Delivery of Nox2-NADPH oxidase siRNA with polyketal nanoparticles for improving cardiac function following myocardial infarction

• Authors: Inthirai Somasuntharam, Emory University; Archana V. Boopathy, Emory University; Raffay S. Khan, Emory University; Mario D. Martinez, Emory University; Milton Brown, Emory University; Niren Murthy, Emory University; Michael Davis, Emory University
• Journal Title: Biomaterials
• Volume: Volume 34, Number 31
• Publisher: Elsevier | 2013-10-01, Pages 7790-7798
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.biomaterials.2013.06.051
• Subjects: Engineering, Biomedical; Biology, Genetics
• Keywords: Science & Technology; Technology; Engineering, Biomedical; Materials Science, Biomaterials; Engineering; Materials Science; Nanoparticles; Macrophages; Myocardial infarction; Gene expression; Gene silencing; NADPH OXIDASE; EXTRACELLULAR-SUPEROXIDE; OXIDATIVE STRESS; CATIONIC LIPIDS; ANGIOTENSIN-II; PARTICLE-SIZE; P38 INHIBITOR; PIVOTAL ROLE; EXPRESSION; INJURY

Abstract

Myocardial infarction (MI) is the most common cause of heart failure (HF), the leading cause of death in the developed world. Oxidative stress due to excessive production of reactive oxygen species (ROS) plays a key role in the pathogenesis of cardiac remodeling leading to HF. NADPH oxidase with Nox2 as the catalytic subunit is a major source for cardiac ROS production. Nox2-NADPH expression is significantly increased in the infarcted myocardium, primarily in neutrophils, macrophages and myocytes. Moreover, mice lacking the Nox2 gene are protected from ischemic injury, implicating Nox2 as a potential therapeutic target. RNAi-mediated gene silencing holds great promise as a therapeutic owing to its high specificity and potency. However, invivo delivery hurdles have limited its effective clinical use. Here, we demonstrate acid-degradable polyketal particles as delivery vehicles for Nox2-siRNA to the post-MI heart. Invitro, Nox2-siRNA particles are effectively taken up by macrophages and significantly knockdown Nox2 expression and activity. Following invivo intramyocardial injection in experimental mice models of MI, Nox2-siRNA particles prevent upregulation of Nox2 and significantly recovered cardiac function. This study highlights the potential of polyketals as siRNA delivery vehicles to the MI heart and represents a viable therapeutic approach for targeting oxidative stress.