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Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group
The conjugation of siRNA to molecules, which can be internalized into the cell via natural transport mechanisms, can result in the enhancement of siRNA cellular uptake. Herein, the carrier-free cellular uptake of nuclease-resistant anti-MDR1 siRNA equipped with lipophilic residues (cholesterol, lith...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299988/ https://www.ncbi.nlm.nih.gov/pubmed/22080508 http://dx.doi.org/10.1093/nar/gkr1002 |
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author | Petrova, Natalya S. Chernikov, Ivan V. Meschaninova, Mariya I. Dovydenko, IIya S. Venyaminova, Aliya G. Zenkova, Marina A. Vlassov, Valentin V. Chernolovskaya, Elena L. |
author_facet | Petrova, Natalya S. Chernikov, Ivan V. Meschaninova, Mariya I. Dovydenko, IIya S. Venyaminova, Aliya G. Zenkova, Marina A. Vlassov, Valentin V. Chernolovskaya, Elena L. |
author_sort | Petrova, Natalya S. |
collection | PubMed |
description | The conjugation of siRNA to molecules, which can be internalized into the cell via natural transport mechanisms, can result in the enhancement of siRNA cellular uptake. Herein, the carrier-free cellular uptake of nuclease-resistant anti-MDR1 siRNA equipped with lipophilic residues (cholesterol, lithocholic acid, oleyl alcohol and litocholic acid oleylamide) attached to the 5′-end of the sense strand via oligomethylene linker of various length was investigated. A convenient combination of H-phosphonate and phosphoramidite methods was developed for the synthesis of 5′-lipophilic conjugates of siRNAs. It was found that lipophilic siRNA are able to effectively penetrate into HEK293, HepG2 and KB-8-5 cancer cells when used in a micromolar concentration range. The efficiency of the uptake is dependent upon the type of lipophilic moiety, the length of the linker between the moiety and the siRNA and cell type. Among all the conjugates tested, the cholesterol-conjugated siRNAs with linkers containing from 6 to 10 carbon atoms demonstrate the optimal uptake and gene silencing properties: the shortening of the linker reduces the efficiency of the cellular uptake of siRNA conjugates, whereas the lengthening of the linker facilitates the uptake but retards the gene silencing effect and decreases the efficiency of the silencing. |
format | Online Article Text |
id | pubmed-3299988 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-32999882012-03-13 Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group Petrova, Natalya S. Chernikov, Ivan V. Meschaninova, Mariya I. Dovydenko, IIya S. Venyaminova, Aliya G. Zenkova, Marina A. Vlassov, Valentin V. Chernolovskaya, Elena L. Nucleic Acids Res Synthetic Biology and Chemistry The conjugation of siRNA to molecules, which can be internalized into the cell via natural transport mechanisms, can result in the enhancement of siRNA cellular uptake. Herein, the carrier-free cellular uptake of nuclease-resistant anti-MDR1 siRNA equipped with lipophilic residues (cholesterol, lithocholic acid, oleyl alcohol and litocholic acid oleylamide) attached to the 5′-end of the sense strand via oligomethylene linker of various length was investigated. A convenient combination of H-phosphonate and phosphoramidite methods was developed for the synthesis of 5′-lipophilic conjugates of siRNAs. It was found that lipophilic siRNA are able to effectively penetrate into HEK293, HepG2 and KB-8-5 cancer cells when used in a micromolar concentration range. The efficiency of the uptake is dependent upon the type of lipophilic moiety, the length of the linker between the moiety and the siRNA and cell type. Among all the conjugates tested, the cholesterol-conjugated siRNAs with linkers containing from 6 to 10 carbon atoms demonstrate the optimal uptake and gene silencing properties: the shortening of the linker reduces the efficiency of the cellular uptake of siRNA conjugates, whereas the lengthening of the linker facilitates the uptake but retards the gene silencing effect and decreases the efficiency of the silencing. Oxford University Press 2012-03 2011-11-10 /pmc/articles/PMC3299988/ /pubmed/22080508 http://dx.doi.org/10.1093/nar/gkr1002 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Synthetic Biology and Chemistry Petrova, Natalya S. Chernikov, Ivan V. Meschaninova, Mariya I. Dovydenko, IIya S. Venyaminova, Aliya G. Zenkova, Marina A. Vlassov, Valentin V. Chernolovskaya, Elena L. Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group |
title | Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group |
title_full | Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group |
title_fullStr | Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group |
title_full_unstemmed | Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group |
title_short | Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group |
title_sort | carrier-free cellular uptake and the gene-silencing activity of the lipophilic sirnas is strongly affected by the length of the linker between sirna and lipophilic group |
topic | Synthetic Biology and Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299988/ https://www.ncbi.nlm.nih.gov/pubmed/22080508 http://dx.doi.org/10.1093/nar/gkr1002 |
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