Physicochemical and Biological Evaluation of siRNA Polyplexes Based on PEGylated Poly(amido amine)s
Identifieur interne : 000181 ( Pmc/Curation ); précédent : 000180; suivant : 000182Physicochemical 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
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<author><name sortKey="Vader, Pieter" sort="Vader, Pieter" uniqKey="Vader P" first="Pieter" last="Vader">Pieter Vader</name>
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<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>
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<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>
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<author><name sortKey="Schiffelers, Raymond M" sort="Schiffelers, Raymond M" uniqKey="Schiffelers R" first="Raymond M." last="Schiffelers">Raymond M. Schiffelers</name>
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<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>
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<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>
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<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>
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<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="1"><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>
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<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>
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<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>
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<author><name sortKey="Storm, Gert" sort="Storm, Gert" uniqKey="Storm G" first="Gert" last="Storm">Gert Storm</name>
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<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>
</affiliation>
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<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="1"><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>
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<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>
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<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>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Pharm Res</journal-id>
<journal-title-group><journal-title>Pharmaceutical Research</journal-title>
</journal-title-group>
<issn pub-type="ppub">0724-8741</issn>
<issn pub-type="epub">1573-904X</issn>
<publisher><publisher-name>Springer US</publisher-name>
<publisher-loc>Boston</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">21833793</article-id>
<article-id pub-id-type="pmc">3264854</article-id>
<article-id pub-id-type="publisher-id">545</article-id>
<article-id pub-id-type="doi">10.1007/s11095-011-0545-z</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Paper</subject>
</subj-group>
</article-categories>
<title-group><article-title>Physicochemical and Biological Evaluation of siRNA Polyplexes Based on PEGylated Poly(amido amine)s</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Vader</surname>
<given-names>Pieter</given-names>
</name>
<address><phone>+31-6-13088433</phone>
<fax>+31-30-2517839</fax>
<email>P.Vader@uu.nl</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van der Aa</surname>
<given-names>Leonardus J.</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Engbersen</surname>
<given-names>Johan F. J.</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Storm</surname>
<given-names>Gert</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schiffelers</surname>
<given-names>Raymond M.</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1"><label>1</label>
Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands</aff>
<aff id="Aff2"><label>2</label>
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</aff>
<aff id="Aff3"><label>3</label>
Universiteitsweg 99, 3584 CG Utrecht, The Netherlands</aff>
</contrib-group>
<pub-date pub-type="epub"><day>11</day>
<month>8</month>
<year>2011</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>11</day>
<month>8</month>
<year>2011</year>
</pub-date>
<pub-date pub-type="ppub"><month>2</month>
<year>2012</year>
</pub-date>
<volume>29</volume>
<issue>2</issue>
<fpage>352</fpage>
<lpage>361</lpage>
<history><date date-type="received"><day>30</day>
<month>5</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>21</day>
<month>7</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2011</copyright-statement>
</permissions>
<abstract id="Abs1"><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>
</abstract>
<kwd-group><title>KEY WORDS</title>
<kwd>biodegradable</kwd>
<kwd>delivery</kwd>
<kwd>PEGylation</kwd>
<kwd>poly(amido amine)s</kwd>
<kwd>siRNA</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© Springer Science+Business Media, LLC 2012</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>
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