Disulfide-Based Poly(amido amine)s for siRNA Delivery: Effects of Structure on siRNA Complexation, Cellular Uptake, Gene Silencing and Toxicity
Identifieur interne : 000D39 ( Main/Exploration ); précédent : 000D38; suivant : 000D40Disulfide-Based Poly(amido amine)s for siRNA Delivery: Effects of Structure on siRNA Complexation, Cellular Uptake, Gene Silencing and Toxicity
Auteurs : Pieter Vader [Pays-Bas] ; Leonardus J. Van Der Aa [Pays-Bas] ; Johan F. J. Engbersen [Pays-Bas] ; Gert Storm [Pays-Bas] ; Raymond M. Schiffelers [Pays-Bas]Source :
- Pharmaceutical Research [ 0724-8741 ] ; 2010.
Abstract
RNA interference (RNAi) is a process by which small interfering RNAs (siRNA) induce sequence-specific gene silencing. Therefore, siRNA is an emerging promise as a novel therapeutic. In order to realize the high expectations for therapeutic applications, efficient delivery systems for siRNA are necessary.
In this study, a new series of biodegradable poly(amido amine)s with disulfide linkages in the backbone was synthesized out of N,N′-cystaminebisacrylamide (CBA), 4-amino-1-butanol (ABOL) and ethylene diamine (EDA). Effects of different percentages of butanolic side chains and protonatable fragments in the main chain on siRNA complexation, cellular uptake, gene silencing and toxicity were investigated.
Incorporation of EDA in the polymer resulted in increased siRNA condensation. Efficient siRNA condensation was shown to be necessary for cellular uptake; however, excess of polymer decreased siRNA uptake for polymers with high amounts of EDA. Silencing efficiency did not correlate with uptake, since silencing increased with increasing w/w ratio for all polymers. More than 80% knockdown was found for polyplexes formed with polymers containing 25% or 50% EDA, which was combined with low cytotoxicity.
Poly(amido amine)s with minor fractions of protonatable fragments in the main chain are promising carriers for delivery of siRNA.
The online version of this article (doi:10.1007/s11095-010-0344-y) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1007/s11095-010-0344-y
PubMed: 21181546
PubMed Central: 3073045
Affiliations:
- Pays-Bas
- Overijssel, Utrecht (province)
- Enschede, Utrecht
- Université d'Utrecht, Université de Twente
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Le document en format XML
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Van Der Aa</name><affiliation wicri:level="4"><nlm:aff id="Aff2">Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box 217, 7500 AE Enschede</wicri:regionArea><orgName type="university">Université de Twente</orgName><placeName><settlement type="city">Enschede</settlement><region nuts="2">Overijssel</region></placeName></affiliation></author><author><name sortKey="Engbersen, Johan F J" sort="Engbersen, Johan F J" uniqKey="Engbersen J" first="Johan F. J." last="Engbersen">Johan F. J. Engbersen</name><affiliation wicri:level="4"><nlm:aff id="Aff2">Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box 217, 7500 AE Enschede</wicri:regionArea><orgName type="university">Université de Twente</orgName><placeName><settlement type="city">Enschede</settlement><region nuts="2">Overijssel</region></placeName></affiliation></author><author><name sortKey="Storm, Gert" sort="Storm, Gert" uniqKey="Storm G" first="Gert" last="Storm">Gert Storm</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht</wicri:regionArea><orgName type="university">Université d'Utrecht</orgName><placeName><settlement type="city">Utrecht</settlement><region nuts="2">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Schiffelers, Raymond M" sort="Schiffelers, Raymond M" uniqKey="Schiffelers R" first="Raymond M." last="Schiffelers">Raymond M. Schiffelers</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht</wicri:regionArea><orgName type="university">Université d'Utrecht</orgName><placeName><settlement type="city">Utrecht</settlement><region nuts="2">Utrecht (province)</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21181546</idno><idno type="pmc">3073045</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073045</idno><idno type="RBID">PMC:3073045</idno><idno type="doi">10.1007/s11095-010-0344-y</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000175</idno><idno type="wicri:Area/Pmc/Curation">000175</idno><idno type="wicri:Area/Pmc/Checkpoint">000396</idno><idno