Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: Evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer
Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intrape...
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| description | Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-Drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET imaging, and overall survival. 18F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles.
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| doi_str_mv | 10.1016/j.jconrel.2012.12.005 |
| format | Article |
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[Display omitted]</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2012.12.005</identifier><identifier>PMID: 23246471</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>animal ovaries ; Animals ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - chemistry ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; bioluminescence ; Bioluminescence imaging ; cell culture ; Cell Line, Tumor ; Cell Survival - drug effects ; Combination drug delivery ; combination drug therapy ; cyclopamine ; cytotoxicity ; Drug Carriers - chemistry ; drug delivery systems ; drugs ; ethylene glycol ; Female ; gossypol ; Gossypol - administration & dosage ; Gossypol - chemistry ; Gossypol - pharmacology ; Gossypol - therapeutic use ; growth retardation ; Humans ; image analysis ; Injections, Intraperitoneal ; Kaplan-Meier Estimate ; Lactones - chemistry ; Mice ; Mice, Nude ; Micelles ; Ovarian cancer ; ovarian neoplasms ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - pathology ; Paclitaxel ; Paclitaxel - administration & dosage ; Paclitaxel - chemistry ; Paclitaxel - pharmacology ; Paclitaxel - therapeutic use ; PET imaging ; Polyethylene Glycols - chemistry ; Polymeric micelles ; positron-emission tomography ; Solubility ; solubilization ; Surface Properties ; Treatment Outcome ; Veratrum Alkaloids - administration & dosage ; Veratrum Alkaloids - chemistry ; Veratrum Alkaloids - pharmacology ; Veratrum Alkaloids - therapeutic use ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of controlled release, 2013-02, Vol.166 (1), p.1-9</ispartof><rights>2012 Elsevier B.V.</rights><rights>Copyright © 2012 Elsevier B.V. All rights reserved.</rights><rights>2012 Elsevier B.V. All rights reserved. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c524t-9371343417f41d2065149e1e1a4b7a4100c43d8fcd4a8d1884e4d5791ca9cc5a3</citedby><cites>FETCH-LOGICAL-c524t-9371343417f41d2065149e1e1a4b7a4100c43d8fcd4a8d1884e4d5791ca9cc5a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jconrel.2012.12.005$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23246471$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cho, Hyunah</creatorcontrib><creatorcontrib>Lai, Tsz Chung</creatorcontrib><creatorcontrib>Kwon, Glen S.</creatorcontrib><title>Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: Evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-Drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET imaging, and overall survival. 18F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles.
[Display omitted]</description><subject>animal ovaries</subject><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - chemistry</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>bioluminescence</subject><subject>Bioluminescence imaging</subject><subject>cell culture</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Combination drug delivery</subject><subject>combination drug therapy</subject><subject>cyclopamine</subject><subject>cytotoxicity</subject><subject>Drug Carriers - chemistry</subject><subject>drug delivery systems</subject><subject>drugs</subject><subject>ethylene glycol</subject><subject>Female</subject><subject>gossypol</subject><subject>Gossypol - administration & dosage</subject><subject>Gossypol - chemistry</subject><subject>Gossypol - pharmacology</subject><subject>Gossypol - therapeutic use</subject><subject>growth retardation</subject><subject>Humans</subject><subject>image analysis</subject><subject>Injections, Intraperitoneal</subject><subject>Kaplan-Meier Estimate</subject><subject>Lactones - chemistry</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Micelles</subject><subject>Ovarian cancer</subject><subject>ovarian neoplasms</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Paclitaxel</subject><subject>Paclitaxel - administration & dosage</subject><subject>Paclitaxel - chemistry</subject><subject>Paclitaxel - pharmacology</subject><subject>Paclitaxel - therapeutic use</subject><subject>PET imaging</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Polymeric micelles</subject><subject>positron-emission tomography</subject><subject>Solubility</subject><subject>solubilization</subject><subject>Surface Properties</subject><subject>Treatment Outcome</subject><subject>Veratrum Alkaloids - administration & dosage</subject><subject>Veratrum Alkaloids - chemistry</subject><subject>Veratrum Alkaloids - pharmacology</subject><subject>Veratrum Alkaloids - therapeutic use</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks9u1DAQxiMEosvCIwA-thJZbMfeJBxAqCp_pEogQc_WrDNJvTh2amdXzYPxAjwAz4SjXSo4VRrJh_nNN-OZL8ueM7pilK1fb1db7V1Au-KU8VUKSuWDbMGqsshFXcuH2SJxVV6sZX2SPYlxSxNRiPJxdsILLtaiZIvs11dvp1McryeLDklnJ-3tWb6xXv_Ihzn3-2euYQjegh69wzPSG43WYiStD0T7fmMcjMY70oRdRxq0Zo9hekMu9mB3h4xvyQDamhFu0b4ietLWD9Cb1BFcQzof45SaEeNSjAEGDGZuBpbcovNdgHYkvU_acdbyewgGHNHgNIan2aMWbMRnx3eZXX24-H7-Kb_88vHz-fvLXEsuxrwuSlaIQrCyFazhdC2ZqJEhA7EpQTBKtSiaqtWNgKphVSVQNLKsmYZaawnFMnt70B12mx4bjfOkVg3B9BAm5cGo_zPOXKvO71Uh15IKngROjwLB3-wwjqo3cd4lOPS7qJjktKgk5cX9KK_EmgvJ6oTKA6pDWmPA9m4iRtVsFbVVR6uo2SqpVs1GWGYv_v3OXdVfbyTg5QFowSvogonq6ltSkJSysqRcJOLdgUh3wb3BoKI2mG7SmIB6VI039wzxB0Xw4lo</recordid><startdate>20130228</startdate><enddate>20130228</enddate><creator>Cho, Hyunah</creator><creator>Lai, Tsz Chung</creator><creator>Kwon, Glen S.