PEGylated PAMAM Dendrimer-Doxorubicin Conjugates: In Vitro Evaluation and In Vivo Tumor Accumulation
Identifieur interne : 001842 ( Main/Exploration ); précédent : 001841; suivant : 001843PEGylated PAMAM Dendrimer-Doxorubicin Conjugates: In Vitro Evaluation and In Vivo Tumor Accumulation
Auteurs : Saijie Zhu [République populaire de Chine] ; Minghuang Hong [République populaire de Chine] ; Lihong Zhang [République populaire de Chine] ; Guotao Tang [République populaire de Chine] ; Yanyan Jiang [République populaire de Chine] ; Yuanying Pei [République populaire de Chine]Source :
- Pharmaceutical Research [ 0724-8741 ] ; 2010-01-01.
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Abstract
Abstract: Purpose: To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system. Methods: Doxorubicin (DOX) was conjugated to differently PEGylated PAMAM dendrimers by acid-sensitive cis-aconityl linkage and acid-insensitive succinic linkage to produce the products of PPCD and PPSD conjugates, respectively. In vitro evaluations including pH-dependent DOX release, cytotoxicity, cellular uptake, cell internalization mechanism, and intracellular localization were performed. Tumor accumulation was also visualized by in vivo fluorescence imaging. Results: DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against ovarian cancer (SKOV-3) cells increased, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. The conjugates were internalized by SKOV-3 cells via clathrin-mediated and adsorptive endocytosis, and were delivered to acidic lysosomes where DOX was released from PPCD conjugates and diffused into the nuclei. PPCD conjugates with highest PEGylation degree showed the highest tumor accumulation in mice inoculated with SKOV-3 cells. Conclusion: The obtained results suggested that PPCD conjugates with highest PEGylation degree would be a potential candidate for solid tumor treatment.
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DOI: 10.1007/s11095-009-9992-1
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xml:lang="en">PEGylated PAMAM Dendrimer-Doxorubicin Conjugates: In Vitro Evaluation and In Vivo Tumor Accumulation</title><author><name sortKey="Zhu, Saijie" sort="Zhu, Saijie" uniqKey="Zhu S" first="Saijie" last="Zhu">Saijie Zhu</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Pharmaceutics, School of Pharmacy, Fudan Univeristy, 826 Zhangheng Road, 201203, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Hong, Minghuang" sort="Hong, Minghuang" uniqKey="Hong M" first="Minghuang" last="Hong">Minghuang Hong</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Pharmaceutics, School of Pharmacy, Fudan Univeristy, 826 Zhangheng Road, 201203, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Lihong" sort="Zhang, Lihong" uniqKey="Zhang L" first="Lihong" last="Zhang">Lihong Zhang</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Pharmaceutics, School of Pharmacy, Fudan Univeristy, 826 Zhangheng Road, 201203, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Tang, Guotao" sort="Tang, Guotao" uniqKey="Tang G" first="Guotao" last="Tang">Guotao Tang</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Pharmaceutics, School of Pharmacy, Fudan Univeristy, 826 Zhangheng Road, 201203, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Jiang, Yanyan" sort="Jiang, Yanyan" uniqKey="Jiang Y" first="Yanyan" last="Jiang">Yanyan Jiang</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Pharmaceutics, School of Pharmacy, Fudan Univeristy, 826 Zhangheng Road, 201203, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">République populaire de Chine</country></affiliation></author><author><name sortKey="Pei, Yuanying" sort="Pei, Yuanying" uniqKey="Pei Y" first="Yuanying" last="Pei">Yuanying Pei</name><affiliation wicri:level="1"><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Pharmaceutics, School of Pharmacy, Fudan Univeristy, 826 Zhangheng Road, 201203, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Pharmaceutical Research</title><title level="j" type="sub">An Official Journal of the American Association of Pharmaceutical Scientists</title><title level="j" type="abbrev">Pharm Res</title><idno type="ISSN">0724-8741</idno><idno type="eISSN">1573-904X</idno><imprint><publisher>Springer US; http://www.springer-ny.com</publisher><pubPlace>Boston</pubPlace><date type="published" when="2010-01-01">2010-01-01</date><biblScope unit="volume">27</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="161">161</biblScope><biblScope unit="page" to="174">174</biblScope></imprint><idno type="ISSN">0724-8741</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0724-8741</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>acid-sensitive linkage</term><term>cellular uptake</term><term>doxorubicin</term><term>poly(amidoamine) dendrimer</term><term>poly(ethylene glycol)</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Purpose: To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system. Methods: Doxorubicin (DOX) was conjugated to differently PEGylated PAMAM dendrimers by acid-sensitive cis-aconityl linkage and acid-insensitive succinic linkage to produce the products of PPCD and PPSD conjugates, respectively. In vitro evaluations including pH-dependent DOX release, cytotoxicity, cellular uptake, cell internalization mechanism, and intracellular localization were performed. Tumor accumulation was also visualized by in vivo fluorescence imaging. Results: DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against ovarian cancer (SKOV-3) cells increased, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. The conjugates were internalized by SKOV-3 cells via clathrin-mediated and adsorptive endocytosis, and were delivered to acidic lysosomes where DOX was released from PPCD conjugates and diffused into the nuclei. PPCD conjugates with highest PEGylation degree showed the highest tumor accumulation in mice inoculated with SKOV-3 cells. Conclusion: The obtained results suggested that PPCD conjugates with highest PEGylation degree would be a potential candidate for solid tumor treatment.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Zhu, Saijie" sort="Zhu, Saijie" uniqKey="Zhu S" first="Saijie" last="Zhu">Saijie Zhu</name></noRegion><name sortKey="Hong, Minghuang" sort="Hong, Minghuang" uniqKey="Hong M" first="Minghuang" last="Hong">Minghuang Hong</name><name sortKey="Jiang, Yanyan" sort="Jiang, Yanyan" uniqKey="Jiang Y" first="Yanyan" last="Jiang">Yanyan Jiang</name><name sortKey="Jiang, Yanyan" sort="Jiang, Yanyan" uniqKey="Jiang Y" first="Yanyan" last="Jiang">Yanyan Jiang</name><name sortKey="Pei, Yuanying" sort="Pei, Yuanying" uniqKey="Pei Y" first="Yuanying" last="Pei">Yuanying Pei</name><name sortKey="Tang, Guotao" sort="Tang, Guotao" uniqKey="Tang G" first="Guotao" last="Tang">Guotao Tang</name><name sortKey="Zhang, Lihong" sort="Zhang, Lihong" uniqKey="Zhang L" first="Lihong" last="Zhang">Lihong Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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