Functionalized dendrimer-based delivery of angiotensin type 1 receptor siRNA for preserving cardiac function following infarction

• Type of Material: Article
• Authors: Jie Liu, Peking University; Catherine Gu, Emory University; E. Bernadette Cabigas, Emory University; Karl D. Pendergrass, Emory University; Milton Brown, Emory University; Ying Luo, Peking University; Michael Davis, Emory University
• Language: English
• Date: 2013-05-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biomaterials.2013.02.008
• Title of Journal or Parent Work: Biomaterials
• ISSN: 0142-9612
• Volume: 34
• Issue: 14
• Start Page: 3729
• End Page: 3736
• Grant/Funding Information: This publication has been funded in whole or in part with the Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN268201000043C to MED, and the National Natural Science Foundation of China (Project No. 31170933) to YL.; The research was supported by the China Scholarship Council (JL).
• Keywords: IN-VITRO; Materials Science, Biomaterials; Engineering, Biomedical; Materials Science; GENE DELIVERY; Cardiomyocyte; ALDOSTERONE SYSTEM; Dendrimer; Technology; Science & Technology; ISOLATED RAT HEARTS; RANDOMIZED TRIAL; MYOCARDIAL-INFARCTION; Ischemia-reperfusion; Engineering; BLOCKADE; CARDIOVASCULAR-DISEASE; Gene expression; CORONARY-ARTERY-DISEASE; AT(2) RECEPTORS
• Research Categories: Biology, Genetics; Engineering, Biomedical

Abstract

Cardiovascular disease (CVD) is the leading cause of death throughout the world and much pathology is associated with upregulation of inflammatory genes. Gene silencing using RNA interference is a powerful tool in regulating gene expression, but its application in CVDs has been prevented by the lack of efficient delivery systems. We report here the development of tadpole dendrimeric materials for siRNA delivery in a rat ischemia-reperfusion (IR) model. Angiotensin II (Ang II) type 1 receptor (AT1R), the major receptor that mediates most adverse effects of Ang II, was chosen to be the silencing targeting. Among the three tadpole dendrimers synthesized, the oligo-arginine conjugated dendrimer loaded with siRNA demonstrated effective down-regulation in AT1R expression in cardiomyocytes in vitro. When the dendrimeric material was applied in vivo, the siRNA delivery prevented the increase in AT1R levels and significantly improved cardiac function recovery compared to saline injection or empty dendrimer treated groups after IR injury. These experiments demonstrate a potential treatment for dysfunction caused by IR injury and may represent an alternative to AT1R blockade.