type="wicri:Area/Ncbi/Merge">000081</idno><idno type="wicri:Area/Ncbi/Curation">000081</idno><idno type="wicri:Area/Ncbi/Checkpoint">000081</idno><idno type="wicri:doubleKey">0724-8741:2010:Vader P:disulfide:based:poly</idno><idno type="wicri:Area/Main/Merge">000D41</idno><idno type="wicri:Area/Main/Curation">000D39</idno><idno type="wicri:Area/Main/Exploration">000D39</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Disulfide-Based Poly(amido amine)s for siRNA Delivery: Effects of Structure on siRNA Complexation, Cellular Uptake, Gene Silencing and Toxicity</title><author><name sortKey="Vader, Pieter" sort="Vader, Pieter" uniqKey="Vader P" first="Pieter" last="Vader">Pieter Vader</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht</wicri:regionArea><orgName type="university">Université d'Utrecht</orgName><placeName><settlement type="city">Utrecht</settlement><region nuts="2">Utrecht (province)</region></placeName></affiliation><affiliation wicri:level="4"><nlm:aff id="Aff3">Faculty of Science, Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Faculty of Science, Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht</wicri:regionArea><orgName type="university">Université d'Utrecht</orgName><placeName><settlement type="city">Utrecht</settlement><region nuts="2">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Van Der Aa, Leonardus J" sort="Van Der Aa, Leonardus J" uniqKey="Van Der Aa L" first="Leonardus J." last="Van Der Aa">Leonardus J. Van Der Aa</name><affiliation wicri:level="4"><nlm:aff id="Aff2">Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box 217, 7500 AE Enschede</wicri:regionArea><orgName type="university">Université de Twente</orgName><placeName><settlement type="city">Enschede</settlement><region nuts="2">Overijssel</region></placeName></affiliation></author><author><name sortKey="Engbersen, Johan F J" sort="Engbersen, Johan F J" uniqKey="Engbersen J" first="Johan F. J." last="Engbersen">Johan F. J. Engbersen</name><affiliation wicri:level="4"><nlm:aff id="Aff2">Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Depts. of Biomedical Chemistry & Polymer Chemistry & Biomaterials MIRA Institute for Biomedical Technology & Technical Medicine Faculty of Science & Technology, University of Twente, P.O. Box 217, 7500 AE Enschede</wicri:regionArea><orgName type="university">Université de Twente</orgName><placeName><settlement type="city">Enschede</settlement><region nuts="2">Overijssel</region></placeName></affiliation></author><author><name sortKey="Storm, Gert" sort="Storm, Gert" uniqKey="Storm G" first="Gert" last="Storm">Gert Storm</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht</wicri:regionArea><orgName type="university">Université d'Utrecht</orgName><placeName><settlement type="city">Utrecht</settlement><region nuts="2">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Schiffelers, Raymond M" sort="Schiffelers, Raymond M" uniqKey="Schiffelers R" first="Raymond M." last="Schiffelers">Raymond M. Schiffelers</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmaceutics Z-513 Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80082, 3508 TB Utrecht</wicri:regionArea><orgName type="university">Université d'Utrecht</orgName><placeName><settlement type="city">Utrecht</settlement><region nuts="2">Utrecht (province)</region></placeName></affiliation></author></analytic><series><title level="j">Pharmaceutical Research</title><idno type="ISSN">0724-8741</idno><idno type="eISSN">1573-904X</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><sec><title>Purpose</title><p>RNA interference (RNAi) is a process by which small interfering RNAs (siRNA) induce sequence-specific gene silencing. Therefore, siRNA is an emerging promise as a novel therapeutic. In order to realize the high expectations for therapeutic applications, efficient delivery systems for siRNA are necessary.</p></sec><sec><title>Methods</title><p>In this study, a new series of biodegradable poly(amido amine)s with disulfide linkages in the backbone was synthesized out of N,N′-cystaminebisacrylamide (CBA), 4-amino-1-butanol (ABOL) and ethylene diamine (EDA). Effects of different percentages of butanolic side chains and protonatable fragments in the main chain on siRNA complexation, cellular uptake, gene silencing and toxicity were investigated.</p></sec><sec><title>Results</title><p>Incorporation of EDA in the polymer resulted in increased siRNA condensation. Efficient siRNA condensation was shown to be necessary for cellular uptake; however, excess of polymer decreased siRNA uptake for polymers with high amounts of EDA. Silencing efficiency did not correlate with uptake, since silencing increased with increasing w/w ratio for all polymers. More than 80% knockdown was found for polyplexes formed with polymers containing 25% or 50% EDA, which was combined with low cytotoxicity.</p></sec><sec><title>Conclusions</title><p>Poly(amido amine)s with minor fractions of protonatable fragments in the main chain are promising carriers for delivery of siRNA.</p></sec><sec><title>Electronic Supplementary Material</title><p>The online version of this article (doi:10.1007/s11095-010-0344-y) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Fire, A" uniqKey="Fire A">A Fire</name></author><author><name sortKey="Xu, S" uniqKey="Xu S">S Xu</name></author><author><name sortKey="Montgomery, Mk" uniqKey="Montgomery M">MK Montgomery</name></author><author><name sortKey="Kostas, Sa" uniqKey="Kostas S">SA Kostas</name></author><author><name sortKey="Driver, Se" uniqKey="Driver S">SE 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Ogris</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Boussif, O" uniqKey="Boussif O">O Boussif</name></author><author><name sortKey="Lezoualc, F" uniqKey="Lezoualc F">F Lezoualc’h</name></author><author><name sortKey="Zanta, Ma" uniqKey="Zanta M">MA Zanta</name></author><author><name sortKey="Mergny, Md" uniqKey="Mergny M">MD Mergny</name></author><author><name sortKey="Scherman, D" uniqKey="Scherman D">D Scherman</name></author><author><name sortKey="Demeneix, B" uniqKey="Demeneix B">B Demeneix</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Griffiths, Pc" uniqKey="Griffiths P">PC Griffiths</name></author><author><name sortKey="Paul, A" uniqKey="Paul A">A Paul</name></author><author><name sortKey="Khayat, Z" uniqKey="Khayat Z">Z Khayat</name></author><author><name sortKey="Wan, Kw" uniqKey="Wan K">KW Wan</name></author><author><name sortKey="King, Sm" uniqKey="King S">SM King</name></author><author><name sortKey="Grillo, I" uniqKey="Grillo I">I Grillo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sonawane, Nd" uniqKey="Sonawane N">ND Sonawane</name></author><author><name sortKey="Szoka, Fc" uniqKey="Szoka F">FC Szoka</name></author><author><name sortKey="Verkman, As" uniqKey="Verkman A">AS Verkman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fischer, D" uniqKey="Fischer D">D Fischer</name></author><author><name sortKey="Li, Y" uniqKey="Li Y">Y Li</name></author><author><name sortKey="Ahlemeyer, B" uniqKey="Ahlemeyer B">B Ahlemeyer</name></author><author><name sortKey="Krieglstein, J" uniqKey="Krieglstein J">J Krieglstein</name></author><author><name sortKey="Kissel, T" uniqKey="Kissel T">T Kissel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Grayson, Ac" uniqKey="Grayson A">AC Grayson</name></author><author><name sortKey="Doody, Am" uniqKey="Doody A">AM Doody</name></author><author><name sortKey="Putnam, D" uniqKey="Putnam D">D Putnam</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Pays-Bas</li></country><region><li>Overijssel</li><li>Utrecht (province)</li></region><settlement><li>Enschede</li><li>Utrecht</li></settlement><orgName><li>Université d'Utrecht</li><li>Université de Twente</li></orgName></list><tree><country name="Pays-Bas"><region name="Utrecht (province)"><name sortKey="Vader, Pieter" sort="Vader, Pieter" uniqKey="Vader P" first="Pieter" last="Vader">Pieter Vader</name></region><name sortKey="Engbersen, Johan F J" sort="Engbersen, Johan F J" uniqKey="Engbersen J" first="Johan F. J." last="Engbersen">Johan F. J. Engbersen</name><name sortKey="Schiffelers, Raymond M" sort="Schiffelers, Raymond M" uniqKey="Schiffelers R" first="Raymond M." last="Schiffelers">Raymond M. Schiffelers</name><name sortKey="Storm, Gert" sort="Storm, Gert" uniqKey="Storm G" first="Gert" last="Storm">Gert Storm</name><name sortKey="Vader, Pieter" sort="Vader, Pieter" uniqKey="Vader P" first="Pieter" last="Vader">Pieter Vader</name><name sortKey="Van Der Aa, Leonardus J" sort="Van Der Aa, Leonardus J" uniqKey="Van Der Aa L" first="Leonardus J." last="Van Der Aa">Leonardus J. Van Der Aa</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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