Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice
Annonaceous acetogenins (ACGs) are one of the most active constituents isolated from Annona species with potent antitumor activity. However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (...
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| creator | Li, Haowen Li, Yijing Ao, Hui Bi, Dongdong Han, Meihua Guo, Yifei Wang, Xiangtao |
| description | Annonaceous acetogenins (ACGs) are one of the most active constituents isolated from Annona species with potent antitumor activity. However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (FA-PEG-ACGs-NSps) had been successfully prepared using DSPE-PEG-FA and soybean lecithin (SPC) as stabilizers. The resultant FA-PEG-ACGs-NSps had a mean particle size of 119.7 nm, a zeta potential of -23.0 mV and a high drug payload of 49.68%. The obtained ACGs-NSps had a good stability in various physiological media, and showed sustained drug release. Compared to common ACGs nanoparticles (PEG-ACGs-NSps), FA-PEG-ACGs-NSps showed significantly enhanced in vitro cytotoxicity against folate receptor-positive HeLa cell lines (IC50, 0.483 μg/mL vs. 0.915 μg/mL, p |
| doi_str_mv | 10.1080/10717544.2018.1455761 |
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However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (FA-PEG-ACGs-NSps) had been successfully prepared using DSPE-PEG-FA and soybean lecithin (SPC) as stabilizers. The resultant FA-PEG-ACGs-NSps had a mean particle size of 119.7 nm, a zeta potential of -23.0 mV and a high drug payload of 49.68%. The obtained ACGs-NSps had a good stability in various physiological media, and showed sustained drug release. Compared to common ACGs nanoparticles (PEG-ACGs-NSps), FA-PEG-ACGs-NSps showed significantly enhanced in vitro cytotoxicity against folate receptor-positive HeLa cell lines (IC50, 0.483 μg/mL vs. 0.915 μg/mL, p < .05), which could be effectively reversed simply by pretreatment of free FA. In vivo experiments demonstrated that FA-PEG-ACGs-NSps brought more drug molecules into tumors and greatly improved the antitumor efficacy (TIR, 76.45% vs. 25.29%, p < .001). Therefore, DSPE-PEG-FA is considered as a proper stabilizer with active targeting effect for ACGs-NSps to reduce toxicity, enlarge the safe dosage range and apply in clinic for the treatment of folate-positive tumors. Therefore, FA-PEG-ACGs-NSps may be a prospective drug delivery system for ACGs to improve their therapeutic window and find application in clinic to treat FR over-expressed tumors.</description><identifier>ISSN: 1071-7544</identifier><identifier>EISSN: 1521-0464</identifier><identifier>DOI: 10.1080/10717544.2018.1455761</identifier><identifier>PMID: 29608108</identifier><language>eng</language><publisher>England: Taylor & Francis</publisher><subject>Acetogenins - chemistry ; Acetogenins - metabolism ; Acetogenins - pharmacology ; Animals ; Annonaceous acetogenins ; anti-tumor efficiency ; Antineoplastic Agents, Phytogenic - chemistry ; Antineoplastic Agents, Phytogenic - metabolism ; Antineoplastic Agents, Phytogenic - pharmacology ; Binding sites ; Cancer therapies ; Cell Proliferation - drug effects ; Cytotoxicity ; Dose-Response Relationship, Drug ; Drug Compounding ; Drug delivery systems ; Drug Liberation ; DSPE-PEG-FA ; Efficiency ; Excipients - chemistry ; Female ; folate targeting ; Folic Acid - chemistry ; Folic Acid - metabolism ; Folic Acid Transporters - metabolism ; HeLa Cells ; Herbal medicine ; Humans ; Lecithins - chemistry ; Medical research ; Mice, Inbred BALB C ; Mice, Nude ; Nanomedicine ; Nanoparticles ; nanosuspensions ; Ovarian cancer ; Particle Size ; PEGylation ; Phosphatidylethanolamines - chemistry ; Polyethylene Glycols - chemistry ; Solubility ; Technology, Pharmaceutical - methods ; Time Factors ; Tumor Burden - drug effects ; Tumors ; Uterine Cervical Neoplasms - drug therapy ; Uterine Cervical Neoplasms - metabolism ; Uterine Cervical Neoplasms - pathology ; Vitamin B ; Xenograft Model Antitumor Assays</subject><ispartof>Drug delivery, 2018, Vol.25 (1), p.880-887</ispartof><rights>2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. 