1. Simultaneous regulation of apoptotic gene silencing and angiogenic gene expression for myocardial infarction therapy: Single-carrier delivery of SHP-1 siRNA and VEGF-expressing pDNA
- Author
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Hyo-Suk Kim, Dongkyu Kim, Sook Hee Ku, Donghoon Choi, Sun Hwa Kim, Ick Chan Kwon, Minhyung Lee, and Ji Hoon Jeong
- Subjects
Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,Small interfering RNA ,Angiogenesis ,Genetic enhancement ,Myocardial Infarction ,Neovascularization, Physiologic ,Pharmaceutical Science ,Apoptosis ,Myocardial Reperfusion Injury ,02 engineering and technology ,Biology ,Gene delivery ,Rats, Sprague-Dawley ,03 medical and health sciences ,Gene expression ,Animals ,Polyethyleneimine ,Gene silencing ,Gene Silencing ,RNA, Small Interfering ,Expression vector ,Gene Transfer Techniques ,DNA ,Genetic Therapy ,021001 nanoscience & nanotechnology ,Molecular biology ,Rats ,Disease Models, Animal ,Vascular endothelial growth factor A ,030104 developmental biology ,Cancer research ,0210 nano-technology ,Deoxycholic Acid ,Plasmids - Abstract
Gene therapy is aimed at selectively knocking up or knocking down the target genes involved in the development of diseases. In many human diseases, dysregulation of disease-associated genes is occurred concurrently: some genes are abnormally turned up and some are turned down. In the field of non-viral gene therapy, plasmid DNA (pDNA) and small interfering RNA (siRNA) are suggested as representative regulation tools for activating and silencing the expression of genes of interest, representatively. Herein, we simultaneously loaded both siRNA (Src homology region 2 domain-containing tyrosine phosphatase-1 siRNA, siSHP-1) for anti-apoptosis and pDNA (hypoxia-inducible vascular endothelial growth factor expression vector, pHI-VEGF) for angiogenesis in a single polymeric nanocarrier and used to synergistically attenuate ischemia-reperfusion (IR)-induced myocardial infarction, which is mainly caused by dysregulating of cardiac apoptosis and angiogenesis. For dual-modality cardiac gene delivery, siSHP-1 and pHI-VEGF were sequentially incorporated into a stable nanocomplex by using deoxycholic acid-modified polyethylenimine (DA-PEI). The resulting DA-PEI/siSHP-1/pHI-VEGF complexes exhibited the high structural stability against polyanion competition and the improved resistance to digestion by nucleases. The cardiac administration of DA-PEI/siSHP-1/pHI-VEGF reduced cardiomyocyte apoptosis and enhanced cardiac microvessel formation, thereby reducing infarct size in rat ischemia-reperfusion model. The simultaneous anti-apoptotic and angiogenic gene therapies synergized the cardioprotective effects of each strategy; thus our dual-modal single-carrier gene delivery system can be considered as a promising candidate for treating ischemic heart diseases.
- Published
- 2016