Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport

Tianshu Li, Shinji TakeokaDepartment of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), Tokyo, JapanAbstract: With a small amount of maleimide modification on the liposome surface, enhanced cellular uptake of liposomes and drug-de...

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Autores principales:	Li T, Takeoka S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2014
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/bebc0c74290b4ea1befd55cb6a386f4d
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spelling	oai:doaj.org-article:bebc0c74290b4ea1befd55cb6a386f4d2021-12-02T07:22:52ZEnhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport1178-2013https://doaj.org/article/bebc0c74290b4ea1befd55cb6a386f4d2014-06-01T00:00:00Zhttp://www.dovepress.com/enhanced-cellular-uptake-of-maleimide-modified-liposomes-via-thiol-med-a17117https://doaj.org/toc/1178-2013 Tianshu Li, Shinji TakeokaDepartment of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), Tokyo, JapanAbstract: With a small amount of maleimide modification on the liposome surface, enhanced cellular uptake of liposomes and drug-delivery efficiency can be obtained both in vitro and in vivo. Herein, we describe the mechanisms underlying this enhanced cellular uptake. Suppression of the cellular uptake of maleimide-modified liposomes (M-GGLG, composed of 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate [GGLG]/cholesterol/poly(ethylene glycol) – 1,2-distearoyl-sn-glycero-3-phosphoethanolamine [PEG5000-DSPE]/maleimide [M]-PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03) caused by temperature block and addition of serum was alleviated compared with that of liposomes without maleimide modification (GGLG liposomes, composed of GGLG/cholesterol/PEG5000-DSPE/PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03). When 0.01 nM N-ethylmaleimide was used to pre-block cellular thiols, the cellular uptake of M-GGLG liposomes was decreased to approximately 70% in HeLa, HCC1954, MDA-MB-468, and COS-7 cell lines. Moreover, inhibition of a thiol-related reductase such as protein disulfide isomerase resulted in a 15%–45% inhibition of the cellular uptake of M-GGLG liposomes, whereas GGLG liposomes were not influenced. Further, single and mixed inhibitors of clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis did not efficiently inhibit the cellular uptake of M-GGLG liposomes. Using confocal microscopy, we verified that M-GGLG liposomes were localized partially in lysosomes after inhibition of the mentioned conventional endocytic pathways. Therefore, it was hypothesized that the mechanisms underlying the enhanced cellular uptake of liposomes by maleimide modification was thiol-mediated membrane trafficking, including endocytosis and energy-independent transport.Keywords: maleimide, thiol reactive, liposome, endocytosis, energy-independent transport, protein disulfide isomeraseLi TTakeoka SDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2014, Iss Issue 1, Pp 2849-2861 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Li T Takeoka S Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport
description	Tianshu Li, Shinji TakeokaDepartment of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), Tokyo, JapanAbstract: With a small amount of maleimide modification on the liposome surface, enhanced cellular uptake of liposomes and drug-delivery efficiency can be obtained both in vitro and in vivo. Herein, we describe the mechanisms underlying this enhanced cellular uptake. Suppression of the cellular uptake of maleimide-modified liposomes (M-GGLG, composed of 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate [GGLG]/cholesterol/poly(ethylene glycol) – 1,2-distearoyl-sn-glycero-3-phosphoethanolamine [PEG5000-DSPE]/maleimide [M]-PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03) caused by temperature block and addition of serum was alleviated compared with that of liposomes without maleimide modification (GGLG liposomes, composed of GGLG/cholesterol/PEG5000-DSPE/PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03). When 0.01 nM N-ethylmaleimide was used to pre-block cellular thiols, the cellular uptake of M-GGLG liposomes was decreased to approximately 70% in HeLa, HCC1954, MDA-MB-468, and COS-7 cell lines. Moreover, inhibition of a thiol-related reductase such as protein disulfide isomerase resulted in a 15%–45% inhibition of the cellular uptake of M-GGLG liposomes, whereas GGLG liposomes were not influenced. Further, single and mixed inhibitors of clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis did not efficiently inhibit the cellular uptake of M-GGLG liposomes. Using confocal microscopy, we verified that M-GGLG liposomes were localized partially in lysosomes after inhibition of the mentioned conventional endocytic pathways. Therefore, it was hypothesized that the mechanisms underlying the enhanced cellular uptake of liposomes by maleimide modification was thiol-mediated membrane trafficking, including endocytosis and energy-independent transport.Keywords: maleimide, thiol reactive, liposome, endocytosis, energy-independent transport, protein disulfide isomerase
format	article
author	Li T Takeoka S
author_facet	Li T Takeoka S
author_sort	Li T
title	Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport
title_short	Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport
title_full	Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport
title_fullStr	Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport
title_full_unstemmed	Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport
title_sort	enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport
publisher	Dove Medical Press
publishDate	2014
url	https://doaj.org/article/bebc0c74290b4ea1befd55cb6a386f4d
work_keys_str_mv	AT lit enhancedcellularuptakeofmaleimidemodifiedliposomesviathiolmediatedtransport AT takeokas enhancedcellularuptakeofmaleimidemodifiedliposomesviathiolmediatedtransport
_version_	1718399477388148736

Enhanced cellular uptake of maleimide-modified liposomes via thiol-mediated transport

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