A major hurdle for exploring RNA interference (RNAi) in a therapeutic setting is still
the issue of in vivo delivery of small RNA molecules (siRNAs). The chemical modification of
polyethylenimines (PEIs) offers a particularly attractive avenue towards the development of more
efficient non-viral delivery systems. Here, we explore tyrosine-modified polyethylenimines with low
or very low molecular weight (P2Y, P5Y, P10Y) for siRNA delivery. In comparison to their respective
parent PEI, they reveal considerably increased knockdown efficacies and very low cytotoxicity upon
tyrosine modification, as determined in different reporter and wildtype cell lines. The delivery
of siRNAs targeting the anti-apoptotic oncogene survivin or the serine/threonine-protein kinase
PLK1 (polo-like kinase 1; PLK-1) oncogene reveals strong inhibitory effects in vitro. In a therapeutic
in vivo setting, profound anti-tumor effects in a prostate carcinoma xenograft mouse model are
observed upon systemic application of complexes for survivin or PLK1 knockdown, in the absence of
in vivo toxicity. We thus demonstrate the tyrosine-modification of (very) low molecular weight PEIs
for generating effcient nanocarriers for siRNA delivery in vitro and in vivo, present data on their
physicochemical and biological properties, and show their efficacy as siRNA therapeutic in vivo, in
the absence of adverse effects.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84656 |
| Date | 11 April 2023 |
| Creators | Ewe, Alexander, Noske, Sandra, Karimov, Michael, Aigner, Achim |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1999-4923, 600 |
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