The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes
Identifieur interne : 002B10 ( Istex/Corpus ); précédent : 002B09; suivant : 002B11The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes
Auteurs : J.-Y Cherng ; H. Talsma ; R. Verrijk ; D. J. A Crommelin ; W. E HenninkSource :
- European Journal of Pharmaceutics and Biopharmaceutics [ 0939-6411 ] ; 1999.
English descriptors
- Teeft :
- Acetate buffer, Aggregation, Aqueous solution, Aqueous solutions, Biopharmaceutics, Cationic, Cell viability, Cherng, Colloidal systems, Crommelin, Dimensional surface plot, Dynamic light, European journal, Experimental design, Experimental designs, Formulation parameters, Good agreement, Hepes, High concentration, High plasmid concentration, Higher plasmid concentration, Independent variables, Ionic strength, Marginal effect, Molecular weight, Nacl, Optimization, Optimization design, Particle size, Pdmaema, Pharm, Pharmaceutics, Plasmid, Plasmid concentration, Plasmid ratio, Polymer, Polymer concentration, Polyplexes, Relative transfection, Rpmi, Screening design, Small particles, Small polyplexes, Standard deviation, Sucrose, Transfection, Tween.
Abstract
Abstract: The aim of this study was to gain insight into the formulation parameters affecting the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes (polyplexes). Experimental designs were applied to screen and optimize several variables, which may influence the complex size. In a screening design, it was demonstrated that at a fixed concentration of plasmid (40 μg/ml) after incubation with polymer, the size of the resulting polyplexes was highly dependent on the polymer/plasmid ratio as well as on the pH, viscosity (i.e. sucrose concentration) and ionic strength of the aqueous solution. However, the temperature, PEG 600 (up to 5% (v/v)) and Tween 80 (up to 0.2%) had a marginal effect on the size of the polyplexes. In an optimization design, the effect of the pH, polymer/plasmid ratio and Tween on the size of the polymer/plasmid complexes prepared at relatively high concentration of plasmid (50–200 μg/ml) was evaluated. Based on the results of the optimization design, a mathematical model was derived, which describes the relationship between the size of the polyplexes and the different formulation parameters. This model shows that even at high plasmid concentration (200 μg/ml), small sized polyplexes were formed at low pH and ionic strength, especially when the solution contains 20% (w/v) sucrose. This concentrated polyplex dispersion (polymer/plasmid ratio >3/1 (w/w), 200 μg plasmid/ml) can be diluted down to 5 μg/ml plasmid without significant changes in particle size and transfection potential. At lower ratios, a growth in particle size was observed upon dilution of the complexes, which might also explain the low transfection efficiency of these polyplexes in vitro.
Url:
DOI: 10.1016/S0939-6411(98)00103-9
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Verrijk</name><affiliation><mods:affiliation>OctoPlus B.V., Niels Bohrweg, Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Crommelin, D J A" sort="Crommelin, D J A" uniqKey="Crommelin D" first="D. J. A" last="Crommelin">D. J. A Crommelin</name><affiliation><mods:affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Hennink, W E" sort="Hennink, W E" uniqKey="Hennink W" first="W. E" last="Hennink">W. E Hennink</name><affiliation><mods:affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>Corresponding author. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands. Tel.: +31-30-253-6964; fax: +31-30-251-7839; e-mail: w.e.hennink@pharm.uu.nl</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:E6CC41424F378A5D8CE0F6A225EEB3FCFE677B4A</idno><date when="1999" year="1999">1999</date><idno type="doi">10.1016/S0939-6411(98)00103-9</idno><idno type="url">https://api.istex.fr/ark:/67375/6H6-884H1JDH-G/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">002B10</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">002B10</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes</title><author><name sortKey="Cherng, J Y" sort="Cherng, J Y" uniqKey="Cherng J" first="J.-Y" last="Cherng">J.-Y Cherng</name><affiliation><mods:affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Talsma, H" sort="Talsma, H" uniqKey="Talsma H" first="H" last="Talsma">H. Talsma</name><affiliation><mods:affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Verrijk, R" sort="Verrijk, R" uniqKey="Verrijk R" first="R" last="Verrijk">R. Verrijk</name><affiliation><mods:affiliation>OctoPlus B.V., Niels Bohrweg, Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Crommelin, D J A" sort="Crommelin, D J A" uniqKey="Crommelin D" first="D. J. A" last="Crommelin">D. J. A Crommelin</name><affiliation><mods:affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Hennink, W E" sort="Hennink, W E" uniqKey="Hennink W" first="W. E" last="Hennink">W. E Hennink</name><affiliation><mods:affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>Corresponding author. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands. Tel.: +31-30-253-6964; fax: +31-30-251-7839; e-mail: w.e.hennink@pharm.uu.nl</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">European Journal of Pharmaceutics and Biopharmaceutics</title><title level="j" type="abbrev">EJPB</title><idno type="ISSN">0939-6411</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999">1999</date><biblScope unit="volume">47</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="215">215</biblScope><biblScope unit="page" to="224">224</biblScope></imprint><idno type="ISSN">0939-6411</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0939-6411</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Acetate buffer</term><term>Aggregation</term><term>Aqueous solution</term><term>Aqueous solutions</term><term>Biopharmaceutics</term><term>Cationic</term><term>Cell viability</term><term>Cherng</term><term>Colloidal systems</term><term>Crommelin</term><term>Dimensional surface plot</term><term>Dynamic light</term><term>European journal</term><term>Experimental design</term><term>Experimental designs</term><term>Formulation parameters</term><term>Good agreement</term><term>Hepes</term><term>High concentration</term><term>High plasmid concentration</term><term>Higher plasmid concentration</term><term>Independent variables</term><term>Ionic strength</term><term>Marginal effect</term><term>Molecular weight</term><term>Nacl</term><term>Optimization</term><term>Optimization design</term><term>Particle size</term><term>Pdmaema</term><term>Pharm</term><term>Pharmaceutics</term><term>Plasmid</term><term>Plasmid concentration</term><term>Plasmid ratio</term><term>Polymer</term><term>Polymer concentration</term><term>Polyplexes</term><term>Relative transfection</term><term>Rpmi</term><term>Screening design</term><term>Small particles</term><term>Small polyplexes</term><term>Standard deviation</term><term>Sucrose</term><term>Transfection</term><term>Tween</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: The aim of this study was to gain insight into the formulation parameters affecting the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes (polyplexes). Experimental designs were applied to screen and optimize several variables, which may influence the complex size. In a screening design, it was demonstrated that at a fixed concentration of plasmid (40 μg/ml) after incubation with polymer, the size of the resulting polyplexes was highly dependent on the polymer/plasmid ratio as well as on the pH, viscosity (i.e. sucrose concentration) and ionic strength of the aqueous solution. However, the temperature, PEG 600 (up to 5% (v/v)) and Tween 80 (up to 0.2%) had a marginal effect on the size of the polyplexes. In an optimization design, the effect of the pH, polymer/plasmid ratio and Tween on the size of the polymer/plasmid complexes prepared at relatively high concentration of plasmid (50–200 μg/ml) was evaluated. Based on the results of the optimization design, a mathematical model was derived, which describes the relationship between the size of the polyplexes and the different formulation parameters. This model shows that even at high plasmid concentration (200 μg/ml), small sized polyplexes were formed at low pH and ionic strength, especially when the solution contains 20% (w/v) sucrose. This concentrated polyplex dispersion (polymer/plasmid ratio >3/1 (w/w), 200 μg plasmid/ml) can be diluted down to 5 μg/ml plasmid without significant changes in particle size and transfection potential. At lower ratios, a growth in particle size was observed upon dilution of the complexes, which might also explain the low transfection efficiency of these polyplexes in vitro.