SAINT-liposome-polycation particles, a new carrier for improved delivery of siRNAs to inflamed endothelial cells

Piotr S Kowalski; Praneeth R Kuninty; Klaas T Bijlsma; Marc C A Stuart; Niek G J Leus; Marcel H J Ruiters; Grietje Molema; Jan A A M Kamps

doi:10.1016/j.ejpb.2014.11.015

SAINT-liposome-polycation particles, a new carrier for improved delivery of siRNAs to inflamed endothelial cells

Eur J Pharm Biopharm. 2015 Jan:89:40-7. doi: 10.1016/j.ejpb.2014.11.015. Epub 2014 Nov 25.

Authors

Piotr S Kowalski¹, Praneeth R Kuninty¹, Klaas T Bijlsma¹, Marc C A Stuart², Niek G J Leus¹, Marcel H J Ruiters³, Grietje Molema¹, Jan A A M Kamps⁴

Affiliations

¹ University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Groningen, The Netherlands.
² University of Groningen, Groningen Biomolecular Sciences and Biotechnology Institute, The Netherlands; Stratingh Institute, University of Groningen, Groningen, The Netherlands.
³ University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Groningen, The Netherlands; Synvolux Therapeutics, Groningen, The Netherlands.
⁴ University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Groningen, The Netherlands. Electronic address: j.a.a.m.kamps@umcg.nl.

PMID: 25460585
DOI: 10.1016/j.ejpb.2014.11.015

Abstract

Interference with acute and chronic inflammatory processes by means of delivery of siRNAs into microvascular endothelial cells at a site of inflammation demands specific, non-toxic and effective siRNA delivery system. In the current work we describe the design and characterization of siRNA carriers based on cationic pyridinium-derived lipid 1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chloride) (SAINT-C18) and the transfection enhancer protamine, complexed with siRNA/carrier DNA or siRNA only. These carriers, called SAINT-liposome-polycation-DNA (S-LPD) and SAINT-liposome-polycation (S-LP), have a high efficiency of siRNA encapsulation, low cellular toxicity, and superior efficacy of gene downregulation in endothelial cells in vitro as compared to DOTAP-LPD. Incorporation of 10 mol% PEG and anti-E-selectin antibody in these formulations resulted in selective siRNA delivery into activated endothelial cells. Furthermore, we showed that the physicochemical characteristics of S-LPD and S-LP, including size-stability and maintenance of the siRNA integrity in the presence of serum at 37 °C, comply with requirements for in vivo application.

Keywords: Cationic lipid; E-selectin; Endothelium; Inflammation; Liposome-polycation-DNA; Targeted siRNA delivery.

Publication types

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

MeSH terms

Cells, Cultured
Chemistry, Pharmaceutical / methods
DNA / pharmacology
Drug Carriers / pharmacology*
Drug Delivery Systems / methods
E-Selectin / metabolism
Human Umbilical Vein Endothelial Cells / drug effects*
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Inflammation / drug therapy*
Inflammation / metabolism
Lipids / pharmacology
Liposomes / pharmacology*
Particle Size
Polyamines / pharmacology*
Polyelectrolytes
Pyridinium Compounds / pharmacology*
RNA, Small Interfering / pharmacology*
Transfection / methods

Substances

1-methyl-4-(9-dioleyl)methylpyridinium
Drug Carriers
E-Selectin
Lipids
Liposomes
Polyamines
Polyelectrolytes
Pyridinium Compounds
RNA, Small Interfering
polycations
DNA