Tyrosine-modified linear PEIs for highly efficacious and biocompatible siRNA delivery in vitro and in vivo
| Autor: | Heike Franke, Maksim Ionov, Małgorzata Kubczak, Michael Karimov, Ines Gockel, Tim Kahl, Marion Schulz, Alexander Ewe, Achim Aigner, Maria Bryszewska, Ute Krügel, René Thieme, Sandra Noske, Thomas Büch, Anja Reinert |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Small interfering RNA
Biomedical Engineering Mice Nude Pharmaceutical Science Medicine (miscellaneous) Bioengineering Mice SCID 02 engineering and technology Gene delivery Transfection Mice 03 medical and health sciences Mice Inbred NOD RNA interference In vivo Cell Line Tumor Animals Humans Polyethyleneimine Gene silencing General Materials Science RNA Small Interfering 030304 developmental biology 0303 health sciences Gene knockdown Chemistry Genetic Therapy Neoplasms Experimental 021001 nanoscience & nanotechnology Xenograft Model Antitumor Assays In vitro Cell culture Cancer research Molecular Medicine 0210 nano-technology |
| Zdroj: | Nanomedicine: Nanotechnology, Biology and Medicine. 36:102403 |
| ISSN: | 1549-9634 |
| DOI: | 10.1016/j.nano.2021.102403 |
| Popis: | Therapeutic gene silencing by RNA interference relies on the safe and efficient in vivo delivery of small interfering RNAs (siRNAs). Polyethylenimines are among the most studied cationic polymers for gene delivery. For several reasons including superior tolerability, small linear PEIs would be preferable over branched PEIs, but they show poor siRNA complexation. Their chemical modification for siRNA formulation has not been extensively explored so far. We generated a set of small linear PEIs bearing tyrosine modifications (LPxY), leading to substantially enhanced siRNA delivery and knockdown efficacy in vitro in various cell lines, including hard-to-transfect cells. The tyrosine-modified linear 10 kDa PEI (LP10Y) is particularly powerful, associated with favorable physicochemical properties and very high biocompatibility. Systemically administered LP10Y/siRNA complexes reveal antitumor effects in mouse xenograft and patient-derived xenograft (PDX) models, and their direct application into the brain achieves therapeutic inhibition of orthotopic glioma xenografts. LP10Y is particularly interesting for therapeutic siRNA delivery. |
| Databáze: | OpenAIRE |
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