</div></front></TEI><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>polyplexes</json:string><json:string>plasmid</json:string><json:string>plasmid concentration</json:string><json:string>transfection</json:string><json:string>sucrose</json:string><json:string>tween</json:string><json:string>particle size</json:string><json:string>cherng</json:string><json:string>polymer</json:string><json:string>hepes</json:string><json:string>pharmaceutics</json:string><json:string>nacl</json:string><json:string>european journal</json:string><json:string>pharm</json:string><json:string>biopharmaceutics</json:string><json:string>ionic strength</json:string><json:string>cationic</json:string><json:string>optimization design</json:string><json:string>rpmi</json:string><json:string>crommelin</json:string><json:string>screening design</json:string><json:string>pdmaema</json:string><json:string>experimental design</json:string><json:string>aggregation</json:string><json:string>optimization</json:string><json:string>independent variables</json:string><json:string>small polyplexes</json:string><json:string>experimental designs</json:string><json:string>relative transfection</json:string><json:string>formulation parameters</json:string><json:string>dimensional surface plot</json:string><json:string>polymer concentration</json:string><json:string>molecular weight</json:string><json:string>dynamic light</json:string><json:string>aqueous solution</json:string><json:string>aqueous solutions</json:string><json:string>standard deviation</json:string><json:string>plasmid ratio</json:string><json:string>high concentration</json:string><json:string>colloidal systems</json:string><json:string>cell viability</json:string><json:string>good agreement</json:string><json:string>small particles</json:string><json:string>high plasmid concentration</json:string><json:string>acetate buffer</json:string><json:string>higher plasmid concentration</json:string><json:string>marginal effect</json:string></teeft></keywords><author><json:item><name>J.-Y Cherng</name><affiliations><json:string>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</json:string></affiliations></json:item><json:item><name>H Talsma</name><affiliations><json:string>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</json:string></affiliations></json:item><json:item><name>R Verrijk</name><affiliations><json:string>OctoPlus B.V., Niels Bohrweg, Leiden, The Netherlands</json:string></affiliations></json:item><json:item><name>D.J.A Crommelin</name><affiliations><json:string>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</json:string></affiliations></json:item><json:item><name>W.E Hennink</name><affiliations><json:string>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</json:string><json:string>Corresponding author. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands. Tel.: +31-30-253-6964; fax: +31-30-251-7839; e-mail: w.e.hennink@pharm.uu.nl</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Experimental design</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Formulation parameter</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Polymer/plasmid complexes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Polyplexes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Poly((2-dimethylamino)ethyl methacrylate</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Transfection</value></json:item></subject><arkIstex>ark:/67375/6H6-884H1JDH-G</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Abstract: The aim of this study was to gain insight into the formulation parameters affecting the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes (polyplexes). Experimental designs were applied to screen and optimize several variables, which may influence the complex size. In a screening design, it was demonstrated that at a fixed concentration of plasmid (40 μg/ml) after incubation with polymer, the size of the resulting polyplexes was highly dependent on the polymer/plasmid ratio as well as on the pH, viscosity (i.e. sucrose concentration) and ionic strength of the aqueous solution. However, the temperature, PEG 600 (up to 5% (v/v)) and Tween 80 (up to 0.2%) had a marginal effect on the size of the polyplexes. In an optimization design, the effect of the pH, polymer/plasmid ratio and Tween on the size of the polymer/plasmid complexes prepared at relatively high concentration of plasmid (50–200 μg/ml) was evaluated. Based on the results of the optimization design, a mathematical model was derived, which describes the relationship between the size of the polyplexes and the different formulation parameters. This model shows that even at high plasmid concentration (200 μg/ml), small sized polyplexes were formed at low pH and ionic strength, especially when the solution contains 20% (w/v) sucrose. This concentrated polyplex dispersion (polymer/plasmid ratio >3/1 (w/w), 200 μg plasmid/ml) can be diluted down to 5 μg/ml plasmid without significant changes in particle size and transfection potential. At lower ratios, a growth in particle size was observed upon dilution of the complexes, which might also explain the low transfection efficiency of these polyplexes in vitro.