Abstract
The safe and efficient delivery of therapeutic nucleic acid is a prerequisite for an effective DNA therapy. In this study, we condensed the low molecular weight polyethylenimine (PEI, 1.8k Da) with 2,6-pyridinedicarboxaldehyde (PDA), both of which are degradable in vivo, to synthesize a biodegradable polycationic material (PDAPEI) to deliver vascular endothelial growth factor (VEGF) plasmid DNA (pDNA). Particle size and zeta potential of this novel degradable PEI derivatives-pDNA nanoparticle were investigated and in vitro cytotoxicity was estimated on human umbilical vein endothelial cells (HUVECs). Using pDNA-encoding VEGF-A and green fluorescence protein (GFP), we also checked transfection efficiency of the vector (PDAPEI) and found its excellent performance at 40 w/w ratio. We successfully established peripheral ischemia animal model on C57/BL6J mice to evaluate the therapeutic effect of PDAPEI/pVEGF-A polyplex system on ischemic disease and a conclusion was made that PDAPEI is a promising gene vector in the treatment of peripheral ischemic artery disease (PAD).
Highlights
Peripheral ischemic artery disease (PAD) is a congenital or acquired vascular disease caused by inadequate blood supply to a tissue or organ, in which the most severe form is critical limb ischemia (CLI; Shishehbor et al, 2016; Rundback et al, 2017)
Characterization of PDAPEI The structure and average molecular weight (Mw) of PDAPEI were confirmed by Fourier Transform Infrared spectrometry (FTIR), 1H-Nuclear Magnetic Resonance (1H-NMR; Che et al, 2016; Song et al, 2016), and Gel Permeation Chromatography (GPC). 1H-NMR spectrum was obtained in DMSO-d6 with 0.03% (v/v) tetramethylsilane (TMS) as internal standard using a Varian Mercury Plus 400 MHz spectrometer
Agarose Gel Electrophoresis For gene vectors, the binding ability and condensation ability are of great significance to protect plasmid DNA (pDNA) from degradation, and they are evaluated by agarose gel electrophoresis in this study
Summary
Peripheral ischemic artery disease (PAD) is a congenital or acquired vascular disease caused by inadequate blood supply to a tissue or organ, in which the most severe form is critical limb ischemia (CLI; Shishehbor et al, 2016; Rundback et al, 2017). Current pharmacological treatments include revascularization, therapeutic angiogenesis, hyperbaric oxygen, and venous arterialization (Li et al, 2015; Farber and Eberhardt, 2016; Schreve et al, 2017). Therapeutic angiogenesis with proangiogenic proteins, genes, and stem cells has been tested pre-clinically to stimulate the growth of blood vessels (Bauters et al, 1995; Sun et al, 2005; Jazwa et al, 2015; Sanada et al, 2015; Beegle et al, 2016). Vascular endothelial growth factor (VEGF) is one of the signal proteins that could stimulate vasculogenesis and angiogenesis (Nissen et al, 1998; Bobek et al, 2006; Ganta et al, 2017). When a cell is deficient in oxygen, hypoxia-inducible factor (HIF) would be induced, and HIF stimulates the release of VEGF-A, which could relieve the situation of endothelial cell death and vascular regression (Carmeliet, 2000; Smith et al, 2008)
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