Optimized polyethylenimine (PEI)-based nanoparticles for siRNA delivery, analyzed in vitro and in an ex vivo tumor tissue slice culture model
| Autor: | Alexander Ewe, Achim Aigner, Ingo Bechmann, Sabrina Höbel, Lea Merz, Sonja Kallendrusch, Heike Franke, Claudia Heine, Felicitas Merz |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Small interfering RNA
Mice Nude Pharmaceutical Science 02 engineering and technology Receptor tyrosine kinase Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cell Line Tumor Animals Humans Polyethyleneimine RNA Small Interfering Luciferases Liposome Polyethylenimine Gene knockdown biology Chemistry 021001 nanoscience & nanotechnology Lipids In vitro Biochemistry 030220 oncology & carcinogenesis Biophysics biology.protein Nanoparticles 0210 nano-technology Ex vivo |
| Zdroj: | Drug Delivery and Translational Research. 7:206-216 |
| ISSN: | 2190-3948 2190-393X |
| DOI: | 10.1007/s13346-016-0306-y |
| Popis: | The non-viral delivery of small RNA molecules like siRNAs still poses a major bottleneck for their successful application in vivo. This is particularly true with regard to crossing physiological barriers upon systemic administration. We have previously established polyethylenimine (PEI)-based complexes for therapeutic RNA formulation. These nanoplexes mediate full RNA protection against nucleolytic degradation, delivery to target tissues as well as cellular uptake, intracellular release and therapeutic efficacy in preclinical in vivo models. We herein present data on different polyplex modifications for the defined improvement of physicochemical and biological nanoparticle properties and for targeted delivery. (i) By non-covalent modifications of PEI polyplexes with phospholipid liposomes, ternary complexes ("lipopolyplexes") are obtained that combine the favorable features of PEI and lipid systems. Decreased cytotoxicity and highly efficient delivery of siRNA is achieved. Some lipopolyplexes also allow prolonged storage, thus providing formulations with higher stability. (ii) Novel tyrosine modifications of low molecular weight PEI offer further improvement of stability, biocompatibility, and knockdown efficacy of resulting nanoparticles. (iii) For ligand-mediated uptake, the shielding of surface charges is a critical requirement. This is achieved by PEI grafting with polyethylene glycol (PEG), prior to covalent coupling of anti-HER1 antibodies (Erbitux®) as ligand for targeted delivery and uptake. Beyond tumor cell culture, analyses are extended towards tumor slice cultures from tumor xenograft tissues which reflect more realistically the in vivo situation. The determination of siRNA-mediated knockdown of endogenous target genes, i.e., the oncogenic survival factor survivin and the oncogenic receptor tyrosine kinase HER2, reveals nanoparticle penetration and biological efficacy also under intact tissue and stroma conditions. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink