Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines

Nian-Qiu Shi,1 Yan Li,2 Yong Zhang,3 Zheng-Qiang Li,4 Xian-Rong Qi5 1School of Pharmacy, Jilin Medical University, Jilin, Jilin, 132013, China; 2Immunology Department, Laboratory Medical College, Jilin Medical University, Jilin, Jilin, 132013, China; 3College of Life Science, Jilin University, Chan...

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Autores principales:	Shi NQ, Li Y, Zhang Y, Li ZQ, Qi XR
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	“Accelerating” active targeting nanotherapeutics Tandem inserted nona-arginine (tiR9) Cyclic asparagine-glycine-arginine (cNGR) Penetration and tumor therapy Multifunctional nanomedicines. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/29d3744b1e464530ae45c6551f1d6220
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spelling	oai:doaj.org-article:29d3744b1e464530ae45c6551f1d62202021-12-02T03:22:57ZDeepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines1178-2013https://doaj.org/article/29d3744b1e464530ae45c6551f1d62202018-09-01T00:00:00Zhttps://www.dovepress.com/deepened-cellularsubcellular-interface-penetration-and-enhanced-antitu-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Nian-Qiu Shi,1 Yan Li,2 Yong Zhang,3 Zheng-Qiang Li,4 Xian-Rong Qi5 1School of Pharmacy, Jilin Medical University, Jilin, Jilin, 132013, China; 2Immunology Department, Laboratory Medical College, Jilin Medical University, Jilin, Jilin, 132013, China; 3College of Life Science, Jilin University, Changchun, Jilin, 130012, China; 4Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, College of Life Science, Jilin University, Changchun, Jilin, 130012, China; 5Department of Pharmaceutics, School of Pharmaceutical Science, Peking University, Beijing, 100191, China Introduction: Acceleration and improvement of penetration across cell-membrane interfaces of active targeted nanotherapeutics into tumor cells would improve tumor-therapy efficacy by overcoming the issue of poor drug penetration. Cell-penetrating peptides, especially synthetic polyarginine, have shown promise in facilitating cargo delivery. However, it is unknown whether polyarginine can work to overcome the membrane interface in an inserted pattern for cyclic peptide ligand-mediated active targeting drug delivery. Here, we conducted a study to test the hypothesis that tandem-insert nona-arginine (tiR9) can act as an accelerating component for intracellular internalization, enhance cellular penetration, and promote antitumor efficacy of active targeted cyclic asparagine–glycine–arginine (cNGR)-decorated nanoliposomes. Methods: Polyarginine was coupled with the polyethylene glycol (PEG) chain and the cNGR moiety, yielding a cNGR–tiR9–PEG2,000–distearoylphosphatidylethanolamine conjugate. Results: The accelerating active targeted liposome (Lip) nanocarrier (cNGR-tiR9-Lip–doxorubicin [Dox]) constructed in this study held suitable physiochemical features, such as appropriate particle size of ~150 nm and sustained-release profiles. Subsequently, tiR9 was shown to enhance cellular drug delivery of Dox-loaded active targeted systems (cNGR-Lip-Dox) significantly. Layer-by-layer confocal microscopy indicated that the tandem-insert polyarginine accelerated active targeted system entry into deeper intracellular regions based on observations at marginal and center locations. tiR9 enhanced the penetration depth of cNGR-Lip–coumarin 6 through subcellular membrane barriers and caused its specific accumulation in mitochondria, endoplasmic reticulum, and Golgi apparatus. It was also obvious that cNGR-tiR9-Lip-Dox induced enhanced apoptosis and activated caspase 3/7. Moreover, compared with cNGR-Lip-Dox, cNGR-tiR9-Lip-Dox induced a significantly higher antiproliferative effect and markedly suppressed tumor growth in HT1080-bearing nude mice. Conclusion: This active tumor-targeting nanocarrier incorporating a tandem-insert polyarginine (tiR9) as an accelerating motif shows promise as an effective drug-delivery system to accelerate translocation of drugs across tumor-cell/subcellular membrane barriers to achieve improved specific tumor therapy. Keywords: accelerating active targeting nanotherapeutics, tandem-insert nona-arginine, tiR9, cyclic asparagine–glycine–arginine, cNGR, penetration and tumor therapy, multifunctional nanomedicinesShi NQLi YZhang YLi ZQQi XRDove Medical Pressarticle“Accelerating” active targeting nanotherapeuticsTandem inserted nona-arginine (tiR9)Cyclic asparagine-glycine-arginine (cNGR)Penetration and tumor therapyMultifunctional nanomedicines.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 5537-5559 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	“Accelerating” active targeting nanotherapeutics Tandem inserted nona-arginine (tiR9) Cyclic asparagine-glycine-arginine (cNGR) Penetration and tumor therapy Multifunctional nanomedicines. Medicine (General) R5-920
