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

Shouqin Tian,1 Duanwen Cao,2 Haijuan Zou,1 Feng Bai,1 Zhongjuan Wang,1 Shirong Pan,1,3 Min Feng11School of Pharmaceutical Sciences, Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, 2Department of Pharmaceutical Sciences, Nanfang Hospital, Southern Medical University, 3K...

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Autores principales:	Tian S, Cao D, Zou H, Bai F, Wang Z, Pan S, Feng M
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2015
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/56d4bc135a4440a9826d097473ce5f2e
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spelling	oai:doaj.org-article:56d4bc135a4440a9826d097473ce5f2e2021-12-02T07:28:30ZEndothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury1178-2013https://doaj.org/article/56d4bc135a4440a9826d097473ce5f2e2015-09-01T00:00:00Zhttps://www.dovepress.com/endothelial-cell-targeted-pvegf165-polyplex-plays-a-pivotal-role-in-in-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Shouqin Tian,1 Duanwen Cao,2 Haijuan Zou,1 Feng Bai,1 Zhongjuan Wang,1 Shirong Pan,1,3 Min Feng11School of Pharmaceutical Sciences, Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, 2Department of Pharmaceutical Sciences, Nanfang Hospital, Southern Medical University, 3Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, People’s Republic of ChinaAbstract: 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 therapyTian SCao DZou HBai FWang ZPan SFeng MDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2015, Iss default, Pp 5751-5768 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Tian S Cao D Zou H Bai F Wang Z Pan S Feng M Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury
description	Shouqin Tian,1 Duanwen Cao,2 Haijuan Zou,1 Feng Bai,1 Zhongjuan Wang,1 Shirong Pan,1,3 Min Feng11School of Pharmaceutical Sciences, Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, 2Department of Pharmaceutical Sciences, Nanfang Hospital, Southern Medical University, 3Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, People’s Republic of ChinaAbstract: 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
format	article
author	Tian S Cao D Zou H Bai F Wang Z Pan S Feng M
author_facet	Tian S Cao D Zou H Bai F Wang Z Pan S Feng M
author_sort	Tian S
title	Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury
title_short	Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury
title_full	Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury
title_fullStr	Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury
title_full_unstemmed	Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury
title_sort	endothelial cell-targeted pvegf165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury
publisher	Dove Medical Press
publishDate	2015
url	https://doaj.org/article/56d4bc135a4440a9826d097473ce5f2e
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Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury

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