Exosome is a mechanism of intercellular drug transfer: Application of quantitative pharmacology
Exosomes are small membrane vesicles (30–100nm in diameter) secreted by cells into extracellular space. The present study evaluated the effect of chemotherapeutic agents on exosome production and/or release, and quantified the contribution of exosomes to intercellular drug transfer and pharmacodynam...
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| Veröffentlicht in: | Journal of controlled release 2017-12, Vol.268, p.147-158 |
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| creator | Wang, Jin Yeung, Bertrand Z. Cui, Minjian Peer, Cody J. Lu, Ze Figg, William D. Guillaume Wientjes, M. Woo, Sukyung Au, Jessie L.-S. |
| description | Exosomes are small membrane vesicles (30–100nm in diameter) secreted by cells into extracellular space. The present study evaluated the effect of chemotherapeutic agents on exosome production and/or release, and quantified the contribution of exosomes to intercellular drug transfer and pharmacodynamics.
Human cancer cells (breast MCF7, breast-to-lung metastatic LM2, ovarian A2780 and OVCAR4) were treated with paclitaxel (PTX, 2–1000nM) or doxorubicin (DOX, 20–1000nM) for 24–48h. Exosomes were isolated from the culture medium of drug-treated donor cells (Donor cells) using ultra-centrifugation, and analyzed for acetylcholinesterase activity, total proteins, drug concentrations, and biological effects (cytotoxicity and anti-migration) on drug-naïve recipient cells (Recipient cells). These results were used to develop computational predictive quantitative pharmacology models.
Cells in exponential growth phase released ~220 exosomes/cell in culture medium. PTX and DOX significantly promoted exosome production and/or release in a dose- and time-dependent manner, with greater effects in ovarian cancer cells than in breast cancer cells. Exosomes isolated from Donor cells contained appreciable drug levels (2–7pmole/106 cells after 24h treatment with 100–1000nM PTX), and caused cytotoxicity and inhibited migration of Recipient cells. Quantitative pharmacology models that integrated cellular PTX pharmacokinetics with PTX pharmacodynamics successfully predicted effects of exosomes on intercellular drug transfer, cytotoxicity of PTX on Donor cells and cytotoxicity of PTX-containing exosomes on Recipient cells. Additional model simulations indicate that within clinically achievable PTX concentrations, the contribution of exosomes to active drug efflux increased with drug concentration and exceeded the p-glycoprotein efflux when the latter was saturated.
Our results indicate (a) chemotherapeutic agents stimulate exosome production or release, and (b) exosome is a mechanism of intercellular drug transfer that contributes to pharmacodynamics of neighboring cells.
[Display omitted] |
| doi_str_mv | 10.1016/j.jconrel.2017.10.020 |
| format | Article |
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Human cancer cells (breast MCF7, breast-to-lung metastatic LM2, ovarian A2780 and OVCAR4) were treated with paclitaxel (PTX, 2–1000nM) or doxorubicin (DOX, 20–1000nM) for 24–48h. Exosomes were isolated from the culture medium of drug-treated donor cells (Donor cells) using ultra-centrifugation, and analyzed for acetylcholinesterase activity, total proteins, drug concentrations, and biological effects (cytotoxicity and anti-migration) on drug-naïve recipient cells (Recipient cells). These results were used to develop computational predictive quantitative pharmacology models.
Cells in exponential growth phase released ~220 exosomes/cell in culture medium. PTX and DOX significantly promoted exosome production and/or release in a dose- and time-dependent manner, with greater effects in ovarian cancer cells than in breast cancer cells. Exosomes isolated from Donor cells contained appreciable drug levels (2–7pmole/106 cells after 24h treatment with 100–1000nM PTX), and caused cytotoxicity and inhibited migration of Recipient cells. Quantitative pharmacology models that integrated cellular PTX pharmacokinetics with PTX pharmacodynamics successfully predicted effects of exosomes on intercellular drug transfer, cytotoxicity of PTX on Donor cells and cytotoxicity of PTX-containing exosomes on Recipient cells. Additional model simulations indicate that within clinically achievable PTX concentrations, the contribution of exosomes to active drug efflux increased with drug concentration and exceeded the p-glycoprotein efflux when the latter was saturated.
Our results indicate (a) chemotherapeutic agents stimulate exosome production or release, and (b) exosome is a mechanism of intercellular drug transfer that contributes to pharmacodynamics of neighboring cells.
