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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
- Source :
- Journal of Controlled Release. 243:182-194
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
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.
- 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
Subjects
Details
- ISSN :
- 01683659
- Volume :
- 243
- Database :
- OpenAIRE
- Journal :
- Journal of Controlled Release
- Accession number :
- edsair.doi.dedup.....be979271680c412eff50ccaf5c9c7f0c