Physicochemical and Biological Evaluation of siRNA Polyplexes Based on PEGylated Poly(amido amine)s
Identifieur interne : 000A52 ( Main/Exploration ); précédent : 000A51; suivant : 000A53Physicochemical and Biological Evaluation of siRNA Polyplexes Based on PEGylated Poly(amido amine)s
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 ] ; 2011.
Abstract
Use of RNA interference as novel therapeutic strategy is hampered by inefficient delivery of its mediator, siRNA, to target cells. Cationic polymers have been thoroughly investigated for this purpose but often display unfavorable characteristics for systemic administration, such as interactions with serum and/or toxicity.
We report the synthesis of a new PEGylated polymer based on biodegradable poly(amido amine)s with disulfide linkages in the backbone. Various amounts of PEGylated polymers were mixed with their unPEGylated counterparts prior to polyplex formation to alter PEG content in the final complex.
PEGylation effectively decreased polyplex surface charge, salt- or serum-induced aggregation and interaction with erythrocytes. Increasing amount of PEG in formulation also reduced its stability against heparin displacement, cellular uptake and subsequent silencing efficiency. Yet, for polyplexes with high PEG content, significant gene silencing efficacy was found, which was combined with almost no toxicity.
PEGylated poly(amido amine)s are promising carriers for systemic siRNA delivery
Url:
DOI: 10.1007/s11095-011-0545-z
PubMed: 21833793
PubMed Central: 3264854
Affiliations:
- Pays-Bas
- Overijssel, Utrecht (province)
- Enschede, Utrecht
- Université d'Utrecht, Université de Twente
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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="1"><nlm:aff id="Aff3">Universiteitsweg 99, 3584 CG Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Universiteitsweg 99, 3584 CG Utrecht</wicri:regionArea><wicri:noRegion>3584 CG Utrecht</wicri:noRegion></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">Department of Biomedical Chemistry 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>Department of Biomedical Chemistry 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">Department of Biomedical Chemistry 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>Department of Biomedical Chemistry 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 Utrecht Institute for Pharmaceutical Sciences, 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 Utrecht Institute for Pharmaceutical Sciences, 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 Utrecht Institute for Pharmaceutical Sciences, 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 Utrecht Institute for Pharmaceutical Sciences, 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">21833793</idno><idno type="pmc">3264854</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264854</idno><idno type="RBID">PMC:3264854</idno><idno type="doi">10.1007/s11095-011-0545-z</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000181</idno><idno type="wicri:Area/Pmc/Curation">000181</idno><idno type="wicri:Area/Pmc/Checkpoint">000355</idno><idno type="wicri:Area/Ncbi/Merge">000108</idno><idno type="wicri:Area/Ncbi/Curation">000108</idno><idno type="wicri:Area/Ncbi/Checkpoint">000108</idno><idno type="wicri:doubleKey">0724-8741:2011:Vader P:physicochemical:and:biological</idno><idno type="wicri:Area/Main/Merge">000A54</idno><idno type="wicri:Area/Main/Curation">000A52</idno><idno type="wicri:Area/Main/Exploration">000A52</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Physicochemical and Biological Evaluation of siRNA Polyplexes Based on PEGylated Poly(amido amine)s</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 Utrecht Institute for Pharmaceutical Sciences, 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 Utrecht Institute for Pharmaceutical Sciences, 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="1"><nlm:aff id="Aff3">Universiteitsweg 99, 3584 CG Utrecht, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Universiteitsweg 99, 3584 CG Utrecht</wicri:regionArea><wicri:noRegion>3584 CG Utrecht</wicri:noRegion></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">Department of Biomedical Chemistry 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>Department of Biomedical Chemistry 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">Department of Biomedical Chemistry 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>Department of Biomedical Chemistry 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 Utrecht Institute for Pharmaceutical Sciences, 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 Utrecht Institute for Pharmaceutical Sciences, 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 Utrecht Institute for Pharmaceutical Sciences, 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 Utrecht Institute for Pharmaceutical Sciences, 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="2011">2011</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>Use of RNA interference as novel therapeutic strategy is hampered by inefficient delivery of its mediator, siRNA, to target cells. Cationic polymers have been thoroughly investigated for this purpose but often display unfavorable characteristics for systemic administration, such as interactions with serum and/or toxicity.</p></sec><sec><title>Methods</title><p>We report the synthesis of a new PEGylated polymer based on biodegradable poly(amido amine)s with disulfide linkages in the backbone. Various amounts of PEGylated polymers were mixed with their unPEGylated counterparts prior to polyplex formation to alter PEG content in the final complex.</p></sec><sec><title>Results</title><p>PEGylation effectively decreased polyplex surface charge, salt- or serum-induced aggregation and interaction with erythrocytes. Increasing amount of PEG in formulation also reduced its stability against heparin displacement, cellular uptake and subsequent silencing efficiency. Yet, for polyplexes with high PEG content, significant gene silencing efficacy was found, which was combined with almost no toxicity.</p></sec><sec><title>Conclusions</title><p>PEGylated poly(amido amine)s are promising carriers for systemic siRNA delivery <italic>in vivo</italic>.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Fougerolles, A" uniqKey="Fougerolles A">A Fougerolles</name></author><author><name sortKey="Vornlocher, Hp" uniqKey="Vornlocher H">HP Vornlocher</name></author><author><name sortKey="Maraganore, J" uniqKey="Maraganore J">J Maraganore</name></author><author><name sortKey="Lieberman, J" uniqKey="Lieberman J">J Lieberman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schiffelers, Rm" uniqKey="Schiffelers R">RM Schiffelers</name></author><author><name sortKey="Woodle, Mc" uniqKey="Woodle M">MC Woodle</name></author><author><name sortKey="Scaria, P" uniqKey="Scaria 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Davis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mok, H" uniqKey="Mok H">H Mok</name></author><author><name sortKey="Bae, Kh" uniqKey="Bae K">KH Bae</name></author><author><name sortKey="Ahn, Ch" uniqKey="Ahn C">CH Ahn</name></author><author><name sortKey="Park, Tg" uniqKey="Park T">TG Park</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schiffelers, Rm" uniqKey="Schiffelers R">RM Schiffelers</name></author><author><name sortKey="Ansari, A" uniqKey="Ansari A">A Ansari</name></author><author><name sortKey="Xu, J" uniqKey="Xu J">J Xu</name></author><author><name sortKey="Zhou, Q" uniqKey="Zhou Q">Q Zhou</name></author><author><name sortKey="Tang, Q" uniqKey="Tang Q">Q Tang</name></author><author><name sortKey="Storm, G" uniqKey="Storm G">G Storm</name></author><author><name sortKey="Molema, G" uniqKey="Molema G">G Molema</name></author><author><name sortKey="Lu, Py" uniqKey="Lu P">PY 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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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