Tyrosine-modified linear PEIs for highly efficacious and biocompatible siRNA delivery in vitro and in vivo

Michael Karimov; Marion Schulz; Tim Kahl; Sandra Noske; Malgorzata Kubczak; Ines Gockel; René Thieme; Thomas Büch; Anja Reinert; Maksim Ionov; Maria Bryszewska; Heike Franke; Ute Krügel; Alexander Ewe; Achim Aigner

doi:10.1016/j.nano.2021.102403

Tyrosine-modified linear PEIs for highly efficacious and biocompatible siRNA delivery in vitro and in vivo

Nanomedicine. 2021 Aug:36:102403. doi: 10.1016/j.nano.2021.102403. Epub 2021 Apr 29.

Authors

Affiliations

¹ Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig University, Faculty of Medicine, Leipzig, Germany.
² Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Łódź, Poland.
³ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany.
⁴ Faculty of Veterinary Medicine, Institute of Anatomy, Histology and Embryology, Leipzig University, Leipzig, Germany.
⁵ Rudolf-Boehm-Institute for Pharmacology and Toxicology, Leipzig University, Faculty of Medicine, Leipzig, Germany.
⁶ Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig University, Faculty of Medicine, Leipzig, Germany. Electronic address: achim.aigner@medizin.uni-leipzig.de.

PMID: 33932594
DOI: 10.1016/j.nano.2021.102403

Abstract

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.

Keywords: RNAi in vivo; Therapeutic siRNA delivery; Tumor xenografts and PDX models; Tyrosine-modified linear polyethlyenimines; siRNA transfection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Genetic Therapy*
Humans
Mice
Mice, Inbred NOD
Mice, Nude
Mice, SCID
Neoplasms, Experimental* / genetics
Neoplasms, Experimental* / therapy
Polyethyleneimine* / chemistry
Polyethyleneimine* / pharmacology
RNA, Small Interfering* / chemistry
RNA, Small Interfering* / genetics
RNA, Small Interfering* / pharmacology
Transfection*
Xenograft Model Antitumor Assays

Substances

RNA, Small Interfering
Polyethyleneimine