[Display omitted]</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2017.10.020</identifier><identifier>PMID: 29054369</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>acetylcholinesterase ; Antineoplastic Agents - pharmacology ; Biological Transport ; breast neoplasms ; breasts ; Cell Line, Tumor ; Cell Survival - drug effects ; Chemoresistance ; culture media ; cytotoxicity ; developmental stages ; doxorubicin ; Doxorubicin - pharmacology ; drug therapy ; enzyme activity ; Exocytosis ; Exosome ; exosomes ; Exosomes - metabolism ; extracellular space ; Humans ; Intercellular drug transfer ; metastasis ; Models, Biological ; neoplasm cells ; ovarian neoplasms ; P-glycoproteins ; paclitaxel ; Paclitaxel - pharmacology ; pharmacodynamics ; pharmacokinetics ; Pharmacology ; Quantitative pharmacology ; simulation models</subject><ispartof>Journal of controlled release, 2017-12, Vol.268, p.147-158</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c537t-83babf8f5a60a853753d2673a9fe232bd12e7183dab6d8cf3847b019d82fbe463</citedby><cites>FETCH-LOGICAL-c537t-83babf8f5a60a853753d2673a9fe232bd12e7183dab6d8cf3847b019d82fbe463</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0168365917309094$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29054369$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Jin</creatorcontrib><creatorcontrib>Yeung, Bertrand Z.</creatorcontrib><creatorcontrib>Cui, Minjian</creatorcontrib><creatorcontrib>Peer, Cody J.</creatorcontrib><creatorcontrib>Lu, Ze</creatorcontrib><creatorcontrib>Figg, William D.</creatorcontrib><creatorcontrib>Guillaume Wientjes, M.</creatorcontrib><creatorcontrib>Woo, Sukyung</creatorcontrib><creatorcontrib>Au, Jessie L.-S.</creatorcontrib><title>Exosome is a mechanism of intercellular drug transfer: Application of quantitative pharmacology</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>Exosomes are small membrane vesicles (30–100nm in diameter) secreted by cells into extracellular space. The present study evaluated the effect of chemotherapeutic agents on exosome production and/or release, and quantified the contribution of exosomes to intercellular drug transfer and pharmacodynamics.
Human cancer cells (breast MCF7, breast-to-lung metastatic LM2, ovarian A2780 and OVCAR4) were treated with paclitaxel (PTX, 2–1000nM) or doxorubicin (DOX, 20–1000nM) for 24–48h. Exosomes were isolated from the culture medium of drug-treated donor cells (Donor cells) using ultra-centrifugation, and analyzed for acetylcholinesterase activity, total proteins, drug concentrations, and biological effects (cytotoxicity and anti-migration) on drug-naïve recipient cells (Recipient cells). These results were used to develop computational predictive quantitative pharmacology models.
Cells in exponential growth phase released ~220 exosomes/cell in culture medium. PTX and DOX significantly promoted exosome production and/or release in a dose- and time-dependent manner, with greater effects in ovarian cancer cells than in breast cancer cells. Exosomes isolated from Donor cells contained appreciable drug levels (2–7pmole/106 cells after 24h treatment with 100–1000nM PTX), and caused cytotoxicity and inhibited migration of Recipient cells. Quantitative pharmacology models that integrated cellular PTX pharmacokinetics with PTX pharmacodynamics successfully predicted effects of exosomes on intercellular drug transfer, cytotoxicity of PTX on Donor cells and cytotoxicity of PTX-containing exosomes on Recipient cells. Additional model simulations indicate that within clinically achievable PTX concentrations, the contribution of exosomes to active drug efflux increased with drug concentration and exceeded the p-glycoprotein efflux when the latter was saturated.
Our results indicate (a) chemotherapeutic agents stimulate exosome production or release, and (b) exosome is a mechanism of intercellular drug transfer that contributes to pharmacodynamics of neighboring cells.
