Title

Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model

UMMS Affiliation

Department of Pediatrics; Department of Radiology; Department of Surgery

Date

10-17-2010

Document Type

Article

Medical Subject Headings

Animals; Atherosclerosis; Genetic Vectors; Hyperplasia; Male; Membrane Glycoproteins; Mice; Models, Animal; NADPH Oxidase; Nanoparticles; Neointima; RNA, Small Interfering; Rats; Rats, Sprague-Dawley; Recurrence

Disciplines

Hematology | Oncology | Pediatrics

Abstract

Both atherosclerosis and arterial interventions induce oxidative stress mediated in part by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases that have a pivotal role in the development of neointimal hyperplasia and restenosis. For small interfering RNA (siRNA) targeting of the NOX2 (Cybb) component of the NADPH oxidase to prevent restenosis, gene transfer with viral vectors is effective, but raises safety issues in humans. We developed a new approach using the amino-acid-based nanoparticle HB-OLD7 for local delivery of siRNA targeting NOX2 to the arterial wall. siRNA-nanoparticle complexes were transferred into the regional carotid artery walls after angioplasty in an atherosclerotic rat model. Compared with angioplasty controls, Cybb gene expression (measured by quantitative reverse transcriptase-PCR) in the experimental arterial wall 2 weeks after siRNA was reduced by >87%. The neointima-to-media-area ratio was decreased by >83%, and the lumen-to-whole-artery area ratio was increased by >89%. Vital organs showed no abnormalities and splenic Cybb gene expression showed no detectable change. Thus, local arterial wall gene transfer with HB-OLD7 nanoparticles provides an effective, nonviral system for efficient and safe local gene transfer in a clinically applicable approach to knock down an NADPH oxidase gene. Local arterial knockdown of the Cybb gene significantly inhibited neointimal hyperplasia and preserved the vessel lumen without systemic toxicity.

Rights and Permissions

Citation: Gene Ther. 2010 Oct;17(10):1279-87. Epub 2010 May 20. Link to article on publisher's website

Related Resources

Link to article in PubMed

PubMed ID

20485380