Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin

Jingmou Yu,1 Xin Xie,1 Meirong Zheng,1 Ling Yu,2 Lei Zhang,1 Jianguo Zhao,1 Dengzhao Jiang,1 Xiangxin Che11Key Laboratory of Systems Biology Medicine of Jiangxi Province, College of Basic Medical Science, Jiujiang University, Jiujiang, 2Division of Nursing, 2nd Affiliated Hospital, Yichun University...

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Autores principales:	Zhao J, Zhang L, Yu L, Zheng M, Xie X, Yu J, Che X, Jiang D
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2012
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/2f25dbd62b384644a6ec09763c3c7e01
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spelling	oai:doaj.org-article:2f25dbd62b384644a6ec09763c3c7e012021-12-02T07:45:06ZFabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin1176-91141178-2013https://doaj.org/article/2f25dbd62b384644a6ec09763c3c7e012012-09-01T00:00:00Zhttp://www.dovepress.com/fabrication-and-characterization-of-nuclear-localization-signal-conjug-a11054https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Jingmou Yu,1 Xin Xie,1 Meirong Zheng,1 Ling Yu,2 Lei Zhang,1 Jianguo Zhao,1 Dengzhao Jiang,1 Xiangxin Che11Key Laboratory of Systems Biology Medicine of Jiangxi Province, College of Basic Medical Science, Jiujiang University, Jiujiang, 2Division of Nursing, 2nd Affiliated Hospital, Yichun University, Yichun, People&#39;s Republic of ChinaBackground: Supramolecular micelles as drug-delivery vehicles are generally unable to enter the nucleus of nondividing cells. In the work reported here, nuclear localization signal (NLS)-modified polymeric micelles were studied with the aim of improving nuclear drug delivery.Methods: In this research, cholesterol-modified glycol chitosan (CHGC) was synthesized. NLS-conjugated CHGC (NCHGC) was synthesized and characterized using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and fluorescence spectroscopy. Doxorubicin (DOX), an anticancer drug with an intracellular site of action in the nucleus, was chosen as a model drug. DOX-loaded micelles were prepared by an emulsion/solvent evaporation method. The cellular uptake of different DOX formulations was analyzed by flow cytometry and confocal laser scanning microscopy. The cytotoxicity of blank micelles, free DOX, and DOX-loaded micelles in vitro was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in HeLa and HepG2 cells.Results: The degree of substitution was 5.9 cholesterol and 3.8 NLS groups per 100 sugar residues of the NCHGC conjugate. The critical aggregation concentration of the NCHGC micelles in aqueous solution was 0.0209 mg/mL. The DOX-loaded NCHGC (DNCHGC) micelles were observed as being almost spherical in shape under transmission electron microscopy, and the size was determined as 248 nm by dynamic light scattering. The DOX-loading content of the DNCHGC micelles was 10.1%. The DOX-loaded micelles showed slow drug-release behavior within 72 hours in vitro. The DNCHGC micelles exhibited greater cellular uptake and higher amounts of DOX in the nuclei of HeLa cells than free DOX and DOX-loaded CHGC (DCHGC) micelles. The half maximal inhibitory concentration (IC50) values of free DOX, DCHGC, and DNCHGC micelles against HepG2 cells were 4.063, 0.591, and 0.171 &micro;g/mL, respectively. Moreover, the IC50 values of free DOX (3.210 &micro;g/mL) and the DCHGC micelles (1.413 &micro;g/mL) against HeLa cells were nearly 6.96- and 3.07-fold (P &lt; 0.01), respectively, higher than the IC50 value of the DNCHGC micelles (0.461 &micro;g/mL).Conclusion: The results of this study suggest that novel NCHGC micelles could be a potential carrier for nucleus-targeting delivery.Keywords: polymeric micelles, drug delivery, nucleus-targeting deliveryZhao JZhang LYu LZheng MXie XYu JChe XJiang DDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2012, Iss default, Pp 5079-5090 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Zhao J Zhang L Yu L Zheng M Xie X Yu J Che X Jiang D Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin
description	Jingmou Yu,1 Xin Xie,1 Meirong Zheng,1 Ling Yu,2 Lei Zhang,1 Jianguo Zhao,1 Dengzhao Jiang,1 Xiangxin Che11Key Laboratory of Systems Biology Medicine of Jiangxi Province, College of Basic Medical Science, Jiujiang University, Jiujiang, 2Division of Nursing, 2nd Affiliated Hospital, Yichun University, Yichun, People&#39;s Republic of ChinaBackground: Supramolecular micelles as drug-delivery vehicles are generally unable to enter the nucleus of nondividing cells. In the work reported here, nuclear localization signal (NLS)-modified polymeric micelles were studied with the aim of improving nuclear drug delivery.Methods: In this research, cholesterol-modified glycol chitosan (CHGC) was synthesized. NLS-conjugated CHGC (NCHGC) was synthesized and characterized using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and fluorescence spectroscopy. Doxorubicin (DOX), an anticancer drug with an intracellular site of action in the nucleus, was chosen as a model drug. DOX-loaded micelles were prepared by an emulsion/solvent evaporation method. The cellular uptake of different DOX formulations was analyzed by flow cytometry and confocal laser scanning microscopy. The cytotoxicity of blank micelles, free DOX, and DOX-loaded micelles in vitro was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in HeLa and HepG2 cells.Results: The degree of substitution was 5.9 cholesterol and 3.8 NLS groups per 100 sugar residues of the NCHGC conjugate. The critical aggregation concentration of the NCHGC micelles in aqueous solution was 0.0209 mg/mL. The DOX-loaded NCHGC (DNCHGC) micelles were observed as being almost spherical in shape under transmission electron microscopy, and the size was determined as 248 nm by dynamic light scattering. The DOX-loading content of the DNCHGC micelles was 10.1%. The DOX-loaded micelles showed slow drug-release behavior within 72 hours in vitro. The DNCHGC micelles exhibited greater cellular uptake and higher amounts of DOX in the nuclei of HeLa cells than free DOX and DOX-loaded CHGC (DCHGC) micelles. The half maximal inhibitory concentration (IC50) values of free DOX, DCHGC, and DNCHGC micelles against HepG2 cells were 4.063, 0.591, and 0.171 &micro;g/mL, respectively. Moreover, the IC50 values of free DOX (3.210 &micro;g/mL) and the DCHGC micelles (1.413 &micro;g/mL) against HeLa cells were nearly 6.96- and 3.07-fold (P &lt; 0.01), respectively, higher than the IC50 value of the DNCHGC micelles (0.461 &micro;g/mL).Conclusion: The results of this study suggest that novel NCHGC micelles could be a potential carrier for nucleus-targeting delivery.Keywords: polymeric micelles, drug delivery, nucleus-targeting delivery
format	article
author	Zhao J Zhang L Yu L Zheng M Xie X Yu J Che X Jiang D
author_facet	Zhao J Zhang L Yu L Zheng M Xie X Yu J Che X Jiang D
author_sort	Zhao J
title	Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin
title_short	Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin
title_full	Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin
title_fullStr	Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin
title_full_unstemmed	Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin
title_sort	fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin
publisher	Dove Medical Press
publishDate	2012
url	https://doaj.org/article/2f25dbd62b384644a6ec09763c3c7e01
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Fabrication and characterization of nuclear localization signal-conjugated glycol chitosan micelles for improving the nuclear delivery of doxorubicin

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