A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency

Ming Zhao, Ji Li, Hongrui Ji, Dawei Chen, Haiyang HuDepartment of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of ChinaBackground: Polycation carriers show great foreground in the developing efficient and safe gene delivery; neve...

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Autores principales:	Zhao M, Li J, Ji H, Chen D, Hu H
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	gene delivery PEI gene transfection NLS shell-core structure CCTS Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/52b25d38837443c8b7c943b7351fdd61
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spelling	oai:doaj.org-article:52b25d38837443c8b7c943b7351fdd612021-12-02T05:20:33ZA versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency1178-2013https://doaj.org/article/52b25d38837443c8b7c943b7351fdd612019-08-01T00:00:00Zhttps://www.dovepress.com/a-versatile-endosome-acidity-induced-sheddable-gene-delivery-system-in-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Ming Zhao, Ji Li, Hongrui Ji, Dawei Chen, Haiyang HuDepartment of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of ChinaBackground: Polycation carriers show great foreground in the developing efficient and safe gene delivery; nevertheless, they are cytotoxic and unstable in vivo because of the excess cationic charge. PEGylation improves the biocompatibility and stability of polycation, whereas PEGylation restrains the endosomal escape to some extent.Materials and methods: To address this issue and promote the transfection in vivo, a pH-sensitive conjugate folate-polyethylene glycol-carboxylated chitosan (shorten as FA-PEG-CCTS) was designed and coated on the surface of PEI/NLS/pDNA (PNDs), forming a versatile gene carrier FA-PEG-CCTS/PEI/NLS/pDNA (FPCPNDs). The novel carrier exhibited a few picturesque characteristics, including (i) neutral surface charge to restrain nonspecific interactions; (ii) folate receptors (FR)-mediated endocytosis to augment cellular uptake; (iii) dual proton sponge effect to realize endosome escape, and (iv) nuclear localization sequences (NLS) to enhance the transfection of pDNA.Results: FPCPNDs could compress and protect pDNA from degradation. FPCPNDs energetically targeted tumor cells because of their high binding affinity between FA and highly expressed FR on the tumor surface, accordingly enhancing the cellular uptake. In the acidic endosomes, FA-PEG-CCTS segment dissociated from PNDs. Then, PNDs realized endosomal escape through the proton sponge effect of PEI. Furthermore, FPCPNDs showed admirable transfection efficiency with the aid of NLS peptides. What’s more, in vivo studies revealed that FPCPNDs had supreme antitumor activity among the whole preparations.Conclusion: In vitro and in vivo assays thus demonstrate that FPCPNDs is a hopeful strategy for gene delivery.Keywords: gene delivery, PEI, gene transfection, NLS, shell–core structure, CCTSZhao MLi JJi HChen DHu HDove Medical Pressarticlegene deliveryPEIgene transfectionNLSshell-core structureCCTSMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 6519-6538 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	gene delivery PEI gene transfection NLS shell-core structure CCTS Medicine (General) R5-920
spellingShingle	gene delivery PEI gene transfection NLS shell-core structure CCTS Medicine (General) R5-920 Zhao M Li J Ji H Chen D Hu H A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency
description	Ming Zhao, Ji Li, Hongrui Ji, Dawei Chen, Haiyang HuDepartment of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of ChinaBackground: Polycation carriers show great foreground in the developing efficient and safe gene delivery; nevertheless, they are cytotoxic and unstable in vivo because of the excess cationic charge. PEGylation improves the biocompatibility and stability of polycation, whereas PEGylation restrains the endosomal escape to some extent.Materials and methods: To address this issue and promote the transfection in vivo, a pH-sensitive conjugate folate-polyethylene glycol-carboxylated chitosan (shorten as FA-PEG-CCTS) was designed and coated on the surface of PEI/NLS/pDNA (PNDs), forming a versatile gene carrier FA-PEG-CCTS/PEI/NLS/pDNA (FPCPNDs). The novel carrier exhibited a few picturesque characteristics, including (i) neutral surface charge to restrain nonspecific interactions; (ii) folate receptors (FR)-mediated endocytosis to augment cellular uptake; (iii) dual proton sponge effect to realize endosome escape, and (iv) nuclear localization sequences (NLS) to enhance the transfection of pDNA.Results: FPCPNDs could compress and protect pDNA from degradation. FPCPNDs energetically targeted tumor cells because of their high binding affinity between FA and highly expressed FR on the tumor surface, accordingly enhancing the cellular uptake. In the acidic endosomes, FA-PEG-CCTS segment dissociated from PNDs. Then, PNDs realized endosomal escape through the proton sponge effect of PEI. Furthermore, FPCPNDs showed admirable transfection efficiency with the aid of NLS peptides. What’s more, in vivo studies revealed that FPCPNDs had supreme antitumor activity among the whole preparations.Conclusion: In vitro and in vivo assays thus demonstrate that FPCPNDs is a hopeful strategy for gene delivery.Keywords: gene delivery, PEI, gene transfection, NLS, shell–core structure, CCTS
format	article
author	Zhao M Li J Ji H Chen D Hu H
author_facet	Zhao M Li J Ji H Chen D Hu H
author_sort	Zhao M
title	A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency
title_short	A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency
title_full	A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency
title_fullStr	A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency
title_full_unstemmed	A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency
title_sort	versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/52b25d38837443c8b7c943b7351fdd61
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A versatile endosome acidity-induced sheddable gene delivery system: increased tumor targeting and enhanced transfection efficiency

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