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Int J Pharm. 2014 Jul 20;469(1):121-31. doi: 10.1016/j.ijpharm.2014.04.041. Epub 2014 Apr 18.

VCAM-1 specific PEGylated SAINT-based lipoplexes deliver siRNA to activated endothelium in vivo but do not attenuate target gene expression.

Author information

1
University of Groningen, University Medical Center Groningen, Department of Pathology & Medical Biology, Medical Biology section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, the Netherlands.
2
University of Groningen, University Medical Center Groningen, Department of Pathology & Medical Biology, Medical Biology section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, the Netherlands; Synvolux Therapeutics, Groningen, the Netherlands.
3
University of Groningen, University Medical Center Groningen, Department 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.

Abstract

In recent years much research in RNA nanotechnology has been directed to develop an efficient and clinically suitable delivery system for short interfering RNA (siRNA). The current study describes the in vivo siRNA delivery using PEGylated antibody-targeted SAINT-based-lipoplexes (referred to as antibody-SAINTPEGarg/PEG2%), which showed superior siRNA delivery capacity and effective down-regulation of VE-cadherin gene expression in vitro in inflammation-activated primary endothelial cells of different vascular origins. PEGylation of antibody-SAINTPEGarg resulted in more desirable pharmacokinetic behavior than that of non-PEGylated antibody-SAINTPEGarg. To create specificity for inflammation-activated endothelial cells, antibodies against vascular cell adhesion molecule-1 (VCAM-1) were employed. In TNFα-challenged mice, these intravenously administered anti-VCAM-1-SAINTPEGarg/PEG2% homed to VCAM-1 protein expressing vasculature. Confocal laser scanning microscopy revealed that anti-VCAM-1-SAINTPEGarg/PEG2% co-localized with endothelial cells in lung postcapillary venules. Furthermore, they did not exert any liver and kidney toxicity. Yet, lack of in vivo gene silencing as assessed in whole lung and in laser microdissected lung microvascular segments indicates that in vivo internalization and/or intracellular trafficking of the delivery system and its cargo in the target cells are not sufficient, and needs further attention, emphasizing the essence of evaluating siRNA delivery systems in an appropriate in vivo animal model at an early stage in their development.

KEYWORDS:

Cationic lipid; Endothelial cells; Inflammation; Targeted delivery; Vascular cell adhesion molecule-1; siRNA

PMID:
24746643
DOI:
10.1016/j.ijpharm.2014.04.041
[Indexed for MEDLINE]

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