[Display omitted]</description><subject>acetylcholinesterase</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological Transport</subject><subject>breast neoplasms</subject><subject>breasts</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chemoresistance</subject><subject>culture media</subject><subject>cytotoxicity</subject><subject>developmental stages</subject><subject>doxorubicin</subject><subject>Doxorubicin - pharmacology</subject><subject>drug therapy</subject><subject>enzyme activity</subject><subject>Exocytosis</subject><subject>Exosome</subject><subject>exosomes</subject><subject>Exosomes - metabolism</subject><subject>extracellular space</subject><subject>Humans</subject><subject>Intercellular drug transfer</subject><subject>metastasis</subject><subject>Models, Biological</subject><subject>neoplasm cells</subject><subject>ovarian neoplasms</subject><subject>P-glycoproteins</subject><subject>paclitaxel</subject><subject>Paclitaxel - pharmacology</subject><subject>pharmacodynamics</subject><subject>pharmacokinetics</subject><subject>Pharmacology</subject><subject>Quantitative pharmacology</subject><subject>simulation models</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi0EokvhJ4B85JLFH3HscABVVWmRKnGBs-XYk12vEju1kxX99zjapYJTT5Znnnnn40XoPSVbSmjz6bA92BgSDFtGqCyxLWHkBdpQJXlVt614iTaFUxVvRHuB3uR8IIQIXsvX6IK1RNS8aTdI3_yOOY6AfcYGj2D3Jvg84thjH2ZIFoZhGUzCLi07PCcTcg_pM76apsFbM_sYVvZhMWH2c_kfAU97k0Zj4xB3j2_Rq94MGd6d30v069vNz-u76v7H7ffrq_vKCi7nSvHOdL3qhWmIUSUkuGON5KbtgXHWOcpAUsWd6RqnbM9VLTtCW6dY30Hd8Ev05aQ7Ld0IzkIosw56Sn406VFH4_X_meD3ehePWkjGJK2LwMezQIoPC-RZjz6v25sAccm6XJkwxmrKn0VpK2oilWSrqjihNsWcE_RPE1GiVx_1QZ99XDvINVx8LHUf_l3nqeqvcQX4egKgHPXoIelsPQQLziews3bRP9PiD1djtAk</recordid><startdate>20171228</startdate><enddate>20171228</enddate><creator>Wang, Jin</creator><creator>Yeung, Bertrand Z.</creator><creator>Cui, Minjian</creator><creator>Peer, Cody J.</creator><creator>Lu, Ze</creator><creator>Figg, William D.</creator><creator>Guillaume Wientjes, M.</creator><creator>Woo, Sukyung</creator><creator>Au, Jessie L.-S.</creator><general>Elsevier B.V</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>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20171228</creationdate><title>Exosome is a mechanism of intercellular drug transfer: Application of quantitative pharmacology</title><author>Wang, Jin ; Yeung, Bertrand Z. ; Cui, Minjian ; Peer, Cody J. ; Lu, Ze ; Figg, William D. ; Guillaume Wientjes, M. ; Woo, Sukyung ; Au, Jessie L.-S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c537t-83babf8f5a60a853753d2673a9fe232bd12e7183dab6d8cf3847b019d82fbe463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>acetylcholinesterase</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological Transport</topic><topic>breast neoplasms</topic><topic>breasts</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Chemoresistance</topic><topic>culture media</topic><topic>cytotoxicity</topic><topic>developmental stages</topic><topic>doxorubicin</topic><topic>Doxorubicin - pharmacology</topic><topic>drug therapy</topic><topic>enzyme activity</topic><topic>Exocytosis</topic><topic>Exosome</topic><topic>exosomes</topic><topic>Exosomes - metabolism</topic><topic>extracellular space</topic><topic>Humans</topic><topic>Intercellular drug transfer</topic><topic>metastasis</topic><topic>Models, Biological</topic><topic>neoplasm cells</topic><topic>ovarian neoplasms</topic><topic>P-glycoproteins</topic><topic>paclitaxel</topic><topic>Paclitaxel - pharmacology</topic><topic>pharmacodynamics</topic><topic>pharmacokinetics</topic><topic>Pharmacology</topic><topic>Quantitative pharmacology</topic><topic>simulation models</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Jin</creatorcontrib><creatorcontrib>Yeung, Bertrand Z.</creatorcontrib><creatorcontrib>Cui, Minjian</creatorcontrib><creatorcontrib>Peer, Cody J.</creatorcontrib><creatorcontrib>Lu, Ze</creatorcontrib><creatorcontrib>Figg, William D.</creatorcontrib><creatorcontrib>Guillaume Wientjes, M.</creatorcontrib><creatorcontrib>Woo, Sukyung</creatorcontrib><creatorcontrib>Au, