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Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury

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      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 α vβ 3 integrin is overexpressed on activated endothelial cells but not on normal quiescent vessels. In this study, CDG2-cRGD, synthesized by conjugating an α vβ 3 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.

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      Most cited references 41

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            Author and article information

            Affiliations
            [1 ]School of Pharmaceutical Sciences, Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China
            [2 ]Department of Pharmaceutical Sciences, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
            [3 ]Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, People’s Republic of China
            Author notes
            Correspondence: Shirong Pan; Min Feng, School of Pharmaceutical Sciences, Department of Pharmacy, Sun Yat-sen University, Zhongshan II Road 58, Guangzhou, People’s Republic of China 510080, Tel +86 20 3994 3073, Fax +86 20 8733 0396, Email gzpshr@ 123456163.com ; fengmin@ 123456mail.sysu.edu.cn
            Journal
            Int J Nanomedicine
            Int J Nanomedicine
            International Journal of Nanomedicine
            International Journal of Nanomedicine
            Dove Medical Press
            1176-9114
            1178-2013
            2015
            10 September 2015
            : 10
            : 5751-5768
            26425083 4583553 10.2147/IJN.S88109 ijn-10-5751
            © 2015 Tian et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

            The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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            Original Research

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