</abstract><qualityIndicators><refBibsNative>true</refBibsNative><abstractWordCount>258</abstractWordCount><abstractCharCount>1714</abstractCharCount><keywordCount>6</keywordCount><score>10</score><pdfWordCount>5287</pdfWordCount><pdfCharCount>33279</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>10</pdfPageCount><pdfPageSize>593 x 793 pts</pdfPageSize></qualityIndicators><title>The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes</title><pmid><json:string>10382105</json:string></pmid><pii><json:string>S0939-6411(98)00103-9</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>European Journal of Pharmaceutics and Biopharmaceutics</title><language><json:string>unknown</json:string></language><publicationDate>1999</publicationDate><issn><json:string>0939-6411</json:string></issn><pii><json:string>S0939-6411(00)X0015-X</json:string></pii><volume>47</volume><issue>3</issue><pages><first>215</first><last>224</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>1 or 5/1</json:string><json:string>1999</json:string><json:string>1 and 5/1</json:string></date><geogName></geogName><orgName><json:string>Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences</json:string><json:string>Netherlands Received</json:string><json:string>UIPS</json:string><json:string>Utrecht University</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Box</json:string><json:string>P.O. 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Cherng et al.</json:string><json:string>[28]</json:string><json:string>[27]</json:string><json:string>[3]</json:string><json:string>[20]</json:string><json:string>[18,19]</json:string><json:string>[26]</json:string><json:string>[25]</json:string><json:string>[1,2]</json:string><json:string>[2]</json:string><json:string>[24]</json:string><json:string>[16,17]</json:string><json:string>[4,5]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/6H6-884H1JDH-G</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - pharmacology & pharmacy</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - clinical medicine</json:string><json:string>3 - pharmacology & pharmacy</json:string></scienceMetrix><scopus><json:string>1 - Life Sciences</json:string><json:string>2 - Pharmacology, Toxicology and Pharmaceutics</json:string><json:string>3 - Pharmaceutical Science</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - General Medicine</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Biotechnology</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences biologiques fondamentales et appliquees. psychologie</json:string><json:string>4 - biotechnologie</json:string></inist></categories><publicationDate>1999</publicationDate><copyrightDate>1999</copyrightDate><doi><json:string>10.1016/S0939-6411(98)00103-9</json:string></doi><id>E6CC41424F378A5D8CE0F6A225EEB3FCFE677B4A</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-884H1JDH-G/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-884H1JDH-G/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/6H6-884H1JDH-G/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a">The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">ELSEVIER</publisher><availability><licence><p>©1999 Elsevier Science B.V.</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</p></availability><date>1999</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note type="content">Section title: Research paper</note><note type="content">Fig. 1: Three dimensional surface plot illustrating the effect of sucrose and the polymer/plasmid ratio on the size of the polyplexes prepared at pH 5.0 and 20°C without Tween 80, PEG and NaCl. Normalized values of sucrose: 1=0%, 0=20% and −1=40%. For polymer/plasmid ratio: 1=5/1 and −1=1/1.