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Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter

PURPOSE: In order to overcome the obstacles and side effects of classical chemotherapy, numerous studies have been performed to develop the treatment based on targeted transport of active compounds directly to the site of action. Since tumor cells are featured with intensified glucose metabolism, we...

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Autores principales: Sztandera, Krzysztof, Działak, Paula, Marcinkowska, Monika, Stańczyk, Maciej, Gorzkiewicz, Michał, Janaszewska, Anna, Klajnert-Maculewicz, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669199/
https://www.ncbi.nlm.nih.gov/pubmed/31367876
http://dx.doi.org/10.1007/s11095-019-2673-9
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author Sztandera, Krzysztof
Działak, Paula
Marcinkowska, Monika
Stańczyk, Maciej
Gorzkiewicz, Michał
Janaszewska, Anna
Klajnert-Maculewicz, Barbara
author_facet Sztandera, Krzysztof
Działak, Paula
Marcinkowska, Monika
Stańczyk, Maciej
Gorzkiewicz, Michał
Janaszewska, Anna
Klajnert-Maculewicz, Barbara
author_sort Sztandera, Krzysztof
collection PubMed
description PURPOSE: In order to overcome the obstacles and side effects of classical chemotherapy, numerous studies have been performed to develop the treatment based on targeted transport of active compounds directly to the site of action. Since tumor cells are featured with intensified glucose metabolism, we set out to develop innovative, glucose-modified PAMAM dendrimer for the delivery of doxorubicin to breast cancer cells. METHODS: PAMAM-dox-glc conjugate was synthesized and characterized by (1)H NMR, FT-IR, size and zeta potential measurements. The drug release rate from conjugate was evaluated by dialysis under different pH conditions. The expression level of GLUT family receptors in cells cultured in full and glucose-deprived medium was evaluated by quantitative real-time RT-PCR and flow cytometry. The cytotoxicity of conjugate in presence or absence of GLUT1 inhibitors was determined by MTT assay. RESULTS: We showed that PAMAM-dox-glc conjugate exhibits pH-dependent drug release and increased cytotoxic activity compared to free drug in cells cultured in medium without glucose. Further, we proved that these cells overexpress transporters of GLUT family. The toxic effect of conjugate was eliminated by the application of specific GLUT1 inhibitors. CONCLUSION: Our findings revealed that the glucose moiety plays a crucial role in the recognition of cells with high expression of GLUT receptors. By selectively blocking GLUT1 transporter we showed its importance for the cytotoxic activity of PAMAM-dox-glc conjugate. These results suggest that PAMAM-glucose formulations may constitute an efficient platform for the specific delivery of anticancer drugs to tumor cells overexpressing transporters of GLUT family. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-019-2673-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-66691992019-08-14 Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter Sztandera, Krzysztof Działak, Paula Marcinkowska, Monika Stańczyk, Maciej Gorzkiewicz, Michał Janaszewska, Anna Klajnert-Maculewicz, Barbara Pharm Res Research Paper PURPOSE: In order to overcome the obstacles and side effects of classical chemotherapy, numerous studies have been performed to develop the treatment based on targeted transport of active compounds directly to the site of action. Since tumor cells are featured with intensified glucose metabolism, we set out to develop innovative, glucose-modified PAMAM dendrimer for the delivery of doxorubicin to breast cancer cells. METHODS: PAMAM-dox-glc conjugate was synthesized and characterized by (1)H NMR, FT-IR, size and zeta potential measurements. The drug release rate from conjugate was evaluated by dialysis under different pH conditions. The expression level of GLUT family receptors in cells cultured in full and glucose-deprived medium was evaluated by quantitative real-time RT-PCR and flow cytometry. The cytotoxicity of conjugate in presence or absence of GLUT1 inhibitors was determined by MTT assay. RESULTS: We showed that PAMAM-dox-glc conjugate exhibits pH-dependent drug release and increased cytotoxic activity compared to free drug in cells cultured in medium without glucose. Further, we proved that these cells overexpress transporters of GLUT family. The toxic effect of conjugate was eliminated by the application of specific GLUT1 inhibitors. CONCLUSION: Our findings revealed that the glucose moiety plays a crucial role in the recognition of cells with high expression of GLUT receptors. By selectively blocking GLUT1 transporter we showed its importance for the cytotoxic activity of PAMAM-dox-glc conjugate. These results suggest that PAMAM-glucose formulations may constitute an efficient platform for the specific delivery of anticancer drugs to tumor cells overexpressing transporters of GLUT family. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-019-2673-9) contains supplementary material, which is available to authorized users. Springer US 2019-07-31 2019 /pmc/articles/PMC6669199/ /pubmed/31367876 http://dx.doi.org/10.1007/s11095-019-2673-9 Text en © The Author(s) 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Research Paper
Sztandera, Krzysztof
Działak, Paula
Marcinkowska, Monika
Stańczyk, Maciej
Gorzkiewicz, Michał
Janaszewska, Anna
Klajnert-Maculewicz, Barbara
Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter
title Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter
title_full Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter
title_fullStr Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter
title_full_unstemmed Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter
title_short Sugar Modification Enhances Cytotoxic Activity of PAMAM-Doxorubicin Conjugate in Glucose-Deprived MCF-7 Cells – Possible Role of GLUT1 Transporter
title_sort sugar modification enhances cytotoxic activity of pamam-doxorubicin conjugate in glucose-deprived mcf-7 cells – possible role of glut1 transporter
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669199/
https://www.ncbi.nlm.nih.gov/pubmed/31367876
http://dx.doi.org/10.1007/s11095-019-2673-9
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