</creator><general>Elsevier B.V</general><scope>FBQ</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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20130228</creationdate><title>Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: Evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer</title><author>Cho, Hyunah ; Lai, Tsz Chung ; Kwon, Glen S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-9371343417f41d2065149e1e1a4b7a4100c43d8fcd4a8d1884e4d5791ca9cc5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>animal ovaries</topic><topic>Animals</topic><topic>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - chemistry</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>bioluminescence</topic><topic>Bioluminescence imaging</topic><topic>cell culture</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Combination drug delivery</topic><topic>combination drug therapy</topic><topic>cyclopamine</topic><topic>cytotoxicity</topic><topic>Drug Carriers - chemistry</topic><topic>drug delivery systems</topic><topic>drugs</topic><topic>ethylene glycol</topic><topic>Female</topic><topic>gossypol</topic><topic>Gossypol - administration & dosage</topic><topic>Gossypol - chemistry</topic><topic>Gossypol - pharmacology</topic><topic>Gossypol - therapeutic use</topic><topic>growth retardation</topic><topic>Humans</topic><topic>image analysis</topic><topic>Injections, Intraperitoneal</topic><topic>Kaplan-Meier Estimate</topic><topic>Lactones - chemistry</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Micelles</topic><topic>Ovarian cancer</topic><topic>ovarian neoplasms</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Paclitaxel</topic><topic>Paclitaxel - administration & dosage</topic><topic>Paclitaxel - chemistry</topic><topic>Paclitaxel - pharmacology</topic><topic>Paclitaxel - therapeutic use</topic><topic>PET imaging</topic><topic>Polyethylene Glycols - chemistry</topic><topic>Polymeric micelles</topic><topic>positron-emission tomography</topic><topic>Solubility</topic><topic>solubilization</topic><topic>Surface Properties</topic><topic>Treatment Outcome</topic><topic>Veratrum Alkaloids - administration & dosage</topic><topic>Veratrum Alkaloids - chemistry</topic><topic>Veratrum Alkaloids - pharmacology</topic><topic>Veratrum Alkaloids - therapeutic use</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cho, Hyunah</creatorcontrib><creatorcontrib>Lai, Tsz Chung</creatorcontrib><creatorcontrib>Kwon, Glen S.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of controlled release</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cho, Hyunah</au><au>Lai, Tsz Chung</au><au>Kwon, Glen S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: Evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer</atitle><jtitle>Journal of controlled release</jtitle><addtitle>J Control Release</addtitle><date>2013-02-28</date><risdate>2013</risdate><volume>166</volume><issue>1</issue><spage>1</spage><epage>9</epage><pages>1-9</pages><issn>0168-3659</issn><eissn>1873-4995</eissn><abstract>Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-Drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET imaging, and overall survival. 18F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles.
[Display omitted]</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>23246471</pmid><doi>10.1016/j.jconrel.2012.12.005</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0168-3659 |
| ispartof | Journal of controlled release, 2013-02, Vol.166 (1), p.1-9 |
| issn | 0168-3659 1873-4995 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | animal ovaries Animals Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - chemistry Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use bioluminescence Bioluminescence imaging cell culture Cell Line, Tumor Cell Survival - drug effects Combination drug delivery combination drug therapy cyclopamine cytotoxicity Drug Carriers - chemistry drug delivery systems drugs ethylene glycol Female gossypol Gossypol - administration & dosage Gossypol - chemistry Gossypol - pharmacology Gossypol - therapeutic use growth retardation Humans image analysis Injections, Intraperitoneal Kaplan-Meier Estimate Lactones - chemistry Mice Mice, Nude Micelles Ovarian cancer ovarian neoplasms Ovarian Neoplasms - drug therapy Ovarian Neoplasms - pathology Paclitaxel Paclitaxel - administration & dosage Paclitaxel - chemistry Paclitaxel - pharmacology Paclitaxel - therapeutic use PET imaging Polyethylene Glycols - chemistry Polymeric micelles positron-emission tomography Solubility solubilization Surface Properties Treatment Outcome Veratrum Alkaloids - administration & dosage Veratrum Alkaloids - chemistry Veratrum Alkaloids - pharmacology Veratrum Alkaloids - therapeutic use Xenograft Model Antitumor Assays |
| title | Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: Evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer |
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