Anti-VCAM-1 SAINT-O-Somes enable endothelial-specific delivery of siRNA and downregulation of inflammatory genes in activated endothelium in vivo.

Autor: Kowalski PS; University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, The Netherlands., Zwiers PJ; University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, The Netherlands., Morselt HW; University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, The Netherlands., Kuldo JM; University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, The Netherlands., Leus NG; University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, The Netherlands., Ruiters MH; University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, The Netherlands; Synvolux Therapeutics, L.J. Zielstraweg 1, Groningen, The Netherlands., Molema G; University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, The Netherlands., Kamps JA; University of Groningen, University Medical Center Groningen, Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, The Netherlands. Electronic address: j.a.a.m.kamps@umcg.nl.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2014 Feb 28; Vol. 176, pp. 64-75. Date of Electronic Publication: 2014 Jan 03.
DOI: 10.1016/j.jconrel.2013.12.029
Abstrakt: The pivotal role of endothelial cells in the pathology of inflammatory diseases raised interest in the development of short interfering RNA (siRNA) delivery devices for selective pharmacological intervention in the inflamed endothelium. The current study demonstrates endothelial specific delivery of siRNAs and downregulation of inflammatory genes in activated endothelium in vivo by applying a novel type of targeted liposomes based on the cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chloride). To create specificity for inflamed endothelial cells, these so-called SAINT-O-Somes were harnessed with antibodies against vascular cell adhesion protein 1 (VCAM-1). In TNFα challenged mice, intravenously administered anti-VCAM-1 SAINT-O-Somes exerted long circulation times and homed to VCAM-1 expressing endothelial cells in inflamed organs. The formulations were devoid of liver and kidney toxicity. Using anti-VCAM-1 SAINT-O-Somes we successfully delivered siRNA to knock down VE-cadherin mRNA in inflamed renal microvasculature, as demonstrated by using laser microdissection of different microvascular beds prior to analysis of gene expression. Using the same strategy, we demonstrated local attenuation of endothelial inflammatory response towards lipopolysaccharide in kidneys of mice treated with anti-VCAM-1 SAINT-O-Somes containing NFκB p65 specific siRNA. This study is the first demonstration of a novel, endothelial specific carrier that is suitable for selective in vivo delivery of siRNAs into inflamed microvascular segments and interference with disease associated endothelial activation.
(Copyright © 2014 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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