Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells

Abstract Positively charged cyclodextrins (PCCDs) are molecular carriers of particular interest for their ability to readily enter into cancer cells. Of main interest, guanidino- and aminoalkyl- PCCDs can be conveniently synthesized and form stable and strong inclusion complexes with various active...

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Autores principales:	Violeta Rodriguez-Ruiz, Andrey Maksimenko, Giuseppina Salzano, Maria Lampropoulou, Yannis G. Lazarou, Valentina Agostoni, Patrick Couvreur, Ruxandra Gref, Konstantina Yannakopoulou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a0262cc84fcf4c63a715006d2aceba86
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spelling	oai:doaj.org-article:a0262cc84fcf4c63a715006d2aceba862021-12-02T16:07:01ZPositively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells10.1038/s41598-017-08727-y2045-2322https://doaj.org/article/a0262cc84fcf4c63a715006d2aceba862017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08727-yhttps://doaj.org/toc/2045-2322Abstract Positively charged cyclodextrins (PCCDs) are molecular carriers of particular interest for their ability to readily enter into cancer cells. Of main interest, guanidino- and aminoalkyl- PCCDs can be conveniently synthesized and form stable and strong inclusion complexes with various active molecules bearing phosphate groups. We have addressed here the challenge to deliver into cancer cells phosphorylated gemcitabine drugs well known for their instability and inability to permeate cell membranes. NMR data corroborated by semiempirical theoretical calculations have shown that aminoalkyl-CDs form sufficiently stable complexes with both mono- and tri-phosphate forms of gemcitabine by simple mixing of the compounds in aqueous solution at physiological pH. Confocal microscopy and radioactivity counting experiments revealed that the developed systems enabled phosphorylated gemcitabine to penetrate efficiently into aggressive human breast cancer cells (MCF7), eventually leading to a substantial reduction of IC50 values. Moreover, compared to free drugs, phosphorylated metabolites of gemcitabine encapsulated in PCCDs displayed improved in vitro activities also on the aggressive human cancer cells CCRF-CEM Ara-C/8 C, a nucleoside transport-deficient T leukemia cell line. The current study offers the proof-of-principle that phosphorylated nucleoside drugs could be efficiently transported by PCCDs into cancer cells.Violeta Rodriguez-RuizAndrey MaksimenkoGiuseppina SalzanoMaria LampropoulouYannis G. LazarouValentina AgostoniPatrick CouvreurRuxandra GrefKonstantina YannakopoulouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Violeta Rodriguez-Ruiz Andrey Maksimenko Giuseppina Salzano Maria Lampropoulou Yannis G. Lazarou Valentina Agostoni Patrick Couvreur Ruxandra Gref Konstantina Yannakopoulou Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells
description	Abstract Positively charged cyclodextrins (PCCDs) are molecular carriers of particular interest for their ability to readily enter into cancer cells. Of main interest, guanidino- and aminoalkyl- PCCDs can be conveniently synthesized and form stable and strong inclusion complexes with various active molecules bearing phosphate groups. We have addressed here the challenge to deliver into cancer cells phosphorylated gemcitabine drugs well known for their instability and inability to permeate cell membranes. NMR data corroborated by semiempirical theoretical calculations have shown that aminoalkyl-CDs form sufficiently stable complexes with both mono- and tri-phosphate forms of gemcitabine by simple mixing of the compounds in aqueous solution at physiological pH. Confocal microscopy and radioactivity counting experiments revealed that the developed systems enabled phosphorylated gemcitabine to penetrate efficiently into aggressive human breast cancer cells (MCF7), eventually leading to a substantial reduction of IC50 values. Moreover, compared to free drugs, phosphorylated metabolites of gemcitabine encapsulated in PCCDs displayed improved in vitro activities also on the aggressive human cancer cells CCRF-CEM Ara-C/8 C, a nucleoside transport-deficient T leukemia cell line. The current study offers the proof-of-principle that phosphorylated nucleoside drugs could be efficiently transported by PCCDs into cancer cells.
format	article
author	Violeta Rodriguez-Ruiz Andrey Maksimenko Giuseppina Salzano Maria Lampropoulou Yannis G. Lazarou Valentina Agostoni Patrick Couvreur Ruxandra Gref Konstantina Yannakopoulou
author_facet	Violeta Rodriguez-Ruiz Andrey Maksimenko Giuseppina Salzano Maria Lampropoulou Yannis G. Lazarou Valentina Agostoni Patrick Couvreur Ruxandra Gref Konstantina Yannakopoulou
author_sort	Violeta Rodriguez-Ruiz
title	Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells
title_short	Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells
title_full	Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells
title_fullStr	Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells
title_full_unstemmed	Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells
title_sort	positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a0262cc84fcf4c63a715006d2aceba86
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Positively charged cyclodextrins as effective molecular transporters of active phosphorylated forms of gemcitabine into cancer cells

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