High-Density Lipoprotein Nanoparticles Deliver RNAi to Endothelial Cells to Inhibit Angiogenesis

Systemic delivery of therapeutic nucleic acids to target cells and tissues outside of the liver remains a major challenge. A biomimetic high‐density lipoprotein nanoparticle (HDL NP) is synthesized for delivery of a cholesteryl‐modified therapeutic nucleic acid to vascular endothelial cells (ECs), a...

Full description

Saved in:
Bibliographic Details
Published in:Particle & particle systems characterization 2014-11, Vol.31 (11), p.1141-1150
Main Authors: Tripathy, Sushant, Vinokour, Elena, McMahon, Kaylin M., Volpert, Olga V., Thaxton, C. Shad
Format: Article
Language:English
Subjects:
Angiogenesis
Biocompatibility
Biomedical materials
Cholesterol
Endothelial cells
Gene expression
Genes
HDL
In vitro testing
Lipoproteins
Medical research
Receptors
RNAi
Surgical implants
tumor
VEGFR2
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Systemic delivery of therapeutic nucleic acids to target cells and tissues outside of the liver remains a major challenge. A biomimetic high‐density lipoprotein nanoparticle (HDL NP) is synthesized for delivery of a cholesteryl‐modified therapeutic nucleic acid to vascular endothelial cells (ECs), a cell type naturally targeted by HDL. HDL NPs adsorb cholesteryl‐modified oligonucleotides and protect them from nuclease degradation. As proof of principle, we deliver RNAi targeting vascular endothelial growth factor receptor 2 (VEGFR2) to ECs to effectively silence target mRNA and protein expression in vitro. In addition, data show that treatment strongly attenuates in vivo neovascularization measured using a standard angiogenesis assay and in hypervascular tumor allografts where a striking reduction in tumor growth is observed. For effective delivery, HDL NPs require the expression of the cell surface protein scavenger receptor type‐B1 (SR‐B1). No toxicity of HDL NPs is measured in vitro or after in vivo administration. Thus, by using a biomimetic approach to nucleic acid delivery, data demonstrate that systemically administered RNAi–HDL NPs target SR‐B1 expressing ECs to deliver functional anti‐angiogenic RNAi as a potential treatment of cancer and other neovascular diseases. Synthetic high‐density lipoprotein nanoparticles (HDL NPs) functionalized with RNAi (RNAi–HDL NPs) are efficient delivery vehicles for regulating target gene expression in endothelial cells (ECs) that express scavenger receptor type B‐1. RNAi–HDL NPs carrying RNAi against vascular endothelial growth factor receptor 2 (VEGFR2) inhibit VEGF‐dependent EC processes in vitro and reduce angiogenesis in in vivo model systems.
ISSN:0934-0866
1521-4117
DOI:10.1002/ppsc.201400036