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Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers
Co-delivery systems of siRNA and chemotherapeutic drugs have been developed as an attractive strategy to optimize the efficacy of chemotherapy towards cancer cells with multidrug resistance. In these typical systems, siRNAs are usually associated to drugs within a carrier but without covalent intera...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321315/ https://www.ncbi.nlm.nih.gov/pubmed/32545345 http://dx.doi.org/10.3390/molecules25112714 |
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author | Gauthier, Florian Bertrand, Jean-Rémi Vasseur, Jean-Jacques Dupouy, Christelle Debart, Françoise |
author_facet | Gauthier, Florian Bertrand, Jean-Rémi Vasseur, Jean-Jacques Dupouy, Christelle Debart, Françoise |
author_sort | Gauthier, Florian |
collection | PubMed |
description | Co-delivery systems of siRNA and chemotherapeutic drugs have been developed as an attractive strategy to optimize the efficacy of chemotherapy towards cancer cells with multidrug resistance. In these typical systems, siRNAs are usually associated to drugs within a carrier but without covalent interactions with the risk of a premature release and degradation of the drugs inside the cells. To address this issue, we propose a covalent approach to co-deliver a siRNA-drug conjugate with a redox-responsive self-immolative linker prone to intracellular glutathione-mediated disulfide cleavage. Herein, we report the use of two disulfide bonds connected by a pentane spacer or a p-xylene spacer as self-immolative linker between the primary amine of the anticancer drug doxorubicin (Dox) and the 2′-position of one or two ribonucleotides in RNA. Five Dox-RNA conjugates were successfully synthesized using two successive thiol-disulfide exchange reactions. The Dox-RNA conjugates were annealed with their complementary strands and the duplexes were shown to form an A-helix sufficiently stable under physiological conditions. The enzymatic stability of Dox-siRNAs in human serum was enhanced compared to the unmodified siRNA, especially when two Dox are attached to siRNA. The release of native Dox and RNA from the bioconjugate was demonstrated under reducing conditions suggesting efficient linker disintegration. These results demonstrate the feasibility of making siRNA-drug conjugates via disulfide-based self-immolative linkers for potential therapeutic applications. |
format | Online Article Text |
id | pubmed-7321315 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73213152020-06-29 Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers Gauthier, Florian Bertrand, Jean-Rémi Vasseur, Jean-Jacques Dupouy, Christelle Debart, Françoise Molecules Article Co-delivery systems of siRNA and chemotherapeutic drugs have been developed as an attractive strategy to optimize the efficacy of chemotherapy towards cancer cells with multidrug resistance. In these typical systems, siRNAs are usually associated to drugs within a carrier but without covalent interactions with the risk of a premature release and degradation of the drugs inside the cells. To address this issue, we propose a covalent approach to co-deliver a siRNA-drug conjugate with a redox-responsive self-immolative linker prone to intracellular glutathione-mediated disulfide cleavage. Herein, we report the use of two disulfide bonds connected by a pentane spacer or a p-xylene spacer as self-immolative linker between the primary amine of the anticancer drug doxorubicin (Dox) and the 2′-position of one or two ribonucleotides in RNA. Five Dox-RNA conjugates were successfully synthesized using two successive thiol-disulfide exchange reactions. The Dox-RNA conjugates were annealed with their complementary strands and the duplexes were shown to form an A-helix sufficiently stable under physiological conditions. The enzymatic stability of Dox-siRNAs in human serum was enhanced compared to the unmodified siRNA, especially when two Dox are attached to siRNA. The release of native Dox and RNA from the bioconjugate was demonstrated under reducing conditions suggesting efficient linker disintegration. These results demonstrate the feasibility of making siRNA-drug conjugates via disulfide-based self-immolative linkers for potential therapeutic applications. MDPI 2020-06-11 /pmc/articles/PMC7321315/ /pubmed/32545345 http://dx.doi.org/10.3390/molecules25112714 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gauthier, Florian Bertrand, Jean-Rémi Vasseur, Jean-Jacques Dupouy, Christelle Debart, Françoise Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers |
title | Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers |
title_full | Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers |
title_fullStr | Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers |
title_full_unstemmed | Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers |
title_short | Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers |
title_sort | conjugation of doxorubicin to sirna through disulfide-based self-immolative linkers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321315/ https://www.ncbi.nlm.nih.gov/pubmed/32545345 http://dx.doi.org/10.3390/molecules25112714 |
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