Stabilization of resveratrol in blood circulation by conjugation to mPEG and mPEG-PLA polymers: investigation of conjugate linker and polymer composition on stability, metabolism, antioxidant activity and pharmacokinetic profile
Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer composit...
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| Veröffentlicht in: | PloS one 2015-03, Vol.10 (3), p.e0118824-e0118824 |
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| description | Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol. |
| doi_str_mv | 10.1371/journal.pone.0118824 |
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But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0118824</identifier><identifier>PMID: 25799413</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aggregation behavior ; Animals ; Antioxidants ; Antioxidants (Nutrients) ; Antioxidants - administration & dosage ; Antioxidants - chemistry ; Antioxidants - metabolism ; Antioxidants - pharmacokinetics ; Blood circulation ; Buffers (chemistry) ; Cancer ; Carbodiimide ; Carboxylic acids ; Chemical reactions ; Chemical synthesis ; Chemotherapy ; Conjugates ; Conjugation ; Corona ; Drug Stability ; Ethers ; Ethylene glycols ; Half-life ; Hydrophobicity ; Inflammation ; Investigations ; Male ; Metabolism ; Metabolites ; MPEG encoders ; Pharmacokinetics ; Pharmacology ; Polyesters - chemistry ; Polyethylene glycol ; Polyethylene Glycols - chemistry ; Polyethylene Glycols - metabolism ; Polylactic acid ; Polymer industry ; Polymers ; Rats ; Rats, Wistar ; Resveratrol ; Rodents ; Stability ; Stilbenes - administration & dosage ; Stilbenes - blood ; Stilbenes - chemistry ; Stilbenes - metabolism ; Stilbenes - pharmacokinetics ; Studies ; Succinic Acid - chemistry ; Video compression</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0118824-e0118824</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Siddalingappa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Siddalingappa et al 2015 Siddalingappa et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-f88ba91423344693852f37be3cfa6ddb4e5815bd3a33ae14e9b8fff107801a2b3</citedby><cites>FETCH-LOGICAL-c692t-f88ba91423344693852f37be3cfa6ddb4e5815bd3a33ae14e9b8fff107801a2b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370505/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370505/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25799413$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Delmas, Dominique</contributor><creatorcontrib>Siddalingappa, Basavaraj</creatorcontrib><creatorcontrib>Benson, Heather A E</creatorcontrib><creatorcontrib>Brown, David H</creatorcontrib><creatorcontrib>Batty, Kevin T</creatorcontrib><creatorcontrib>Chen, Yan</creatorcontrib><title>Stabilization of resveratrol in blood circulation by conjugation to mPEG and mPEG-PLA polymers: investigation of conjugate linker and polymer composition on stability, metabolism, antioxidant activity and pharmacokinetic profile</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. 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chemistry</subject><subject>Polyethylene glycol</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Polyethylene Glycols - metabolism</subject><subject>Polylactic acid</subject><subject>Polymer industry</subject><subject>Polymers</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Resveratrol</subject><subject>Rodents</subject><subject>Stability</subject><subject>Stilbenes - administration & dosage</subject><subject>Stilbenes - blood</subject><subject>Stilbenes - chemistry</subject><subject>Stilbenes - metabolism</subject><subject>Stilbenes - pharmacokinetics</subject><subject>Studies</subject><subject>Succinic Acid - chemistry</subject><subject>Video compression</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9Fu0zAUhiMEYmPwBggsTUIgrSWOncThAmmaxpg0aRMDbi3HOW7dOXaxk2rleXkQ3CabVrQLlAsfx9__-9jHJ0le43SKSYk_LlzvrTDTpbMwTTFmLKNPkn1ckWxSZCl5-iDeS16EsEjTnLCieJ7sZXlZVRST_eTPdSdqbfRv0WlnkVPIQ1iBF513BmmLauNcg6T2sjcDU6-RdHbRz4Zp51B7dXqGhG22weTq4hgtnVm34MOnaLGC0OnZvf-dFpDR9gb8VjjycbFduqAH1qIwJNetj1ALMXZGh_YoKiJwq5s4IiE7vYrEYDMXvhXS3WgLnZZo6Z3SBl4mz5QwAV6N40Hy48vp95Ovk4vLs_OT44uJLKqsmyjGalFhmhFCaVERlmeKlDUQqUTRNDWFnOG8boggRACmUNVMKYXTkqVYZDU5SN4OvkvjAh8LFDguihKzlBUkEucD0Tix4EuvW-HX3AnNtz-cn3HhY-YGuKqBqjKXMqOMYlkyInGpoGZpU9WkoNHr87hbX7fQSLCdF2bHdHfF6jmfuRWnpEzz-BYOkvejgXe_-lgl3uogwRhhwfXbvIsyK2hVRPTwH_Tx043UTMQDaKtc3FduTPkxzbKcMpKnkZo-QsWvgVbH1wGbku0KPuwIItPBbTcTfQj8_Prb_7OXP3fZdw_YOQjTzYMz_eb1hV2QDqD0LgQP6v6Scco3zXh3G3zTjHxsxih787BA96K77iN_ATS1NdE</recordid><startdate>20150323</startdate><enddate>20150323</enddate><creator>Siddalingappa, Basavaraj</creator><creator>Benson, Heather A E</creator><creator>Brown, David H</creator><creator>Batty, Kevin T</creator><creator>Chen, Yan</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150323</creationdate><title>Stabilization of resveratrol in blood circulation by conjugation to mPEG and mPEG-PLA polymers: investigation of conjugate linker and polymer composition on stability, metabolism, antioxidant activity and pharmacokinetic profile</title><author>Siddalingappa, Basavaraj ; Benson, Heather A E ; Brown, David H ; Batty, Kevin T ; Chen, Yan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-f88ba91423344693852f37be3cfa6ddb4e5815bd3a33ae14e9b8fff107801a2b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aggregation behavior</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Antioxidants (Nutrients)</topic><topic>Antioxidants - 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But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25799413</pmid><doi>10.1371/journal.pone.0118824</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-03, Vol.10 (3), p.e0118824-e0118824 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1667180863 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Aggregation behavior Animals Antioxidants Antioxidants (Nutrients) Antioxidants - administration & dosage Antioxidants - chemistry Antioxidants - metabolism Antioxidants - pharmacokinetics Blood circulation Buffers (chemistry) Cancer Carbodiimide Carboxylic acids Chemical reactions Chemical synthesis Chemotherapy Conjugates Conjugation Corona Drug Stability Ethers Ethylene glycols Half-life Hydrophobicity Inflammation Investigations Male Metabolism Metabolites MPEG encoders Pharmacokinetics Pharmacology Polyesters - chemistry Polyethylene glycol Polyethylene Glycols - chemistry Polyethylene Glycols - metabolism Polylactic acid Polymer industry Polymers Rats Rats, Wistar Resveratrol Rodents Stability Stilbenes - administration & dosage Stilbenes - blood Stilbenes - chemistry Stilbenes - metabolism Stilbenes - pharmacokinetics Studies Succinic Acid - chemistry Video compression |
| title | Stabilization of resveratrol in blood circulation by conjugation to mPEG and mPEG-PLA polymers: investigation of conjugate linker and polymer composition on stability, metabolism, antioxidant activity and pharmacokinetic profile |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T07%3A23%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Stabilization%20of%20resveratrol%20in%20blood%20circulation%20by%20conjugation%20to%20mPEG%20and%20mPEG-PLA%20polymers:%20investigation%20of%20conjugate%20linker%20and%20polymer%20composition%20on%20stability,%20metabolism,%20antioxidant%20activity%20and%20pharmacokinetic%20profile&rft.jtitle=PloS%20one&rft.au=Siddalingappa,%20Basavaraj&rft.date=2015-03-23&rft.volume=10&rft.issue=3&rft.spage=e0118824&rft.epage=e0118824&rft.pages=e0118824-e0118824&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0118824&rft_dat=%3Cgale_plos_%3EA422548350%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1667180863&rft_id=info:pmid/25799413&rft_galeid=A422548350&rft_doaj_id=oai_doaj_org_article_fbe4f75cc24841c783c17feb80d9b364&rfr_iscdi=true |