</note><note type="content">Fig. 2: (a) Three dimensional surface plot illustrating the effect of pH and plasmid concentration on the size of polyplexes prepared in the presence of 0.1% Tween 80 and at polymer/plasmid ratio of 5/1 (w/w). Normalized values of plasmid concentration: 1=50 μg/ml, 0=125 μg/ml and −1=200 μg/ml. For pH: 1=5, 0=6.5 and −1=8. (b) Three dimensional surface plot illustrating the effect of polymer/plasmid ratio and plasmid concentration on the size of polyplexes in the presence of 0.1% Tween 80 and at pH=5.0. Normalized values of polymer/plasmid ratio: 1=5/1, 0=2/1 and −1=1/1. (c) Three dimensional surface plot illustrating the effect of Tween 80 and plasmid concentration on the size of the polyplexes prepared at a polymer/plasmid ratio 5/1 and pH=5.0. Normalized values of Tween 80, 1=0.1%, 0=0.3% and −1=0.5%.</note><note type="content">Fig. 3: Effect of pH on the size and zetapotential (○) of polyplexes. Polyplexes were prepared at a polymer/plasmid ratio of 5:1 and at a fixed plasmid concentration of 200 μg/ml in 20 mM Hepes containing 20% (w/v) sucrose. The observed particle sizes (•) and predicted values (▴) were compared. The results are expressed as mean values ±S.D. of three experiments. Zetapotential was not determined for those samples results in aggregates at pH 7.7 and 8.0.</note><note type="content">Fig. 4: (a) Relative transfection efficiency of polyplexes after dilution with RPMI to a varying plasmid concentration. The results are expressed as mean values ±S.D. of two to three experiments. Polyplexes were prepared at a polymer/plasmid ratio of 5:1 (•), 3:1 (▴) and 1:1 (■) at a fixed plasmid concentration of 200 μg/ml in 20 mM acetate buffer (pH 5.7) containing 20% (w/v) sucrose. (b) Effect of polyplexes on cell viability. The results are expressed as mean values ±S.D. of two to three experiments. Polyplexes were prepared at a polymer/plasmid ratio of 5:1 (•), 3:1 (▴) and 1:1 (■) at a fixed plasmid concentration of 200 μg/ml in 20 mM acetate buffer (pH 5.7) containing 20% (w/v) sucrose. Subsequently, polyplexes were diluted in RPMI to the desired plasmid concentration.</note><note type="content">Table 1: Levels of the independent variables evaluated in the screening design and the effect of independent variables on the size of polyplexes (a standard deviation in the size around 0.01 μm was observed (n=3))</note><note type="content">Table 2: Levels of the independent variables evaluated in the optimization design and the effect of independent variables on the size of polyplexes in the optimization design (a standard deviation in the size around 0.01 μm was observed (n=3))</note><note type="content">Table 3: The size of polyplexes prepared under different conditions*</note><note type="content">Table 4: The size of polyplexes upon dilution with RPMI*</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes</title><author xml:id="author-0000"><persName><forename type="first">J.-Y</forename><surname>Cherng</surname></persName><affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</affiliation></author><author xml:id="author-0001"><persName><forename type="first">H</forename><surname>Talsma</surname></persName><affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</affiliation></author><author xml:id="author-0002"><persName><forename type="first">R</forename><surname>Verrijk</surname></persName><affiliation>OctoPlus B.V., Niels Bohrweg, Leiden, The Netherlands</affiliation></author><author xml:id="author-0003"><persName><forename type="first">D.J.A</forename><surname>Crommelin</surname></persName><affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</affiliation></author><author xml:id="author-0004"><persName><forename type="first">W.E</forename><surname>Hennink</surname></persName><affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</affiliation><affiliation>Corresponding author. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands. Tel.: +31-30-253-6964; fax: +31-30-251-7839; e-mail: w.e.hennink@pharm.uu.nl</affiliation></author><idno type="istex">E6CC41424F378A5D8CE0F6A225EEB3FCFE677B4A</idno><idno type="ark">ark:/67375/6H6-884H1JDH-G</idno><idno type="DOI">10.1016/S0939-6411(98)00103-9</idno><idno type="PII">S0939-6411(98)00103-9</idno></analytic><monogr><title level="j">European Journal of Pharmaceutics and Biopharmaceutics</title><title level="j" type="abbrev">EJPB</title><idno type="pISSN">0939-6411</idno><idno type="PII">S0939-6411(00)X0015-X</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999"></date><biblScope unit="volume">47</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="215">215</biblScope><biblScope unit="page" to="224">224</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1999</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: The aim of this study was to gain insight into the formulation parameters affecting the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes (polyplexes). Experimental designs were applied to screen and optimize several variables, which may influence the complex size. In a screening design, it was demonstrated that at a fixed concentration of plasmid (40 μg/ml) after incubation with polymer, the size of the resulting polyplexes was highly dependent on the polymer/plasmid ratio as well as on the pH, viscosity (i.e. sucrose concentration) and ionic strength of the aqueous solution. However, the temperature, PEG 600 (up to 5% (v/v)) and Tween 80 (up to 0.2%) had a marginal effect on the size of the polyplexes. In an optimization design, the effect of the pH, polymer/plasmid ratio and Tween on the size of the polymer/plasmid complexes prepared at relatively high concentration of plasmid (50–200 μg/ml) was evaluated. Based on the results of the optimization design, a mathematical model was derived, which describes the relationship between the size of the polyplexes and the different formulation parameters. This model shows that even at high plasmid concentration (200 μg/ml), small sized polyplexes were formed at low pH and ionic strength, especially when the solution contains 20% (w/v) sucrose. This concentrated polyplex dispersion (polymer/plasmid ratio >3/1 (w/w), 200 μg plasmid/ml) can be diluted down to 5 μg/ml plasmid without significant changes in particle size and transfection potential. At lower ratios, a growth in particle size was observed upon dilution of the complexes, which might also explain the low transfection efficiency of these polyplexes in vitro.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Experimental design</term></item><item><term>Formulation parameter</term></item><item><term>Polymer/plasmid complexes</term></item><item><term>Polyplexes</term></item><item><term>Poly((2-dimethylamino)ethyl methacrylate</term></item><item><term>Transfection</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1999">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-884H1JDH-G/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity><istex:entity SYSTEM="gr4" NDATA="IMAGE" name="gr4"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla"><item-info><jid>EJPB</jid><aid>265</aid><ce:pii>S0939-6411(98)00103-9</ce:pii><ce:doi>10.1016/S0939-6411(98)00103-9</ce:doi><ce:copyright year="1999" type="full-transfer">Elsevier Science B.V.</ce:copyright></item-info><head><ce:dochead><ce:textfn>Research paper</ce:textfn></ce:dochead><ce:title>The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes</ce:title><ce:author-group><ce:author><ce:given-name>J.-Y</ce:given-name><ce:surname>Cherng</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:author><ce:given-name>H</ce:given-name><ce:surname>Talsma</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:author><ce:given-name>R</ce:given-name><ce:surname>Verrijk</ce:surname><ce:cross-ref refid="AFF2">b</ce:cross-ref></ce:author><ce:author><ce:given-name>D.J.A</ce:given-name><ce:surname>Crommelin</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:author><ce:given-name>W.E</ce:given-name><ce:surname>Hennink</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>OctoPlus B.V., Niels Bohrweg, Leiden, The Netherlands</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands. Tel.: +31-30-253-6964; fax: +31-30-251-7839; e-mail: w.e.hennink@pharm.uu.nl</ce:text></ce:correspondence></ce:author-group><ce:date-received day="20" month="9" year="1998"></ce:date-received><ce:date-accepted day="15" month="12" year="1998"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>The aim of this study was to gain insight into the formulation parameters affecting the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes (polyplexes). Experimental designs were applied to screen and optimize several variables, which may influence the complex size. In a screening design, it was demonstrated that at a fixed concentration of plasmid (40 <ce:italic>μ</ce:italic>g/ml) after incubation with polymer, the size of the resulting polyplexes was highly dependent on the polymer/plasmid ratio as well as on the pH, viscosity (i.e. sucrose concentration) and ionic strength of the aqueous solution. However, the temperature, PEG 600 (up to 5% (v/v)) and Tween 80 (up to 0.2%) had a marginal effect on the size of the polyplexes. In an optimization design, the effect of the pH, polymer/plasmid ratio and Tween on the size of the polymer/plasmid complexes prepared