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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...

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Autores principales: Petrova, Natalya S., Chernikov, Ivan V., Meschaninova, Mariya I., Dovydenko, IIya S., Venyaminova, Aliya G., Zenkova, Marina A., Vlassov, Valentin V., Chernolovskaya, Elena L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2012
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.
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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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