spellingShingle	“Accelerating” active targeting nanotherapeutics Tandem inserted nona-arginine (tiR9) Cyclic asparagine-glycine-arginine (cNGR) Penetration and tumor therapy Multifunctional nanomedicines. Medicine (General) R5-920 Shi NQ Li Y Zhang Y Li ZQ Qi XR Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines
description	Nian-Qiu Shi,1 Yan Li,2 Yong Zhang,3 Zheng-Qiang Li,4 Xian-Rong Qi5 1School of Pharmacy, Jilin Medical University, Jilin, Jilin, 132013, China; 2Immunology Department, Laboratory Medical College, Jilin Medical University, Jilin, Jilin, 132013, China; 3College of Life Science, Jilin University, Changchun, Jilin, 130012, China; 4Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, College of Life Science, Jilin University, Changchun, Jilin, 130012, China; 5Department of Pharmaceutics, School of Pharmaceutical Science, Peking University, Beijing, 100191, China Introduction: Acceleration and improvement of penetration across cell-membrane interfaces of active targeted nanotherapeutics into tumor cells would improve tumor-therapy efficacy by overcoming the issue of poor drug penetration. Cell-penetrating peptides, especially synthetic polyarginine, have shown promise in facilitating cargo delivery. However, it is unknown whether polyarginine can work to overcome the membrane interface in an inserted pattern for cyclic peptide ligand-mediated active targeting drug delivery. Here, we conducted a study to test the hypothesis that tandem-insert nona-arginine (tiR9) can act as an accelerating component for intracellular internalization, enhance cellular penetration, and promote antitumor efficacy of active targeted cyclic asparagine–glycine–arginine (cNGR)-decorated nanoliposomes. Methods: Polyarginine was coupled with the polyethylene glycol (PEG) chain and the cNGR moiety, yielding a cNGR–tiR9–PEG2,000–distearoylphosphatidylethanolamine conjugate. Results: The accelerating active targeted liposome (Lip) nanocarrier (cNGR-tiR9-Lip–doxorubicin [Dox]) constructed in this study held suitable physiochemical features, such as appropriate particle size of ~150 nm and sustained-release profiles. Subsequently, tiR9 was shown to enhance cellular drug delivery of Dox-loaded active targeted systems (cNGR-Lip-Dox) significantly. Layer-by-layer confocal microscopy indicated that the tandem-insert polyarginine accelerated active targeted system entry into deeper intracellular regions based on observations at marginal and center locations. tiR9 enhanced the penetration depth of cNGR-Lip–coumarin 6 through subcellular membrane barriers and caused its specific accumulation in mitochondria, endoplasmic reticulum, and Golgi apparatus. It was also obvious that cNGR-tiR9-Lip-Dox induced enhanced apoptosis and activated caspase 3/7. Moreover, compared with cNGR-Lip-Dox, cNGR-tiR9-Lip-Dox induced a significantly higher antiproliferative effect and markedly suppressed tumor growth in HT1080-bearing nude mice. Conclusion: This active tumor-targeting nanocarrier incorporating a tandem-insert polyarginine (tiR9) as an accelerating motif shows promise as an effective drug-delivery system to accelerate translocation of drugs across tumor-cell/subcellular membrane barriers to achieve improved specific tumor therapy. Keywords: accelerating active targeting nanotherapeutics, tandem-insert nona-arginine, tiR9, cyclic asparagine–glycine–arginine, cNGR, penetration and tumor therapy, multifunctional nanomedicines
format	article
author	Shi NQ Li Y Zhang Y Li ZQ Qi XR
author_facet	Shi NQ Li Y Zhang Y Li ZQ Qi XR
author_sort	Shi NQ
title	Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines
title_short	Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines
title_full	Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines
title_fullStr	Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines
title_full_unstemmed	Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines
title_sort	deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines
publisher	Dove Medical Press
publishDate	2018
url	https://doaj.org/article/29d3744b1e464530ae45c6551f1d6220
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_version_	1718401784333991936

Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines

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