2018</rights><rights>2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. 2018 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c562t-a12cb6c7e2be56fd230c85d3f46212f9d4158468c934d407dac65c9965ee6df3</citedby><cites>FETCH-LOGICAL-c562t-a12cb6c7e2be56fd230c85d3f46212f9d4158468c934d407dac65c9965ee6df3</cites><orcidid>0000-0002-8226-2164 ; 0000-0002-8452-288X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058653/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058653/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,4010,27479,27900,27901,27902,53766,53768,59116,59117</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29608108$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Haowen</creatorcontrib><creatorcontrib>Li, Yijing</creatorcontrib><creatorcontrib>Ao, Hui</creatorcontrib><creatorcontrib>Bi, Dongdong</creatorcontrib><creatorcontrib>Han, Meihua</creatorcontrib><creatorcontrib>Guo, Yifei</creatorcontrib><creatorcontrib>Wang, Xiangtao</creatorcontrib><title>Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice</title><title>Drug delivery</title><addtitle>Drug Deliv</addtitle><description>Annonaceous acetogenins (ACGs) are one of the most active constituents isolated from Annona species with potent antitumor activity. However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (FA-PEG-ACGs-NSps) had been successfully prepared using DSPE-PEG-FA and soybean lecithin (SPC) as stabilizers. The resultant FA-PEG-ACGs-NSps had a mean particle size of 119.7 nm, a zeta potential of -23.0 mV and a high drug payload of 49.68%. The obtained ACGs-NSps had a good stability in various physiological media, and showed sustained drug release. Compared to common ACGs nanoparticles (PEG-ACGs-NSps), FA-PEG-ACGs-NSps showed significantly enhanced in vitro cytotoxicity against folate receptor-positive HeLa cell lines (IC50, 0.483 μg/mL vs. 0.915 μg/mL, p < .05), which could be effectively reversed simply by pretreatment of free FA. In vivo experiments demonstrated that FA-PEG-ACGs-NSps brought more drug molecules into tumors and greatly improved the antitumor efficacy (TIR, 76.45% vs. 25.29%, p < .001). Therefore, DSPE-PEG-FA is considered as a proper stabilizer with active targeting effect for ACGs-NSps to reduce toxicity, enlarge the safe dosage range and apply in clinic for the treatment of folate-positive tumors. Therefore, FA-PEG-ACGs-NSps may be a prospective drug delivery system for ACGs to improve their therapeutic window and find application in clinic to treat FR over-expressed tumors.</description><subject>Acetogenins - chemistry</subject><subject>Acetogenins - metabolism</subject><subject>Acetogenins - pharmacology</subject><subject>Animals</subject><subject>Annonaceous acetogenins</subject><subject>anti-tumor efficiency</subject><subject>Antineoplastic Agents, Phytogenic - chemistry</subject><subject>Antineoplastic Agents, Phytogenic - metabolism</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Binding sites</subject><subject>Cancer therapies</subject><subject>Cell Proliferation - drug effects</subject><subject>Cytotoxicity</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Compounding</subject><subject>Drug delivery systems</subject><subject>Drug Liberation</subject><subject>DSPE-PEG-FA</subject><subject>Efficiency</subject><subject>Excipients - chemistry</subject><subject>Female</subject><subject>folate targeting</subject><subject>Folic Acid - chemistry</subject><subject>Folic Acid - metabolism</subject><subject>Folic Acid Transporters - metabolism</subject><subject>HeLa Cells</subject><subject>Herbal medicine</subject><subject>Humans</subject><subject>Lecithins - chemistry</subject><subject>Medical research</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Nanomedicine</subject><subject>Nanoparticles</subject><subject>nanosuspensions</subject><subject>Ovarian