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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / chemistry
  • Antibodies / metabolism*
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Disease Models, Animal
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism*
  • Gene Expression Regulation
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / prevention & control
  • Lipids / chemistry*
  • Lung / blood supply*
  • Male
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Polyethylene Glycols / chemistry*
  • Pyridinium Compounds / chemistry*
  • RNA Interference*
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism*
  • Time Factors
  • Tissue Distribution
  • Transfection / methods*
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1 / immunology
  • Vascular Cell Adhesion Molecule-1 / metabolism*
  • Venules / metabolism


  • 1-methyl-4-(9-dioleyl)methylpyridinium
  • Antibodies
  • Antigens, CD
  • Cadherins
  • Lipids
  • Pyridinium Compounds
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • cadherin 5
  • Polyethylene Glycols