Carbosilane dendrimers with phosphonium terminal groups are low toxic non-viral transfection vectors for siRNA cell delivery
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
30877030
DOI
10.1016/j.ijpharm.2019.03.018
PII: S0378-5173(19)30196-6
Knihovny.cz E-resources
- Keywords
- Gene therapy, Molecular dynamics, Non-viral vectors, Phosphonium carbosilane dendrimers, Small interfering RNA, Transfection,
- MeSH
- Cell Line MeSH
- Cricetulus MeSH
- Zebrafish MeSH
- Dendrimers administration & dosage toxicity MeSH
- Embryo, Nonmammalian MeSH
- Lethal Dose 50 MeSH
- RNA, Small Interfering administration & dosage MeSH
- Organophosphorus Compounds administration & dosage toxicity MeSH
- Silanes administration & dosage toxicity MeSH
- Transfection methods MeSH
- Gene Silencing MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- carbosilane MeSH Browser
- Dendrimers MeSH
- RNA, Small Interfering MeSH
- Organophosphorus Compounds MeSH
- Silanes MeSH
Non-viral gene delivery vectors studied in the gene therapy applications are often designed with the cationic nitrogen containing groups necessary for binding and cell release of nucleic acids. Disadvantage is a relatively high toxicity which restricts the in vivo use of such nanoparticles. Here we show, that the 3rd generation carbosilane dendrimers possessing (trimethyl)phosphonium (PMe3) groups on their periphery were able to effectively deliver the functional siRNA into the cells (B14, Cricetulus griseus), release it into the cytosol and finally to achieve up to 40% gene silencing of targeted gene (glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) with the comparable or, in some cases, even better effectivity as their ammonium counterparts. Moreover, such cationic dendrimers show relatively low in vivo toxicity as compared to their ammonium analogues when analyzed by standard fish embryo test (FET) on Danio rerio in vivo model, with LD50 = 6.26 µM after 48 h of incubation. This is more than 10-fold improvement as compared to published values for various other types of cationic dendrimers. We discuss the potential of further increase of the transfection efficiency, endosomal escape and decrease of toxicity of such non-viral vectors, based on the systematic screening of different types of substituents on central phosphonium atom.
Faculty of Science J E Purkyně University in Ústí nad Labem 40096 Ústí nad Labem Czech Republic
Leibniz Institute of Polymer Research Dresden Hohe Straße 6 D 01069 Dresden Germany
References provided by Crossref.org
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