by nanocapsules or by CTAB-coated nanospheres. In this study, we have used two types of nanospheres (designated as type 1 and type 2 nanospheres) stabilized with chitosan for both intratumoral and systemic administration of oligonucleotides. Inhibition of the tumor growth in vivo was found to be dependent on the carrier type as well as on antisense oligonucleotide modification. Indeed, whereas both types of nanospheres were efficient in reducing tumor growth after intratumoral injection, we have obtained only with type 2 nanospheres an antitumoral effect after intravenous injection in a preliminary experiment. Additionally, the anticancer efficacy of a localized modification of the EWS-Fli-1 phosphodiester/phosphorothioate chimeric antisense oligonucleotide was demonstrated. In cell culture the oligonucleotides inhibit cell growth by their antisense activity. Further investigations are needed in vivo to learn the mechanism of action of the complexes.
Maksimenko
Andrei
A
Bioalliance Pharma SA, Paris 75015, France.
Polard
Valerie
V
Villemeur
Marie
M
Elhamess
Hind
H
Couvreur
Patrick
P
Bertrand
Jean-Remi
JR
Aboubakar
Malam
M
Gottikh
Marina
M
Malvy
Claude
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D048271:Chitosan / Q000737:chemistry; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D041681:NIH 3T3 Cells; D043942:Nanotubes / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000378:metabolism*; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D013997:Time Factors
D000970:Antineoplastic Agents; C106031:EWS-FLI fusion protein; C497426:Fli1 protein, mouse; D016376:Oligonucleotides, Antisense; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D048271:Chitosan