at relatively high concentration of plasmid (50–200 <ce:italic>μ</ce:italic>g/ml) was evaluated. Based on the results of the optimization design, a mathematical model was derived, which describes the relationship between the size of the polyplexes and the different formulation parameters. This model shows that even at high plasmid concentration (200 <ce:italic>μ</ce:italic>g/ml), small sized polyplexes were formed at low pH and ionic strength, especially when the solution contains 20% (w/v) sucrose. This concentrated polyplex dispersion (polymer/plasmid ratio >3/1 (w/w), 200 <ce:italic>μ</ce:italic>g plasmid/ml) can be diluted down to 5 <ce:italic>μ</ce:italic>g/ml plasmid without significant changes in particle size and transfection potential. At lower ratios, a growth in particle size was observed upon dilution of the complexes, which might also explain the low transfection efficiency of these polyplexes in vitro.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>Experimental design</ce:text></ce:keyword><ce:keyword><ce:text>Formulation parameter</ce:text></ce:keyword><ce:keyword><ce:text>Polymer/plasmid complexes</ce:text></ce:keyword><ce:keyword><ce:text>Polyplexes</ce:text></ce:keyword><ce:keyword><ce:text>Poly((2-dimethylamino)ethyl methacrylate</ce:text></ce:keyword><ce:keyword><ce:text>Transfection</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>The effect of formulation parameters on the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes</title></titleInfo><name type="personal"><namePart type="given">J.-Y</namePart><namePart type="family">Cherng</namePart><affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H</namePart><namePart type="family">Talsma</namePart><affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">R</namePart><namePart type="family">Verrijk</namePart><affiliation>OctoPlus B.V., Niels Bohrweg, Leiden, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">D.J.A</namePart><namePart type="family">Crommelin</namePart><affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">W.E</namePart><namePart type="family">Hennink</namePart><affiliation>Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands</affiliation><affiliation>Corresponding author. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands. Tel.: +31-30-253-6964; fax: +31-30-251-7839; e-mail: w.e.hennink@pharm.uu.nl</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1999</dateIssued><copyrightDate encoding="w3cdtf">1999</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Abstract: The aim of this study was to gain insight into the formulation parameters affecting the size of poly((2-dimethylamino)ethyl methacrylate)-plasmid complexes (polyplexes). Experimental designs were applied to screen and optimize several variables, which may influence the complex size. In a screening design, it was demonstrated that at a fixed concentration of plasmid (40 μg/ml) after incubation with polymer, the size of the resulting polyplexes was highly dependent on the polymer/plasmid ratio as well as on the pH, viscosity (i.e. sucrose concentration) and ionic strength of the aqueous solution. However, the temperature, PEG 600 (up to 5% (v/v)) and Tween 80 (up to 0.2%) had a marginal effect on the size of the polyplexes. In an optimization design, the effect of the pH, polymer/plasmid ratio and Tween on the size of the polymer/plasmid complexes prepared at relatively high concentration of plasmid (50–200 μg/ml) was evaluated. Based on the results of the optimization design, a mathematical model was derived, which describes the relationship between the size of the polyplexes and the different formulation parameters. This model shows that even at high plasmid concentration (200 μg/ml), small sized polyplexes were formed at low pH and ionic strength, especially when the solution contains 20% (w/v) sucrose. This concentrated polyplex dispersion (polymer/plasmid ratio >3/1 (w/w), 200 μg plasmid/ml) can be diluted down to 5 μg/ml plasmid without significant changes in particle size and transfection potential. At lower ratios, a growth in particle size was observed upon dilution of the complexes, which might also explain the low transfection efficiency of these polyplexes in vitro.</abstract><note type="content">Section title: Research paper</note><note type="content">Fig. 1: Three dimensional surface plot illustrating the effect of sucrose and the polymer/plasmid ratio on the size of the polyplexes prepared at pH 5.0 and 20°C without Tween 80, PEG and NaCl. Normalized values of sucrose: 1=0%, 0=20% and −1=40%. For polymer/plasmid ratio: 1=5/1 and −1=1/1.