Pyridylthiourea-grafted polyethylenimine offers an effective assistance to siRNA-mediated gene silencing in vitro and in vivo.
Fiche publication
Date publication
février 2012
Journal
Journal of controlled release : official journal of the Controlled Release Society
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DONTENWILL Monique, Dr FRISCH Benoit, Dr GUERIN Eric, Dr ZUBER Guy
Tous les auteurs :
Creusat G, Thomann JS, Maglott A, Pons B, Dontenwill M, Guérin E, Frisch B, Zuber G
Lien Pubmed
Résumé
Success of synthetic interfering nucleic acids (siRNAs)-based therapy relies almost exclusively on effective, safe and preferably nanometric delivery systems which can be easily prepared, even at high concentrations. We prepared by chemical synthesis various self-assembling polymers to entrap siRNAs into stable polyplexes outside cells but with a disassembly potential upon sensing endosomal acidity. Our results revealed that pyridylthiourea-grafted polyethylenimine (πPΕΙ) followed the above-mentioned principles. It led to above 90% siRNA-mediated gene silencing in vitro on U87 cells at 10 nM siRNA concentration and did not have a hemolytic activity. Assembly of siRNA/πPΕΙ at high concentration was then studied and 4.5% glucose solution, pH 6.0, yielded stable colloidal solutions with sizes slightly below 100 nm for several hours. A single injection of these concentrated siRNA polyplexes into luciferase-expressing human glioblastoma tumors, which were subcutaneously xenografted into nude mice, led to a significant 30% siRNA-mediated luciferase gene silencing 4 days post-injection. Our results altogether substantiate the potential of self-assembling cationic polymers with a pH-sensitive disassembly switch for siRNA delivery in vitro and also in vivo experiments.
Mots clés
Animals, Cell Line, Tumor, Cell Survival, drug effects, Erythrocytes, drug effects, Gene Silencing, Hemolysis, drug effects, Humans, Hydrophobic and Hydrophilic Interactions, Male, Mice, Mice, Nude, Neoplasm Transplantation, Neoplasms, metabolism, Polyethyleneimine, administration & dosage, RNA, Small Interfering, administration & dosage, Sheep, Thiourea, administration & dosage
Référence
J Control Release. 2012 Feb;157(3):418-26