Pyridylthiourea-grafted polyethylenimine offers an effective assistance to siRNA-mediated gene silencing in vitro and in vivo
| Autor: | Benoît Frisch, Eric Guérin, Gaëlle Creusat, Anne Maglott, Monique Dontenwill, Guy Zuber, Bénédicte Pons, Jean-Sébastien Thomann |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Small interfering RNA Erythrocytes Endosome Cell Survival Pharmaceutical Science Mice Nude Chemical synthesis Hemolysis chemistry.chemical_compound Mice In vivo Cell Line Tumor Neoplasms Gene silencing Animals Humans Polyethyleneimine Gene Silencing RNA Small Interfering Polyethylenimine Sheep Chemistry Thiourea Molecular biology In vitro Nucleic acid Biophysics Hydrophobic and Hydrophilic Interactions Neoplasm Transplantation |
| Zdroj: | Journal of controlled release : official journal of the Controlled Release Society. 157(3) |
| ISSN: | 1873-4995 |
| Popis: | 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 (πPEΙ) 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/πPEΙ 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. |
| Databáze: | OpenAIRE |
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