</note><note type="content">Fig. 2: (a) Three dimensional surface plot illustrating the effect of pH and plasmid concentration on the size of polyplexes prepared in the presence of 0.1% Tween 80 and at polymer/plasmid ratio of 5/1 (w/w). Normalized values of plasmid concentration: 1=50 μg/ml, 0=125 μg/ml and −1=200 μg/ml. For pH: 1=5, 0=6.5 and −1=8. (b) Three dimensional surface plot illustrating the effect of polymer/plasmid ratio and plasmid concentration on the size of polyplexes in the presence of 0.1% Tween 80 and at pH=5.0. Normalized values of polymer/plasmid ratio: 1=5/1, 0=2/1 and −1=1/1. (c) Three dimensional surface plot illustrating the effect of Tween 80 and plasmid concentration on the size of the polyplexes prepared at a polymer/plasmid ratio 5/1 and pH=5.0. Normalized values of Tween 80, 1=0.1%, 0=0.3% and −1=0.5%.</note><note type="content">Fig. 3: Effect of pH on the size and zetapotential (○) of polyplexes. Polyplexes were prepared at a polymer/plasmid ratio of 5:1 and at a fixed plasmid concentration of 200 μg/ml in 20 mM Hepes containing 20% (w/v) sucrose. The observed particle sizes (•) and predicted values (▴) were compared. The results are expressed as mean values ±S.D. of three experiments. Zetapotential was not determined for those samples results in aggregates at pH 7.7 and 8.0.</note><note type="content">Fig. 4: (a) Relative transfection efficiency of polyplexes after dilution with RPMI to a varying plasmid concentration. The results are expressed as mean values ±S.D. of two to three experiments. Polyplexes were prepared at a polymer/plasmid ratio of 5:1 (•), 3:1 (▴) and 1:1 (■) at a fixed plasmid concentration of 200 μg/ml in 20 mM acetate buffer (pH 5.7) containing 20% (w/v) sucrose. (b) Effect of polyplexes on cell viability. The results are expressed as mean values ±S.D. of two to three experiments. Polyplexes were prepared at a polymer/plasmid ratio of 5:1 (•), 3:1 (▴) and 1:1 (■) at a fixed plasmid concentration of 200 μg/ml in 20 mM acetate buffer (pH 5.7) containing 20% (w/v) sucrose. Subsequently, polyplexes were diluted in RPMI to the desired plasmid concentration.</note><note type="content">Table 1: Levels of the independent variables evaluated in the screening design and the effect of independent variables on the size of polyplexes (a standard deviation in the size around 0.01 μm was observed (n=3))</note><note type="content">Table 2: Levels of the independent variables evaluated in the optimization design and the effect of independent variables on the size of polyplexes in the optimization design (a standard deviation in the size around 0.01 μm was observed (n=3))</note><note type="content">Table 3: The size of polyplexes prepared under different conditions*</note><note type="content">Table 4: The size of polyplexes upon dilution with RPMI*</note><subject><genre>Keywords</genre><topic>Experimental design</topic><topic>Formulation parameter</topic><topic>Polymer/plasmid complexes</topic><topic>Polyplexes</topic><topic>Poly((2-dimethylamino)ethyl methacrylate</topic><topic>Transfection</topic></subject><relatedItem type="host"><titleInfo><title>European Journal of Pharmaceutics and Biopharmaceutics</title></titleInfo><titleInfo type="abbreviated"><title>EJPB</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1999</dateIssued></originInfo><identifier type="ISSN">0939-6411</identifier><identifier type="PII">S0939-6411(00)X0015-X</identifier><part><date>1999</date><detail type="volume"><number>47</number><caption>vol.</caption></detail><detail type="issue"><number>3</number><caption>no.</caption></detail><extent unit="issue-pages"><start>193</start><end>318</end></extent><extent unit="pages"><start>215</start><end>224</end></extent></part></relatedItem><identifier type="istex">E6CC41424F378A5D8CE0F6A225EEB3FCFE677B4A</identifier><identifier type="ark">ark:/67375/6H6-884H1JDH-G</identifier><identifier type="DOI">10.1016/S0939-6411(98)00103-9</identifier><identifier type="PII">S0939-6411(98)00103-9</identifier><accessCondition type="use and reproduction" contentType="copyright">©1999 Elsevier Science B.V.</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource><recordOrigin>Elsevier Science B.V., ©1999</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-884H1JDH-G/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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