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已发表论文
内皮细胞靶向性 pVEGF165 多聚物在血管损伤后抑制内膜增厚方面的关键作用
Authors Tian S, Cao D, Zou H, Bai F, Wang Z, Pan S, Feng M
Received 7 May 2015
Accepted for publication 7 June 2015
Published 10 September 2015 Volume 2015:10 Pages 5751—5768
DOI http://dx.doi.org/10.2147/IJN.S88109
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Jia Fan
Peer reviewer comments 3
Editor who approved publication: Dr Lei Yang
Abstract: Upregulation of vascular endothelial growth factor (VEGF) expression can inhibit intimal thickening after vascular injury. However, the lack of efficient gene delivery systems leads to insufficient VEGF expression, which prevents its application in gene therapy. In the present study, to improve the delivery of the plasmid vector with the VEGF gene (pVEGF165) to the injured vessel wall, we explored the potentially important difference between endothelial cell-targeted and nontargeted polymeric carriers. The αvβ3 integrin is overexpressed on activated endothelial cells but not on normal quiescent vessels. In this study, CDG2-cRGD, synthesized by conjugating an αvβ3 integrin-binding cyclic arginylglycylaspartic acid (cRGD) peptide with the Generation 2 polycation polyamidoamine (PAMAMG2)-g-cyclodextrin (termed as CDG2), was developed as a targetable carrier. It was observed that the specific integrin–ligand interactions greatly enhanced cellular internalization of CDG2-cRGD in human umbilical vein endothelial cells (HUVECs), which are notoriously difficult to transfect. Consequently, HUVECs were found to show remarkably high levels of VEGF165 expression induced by the CDG2-cRGD polyplex. Interestingly, VEGF165 overexpression in vivo was more complex than that in vitro, and in vivo assays demonstrated that the stimulus response to balloon injury in arteries could obviously upregulate VEGF165 expression in the saline-treated group, although it was not enough to prevent intimal thickening. In gene-transfected groups, intravascular delivery of pVEGF165 with the CDG2-cRGD polyplex into rabbits after vascular injury resulted in a significant inhibition of intimal thickening at 4 weeks, whereas the low therapeutic efficacy in the nontargeted CDG2-treated group was only comparable to that in the saline-treated group. It is becoming clear that the conflicting results of VEGF165 gene therapy in two gene-transfected groups are reflective of the pivotal role of the cRGD-conjugated carriers in achieving the beneficial therapeutic effects of vascular gene therapy.
Keywords: pVEGF165, αvβ3 integrin binding, intimal thickening, vascular gene therapy
Keywords: pVEGF165, αvβ3 integrin binding, intimal thickening, vascular gene therapy
