Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

Zhongya Chen,1,2 Jiaxin Deng,1,2 Yan Zhao,1,2 Tao Tao1,21National Pharmaceutical Engineering Research Center, 2Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People&#39;s Republic of ChinaBackground: Integrins &alpha;v&a...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Chen Z, Deng J, Zhao Y, Tao T
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2012
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/15b20fa854d14fa7a54d4d31e24e52d9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:15b20fa854d14fa7a54d4d31e24e52d9
record_format	dspace
spelling	oai:doaj.org-article:15b20fa854d14fa7a54d4d31e24e52d92021-12-02T01:11:23ZCyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats1176-91141178-2013https://doaj.org/article/15b20fa854d14fa7a54d4d31e24e52d92012-07-01T00:00:00Zhttp://www.dovepress.com/cyclic-rgd-peptide-modified-liposomal-drug-delivery-system-enhanced-ce-a10435https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Zhongya Chen,1,2 Jiaxin Deng,1,2 Yan Zhao,1,2 Tao Tao1,21National Pharmaceutical Engineering Research Center, 2Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People&#39;s Republic of ChinaBackground: Integrins &alpha;v&beta;3 and &alpha;v&beta;5, both of which specifically recognize the Arg-Gly-Asp (RGD) motif, are overexpressed on many solid tumors and in tumor neovasculature. Thus, coupling the RGD motif to the liposomal surface for achieving active targeting can be a promising strategy for the treatment of tumors.Methods: Cyclo(Arg-Gly-Asp-D-Phe-Cys) (cRGD) was covalently coupled with the liposomal membrane surface, followed by coating with poly(ethylene glycol) (PEG) using the post-insertion technique. The coupling efficiency of cRGD was determined. Doxorubicin as a model anticancer drug was loaded into liposomes using an ammonium sulfate gradient method to investigate the encapsulation efficiency, cellular uptake by the integrin-overexpressing human glioma cell line U87MG in vitro, and pharmacokinetic properties in Sprague-Dawley rats.Results: cRGD was conjugated to the liposomal surface by a thiol-maleimide coupling reaction. The coupling efficiency reached 98%. The encapsulation efficiency of doxorubicin in liposomes was more than 98%. The flow cytometry test result showed that cRGD-modified liposomes (RGD-DXRL-PEG) had higher cell uptake by U87MG cells, compared with nontargeted liposomes (DXRL-PEG). The cellular uptake was significantly inhibited in the presence of excess free cRGD. Both the targeted (t1/2 = 24.10 hours) and non-targeted (t1/2 = 25.32 hours) liposomes showed long circulating properties in rat plasma. The area under the curve of the targeted and nontargeted liposomes was 6.4-fold and 8.3-fold higher than that of doxorubicin solution, respectively.Conclusion: This study indicates preferential targeting and long circulating properties for cRGD-modified liposomes in vivo, which could be used as a potential targeted liposomal drug delivery system to treat human glioma.Keywords: drug targeting, doxorubicin, covalent coupling, sterically stabilized liposomes, human glioma, post-insertionChen ZDeng JZhao YTao TDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2012, Iss default, Pp 3803-3811 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Chen Z Deng J Zhao Y Tao T Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats
description	Zhongya Chen,1,2 Jiaxin Deng,1,2 Yan Zhao,1,2 Tao Tao1,21National Pharmaceutical Engineering Research Center, 2Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People&#39;s Republic of ChinaBackground: Integrins &alpha;v&beta;3 and &alpha;v&beta;5, both of which specifically recognize the Arg-Gly-Asp (RGD) motif, are overexpressed on many solid tumors and in tumor neovasculature. Thus, coupling the RGD motif to the liposomal surface for achieving active targeting can be a promising strategy for the treatment of tumors.Methods: Cyclo(Arg-Gly-Asp-D-Phe-Cys) (cRGD) was covalently coupled with the liposomal membrane surface, followed by coating with poly(ethylene glycol) (PEG) using the post-insertion technique. The coupling efficiency of cRGD was determined. Doxorubicin as a model anticancer drug was loaded into liposomes using an ammonium sulfate gradient method to investigate the encapsulation efficiency, cellular uptake by the integrin-overexpressing human glioma cell line U87MG in vitro, and pharmacokinetic properties in Sprague-Dawley rats.Results: cRGD was conjugated to the liposomal surface by a thiol-maleimide coupling reaction. The coupling efficiency reached 98%. The encapsulation efficiency of doxorubicin in liposomes was more than 98%. The flow cytometry test result showed that cRGD-modified liposomes (RGD-DXRL-PEG) had higher cell uptake by U87MG cells, compared with nontargeted liposomes (DXRL-PEG). The cellular uptake was significantly inhibited in the presence of excess free cRGD. Both the targeted (t1/2 = 24.10 hours) and non-targeted (t1/2 = 25.32 hours) liposomes showed long circulating properties in rat plasma. The area under the curve of the targeted and nontargeted liposomes was 6.4-fold and 8.3-fold higher than that of doxorubicin solution, respectively.Conclusion: This study indicates preferential targeting and long circulating properties for cRGD-modified liposomes in vivo, which could be used as a potential targeted liposomal drug delivery system to treat human glioma.Keywords: drug targeting, doxorubicin, covalent coupling, sterically stabilized liposomes, human glioma, post-insertion
format	article
author	Chen Z Deng J Zhao Y Tao T
author_facet	Chen Z Deng J Zhao Y Tao T
author_sort	Chen Z
title	Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats
title_short	Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats
title_full	Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats
title_fullStr	Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats
title_full_unstemmed	Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats
title_sort	cyclic rgd peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats
publisher	Dove Medical Press
publishDate	2012
url	https://doaj.org/article/15b20fa854d14fa7a54d4d31e24e52d9
work_keys_str_mv	AT chenz cyclicrgdpeptidemodifiedliposomaldrugdeliverysystemenhancedcellularuptakeinvitroandimprovedpharmacokineticsinrats AT dengj cyclicrgdpeptidemodifiedliposomaldrugdeliverysystemenhancedcellularuptakeinvitroandimprovedpharmacokineticsinrats AT zhaoy cyclicrgdpeptidemodifiedliposomaldrugdeliverysystemenhancedcellularuptakeinvitroandimprovedpharmacokineticsinrats AT taot cyclicrgdpeptidemodifiedliposomaldrugdeliverysystemenhancedcellularuptakeinvitroandimprovedpharmacokineticsinrats
_version_	1718403240478900224

Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

Ejemplares similares