cancer</subject><subject>Particle Size</subject><subject>PEGylation</subject><subject>Phosphatidylethanolamines - chemistry</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Solubility</subject><subject>Technology, Pharmaceutical - methods</subject><subject>Time Factors</subject><subject>Tumor Burden - drug effects</subject><subject>Tumors</subject><subject>Uterine Cervical Neoplasms - drug therapy</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Uterine Cervical Neoplasms - pathology</subject><subject>Vitamin B</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1071-7544</issn><issn>1521-0464</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp9Uktv1DAQjhCIlsJPAEXinMXvOBwQqKK00kpcercce5x6lbUX26HaC78db3db0QunGc18D1vzNc17jFYYSfQJox73nLEVQViuMOO8F_hFc445wR1igr2sfcV0B9BZ8ybnDUJIYsJfN2dkELVF8rz5cxVnXaArOk1QfJhaHUIM2kBccltLiRMEH3IbdIh5yTsI2ceQP7fZT8E7b3Qo876FcKeDAVv5xZdlG1ML7rA1-9aH9hrWun0YdyPodDDaegNvm1dOzxnenepFc3v1_fbyulv__HFz-W3dGS5I6TQmZhSmBzICF84SiozkljomCCZusAxzyYQ0A2WWod5qI7gZBsEBhHX0ork5ytqoN2qX_FanvYraq4dBTJPSqXgzg-ollQ4sADDJqJYSAyOCAtXOkJGPVevLUWu3jFuwBkJJen4m-nwT_J2a4m8lEJeC0yrw8SSQ4q8FclGbuKRQv68Ikf0w0EHIiuJHlEkx5wTuyQEjdUiAekyAOiRAnRJQeR_-fd4T6_HkFfD1CPDBxbTV9zHNVhW9n2Nyqd7QZ0X_7_EX2tzEOA</recordid><startdate>2018</startdate><enddate>2018</enddate><creator>Li, Haowen</creator><creator>Li, Yijing</creator><creator>Ao, Hui</creator><creator>Bi, Dongdong</creator><creator>Han, Meihua</creator><creator>Guo, Yifei</creator><creator>Wang, Xiangtao</creator><general>Taylor & Francis</general><general>Taylor & Francis Ltd</general><general>Taylor & Francis Group</general><scope>0YH</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88I</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M2P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8226-2164</orcidid><orcidid>https://orcid.org/0000-0002-8452-288X</orcidid></search><sort><creationdate>2018</creationdate><title>Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice</title><author>Li, Haowen ; Li, Yijing ; Ao, Hui ; Bi, Dongdong ; Han, Meihua ; Guo, Yifei ; Wang, Xiangtao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c562t-a12cb6c7e2be56fd230c85d3f46212f9d4158468c934d407dac65c9965ee6df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Acetogenins - chemistry</topic><topic>Acetogenins - metabolism</topic><topic>Acetogenins - pharmacology</topic><topic>Animals</topic><topic>Annonaceous acetogenins</topic><topic>anti-tumor efficiency</topic><topic>Antineoplastic Agents, Phytogenic - chemistry</topic><topic>Antineoplastic Agents, Phytogenic - metabolism</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Binding sites</topic><topic>Cancer therapies</topic><topic>Cell Proliferation - drug effects</topic><topic>Cytotoxicity</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Compounding</topic><topic>Drug delivery systems</topic><topic>Drug Liberation</topic><topic>DSPE-PEG-FA</topic><topic>Efficiency</topic><topic>Excipients - chemistry</topic><topic>Female</topic><topic>folate targeting</topic><topic>Folic Acid - chemistry</topic><topic>Folic Acid - metabolism</topic><topic>Folic Acid Transporters - metabolism</topic><topic>HeLa Cells</topic><topic>Herbal medicine</topic><topic>Humans</topic><topic>Lecithins - chemistry</topic><topic>Medical research</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Nanomedicine</topic><topic>Nanoparticles</topic><topic>nanosuspensions</topic><topic>Ovarian cancer</topic><topic>Particle Size</topic><topic>PEGylation</topic><topic>Phosphatidylethanolamines - chemistry</topic><topic>Polyethylene Glycols - chemistry</topic><topic>Solubility</topic><topic>Technology, Pharmaceutical - methods</topic><topic>Time Factors</topic><topic>Tumor Burden - drug effects</topic><topic>Tumors</topic><topic>Uterine Cervical Neoplasms - drug therapy</topic><topic>Uterine Cervical Neoplasms - metabolism</topic><topic>Uterine Cervical Neoplasms - pathology</topic><topic>Vitamin B</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Haowen</creatorcontrib><creatorcontrib>Li, Yijing</creatorcontrib><creatorcontrib>Ao, Hui</creatorcontrib><creatorcontrib>Bi, Dongdong</creatorcontrib><creatorcontrib>Han, Meihua</creatorcontrib><creatorcontrib>Guo, Yifei</creatorcontrib><creatorcontrib>Wang, Xiangtao</creatorcontrib><collection>Taylor & Francis Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Science Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Drug delivery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Haowen</au><au>Li, Yijing</au><au>Ao, Hui</au><au>Bi, Dongdong</au><au>Han, Meihua</au><au>Guo, Yifei</au><au>Wang, Xiangtao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice</atitle><jtitle>Drug delivery</jtitle><addtitle>Drug Deliv</addtitle><date>2018</date><risdate>2018</risdate><volume>25</volume><issue>1</issue><spage>880</spage><epage>887</epage><pages>880-887</pages><issn>1071-7544</issn><eissn>1521-0464</eissn><abstract>Annonaceous acetogenins (ACGs) are one of the most active constituents isolated from Annona species with potent antitumor activity. However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (FA-PEG-ACGs-NSps) had been successfully prepared using DSPE-PEG-FA and soybean lecithin (SPC) as stabilizers. The resultant FA-PEG-ACGs-NSps had a mean particle size of 119.7 nm, a zeta potential of -23.0 mV and a high drug payload of 49.68%. The obtained ACGs-NSps had a good stability in various physiological media, and showed sustained drug release. Compared to common ACGs nanoparticles (PEG-ACGs-NSps), FA-PEG-ACGs-NSps showed significantly enhanced in vitro cytotoxicity against folate receptor-positive HeLa cell lines (IC50, 0.483 μg/mL vs. 0.915 μg/mL, p < .05), which could be effectively reversed simply by pretreatment of free FA. In vivo experiments demonstrated that FA-PEG-ACGs-NSps brought more drug molecules into tumors and greatly improved the antitumor efficacy (TIR, 76.45% vs. 25.29%, p < .001). Therefore, DSPE-PEG-FA is considered as a proper stabilizer with active targeting effect for ACGs-NSps to reduce toxicity, enlarge the safe dosage range and apply in clinic for the treatment of folate-positive tumors. Therefore, FA-PEG-ACGs-NSps may be a prospective drug delivery system for ACGs to improve their therapeutic window and find application in clinic to treat FR over-expressed tumors.</abstract><cop>England</cop><pub>Taylor & Francis</pub><pmid>29608108</pmid><doi>10.1080/10717544.2018.1455761</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-8226-2164</orcidid><orcidid>https://orcid.org/0000-0002-8452-288X</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Taylor & Francis Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Acetogenins - chemistry Acetogenins - metabolism Acetogenins - pharmacology Animals Annonaceous acetogenins anti-tumor efficiency Antineoplastic Agents, Phytogenic - chemistry Antineoplastic Agents, Phytogenic - metabolism Antineoplastic Agents, Phytogenic - pharmacology Binding sites Cancer therapies Cell Proliferation - drug effects Cytotoxicity Dose-Response Relationship, Drug Drug Compounding Drug delivery systems Drug Liberation DSPE-PEG-FA Efficiency Excipients - chemistry Female folate targeting Folic Acid - chemistry Folic Acid - metabolism Folic Acid Transporters - metabolism HeLa Cells Herbal medicine Humans Lecithins - chemistry Medical research Mice, Inbred BALB C Mice, Nude Nanomedicine Nanoparticles nanosuspensions Ovarian cancer Particle Size PEGylation Phosphatidylethanolamines - chemistry Polyethylene Glycols - chemistry Solubility Technology, Pharmaceutical - methods Time Factors Tumor Burden - drug effects Tumors Uterine Cervical Neoplasms - drug therapy Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - pathology Vitamin B Xenograft Model Antitumor Assays |
| title | Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice |
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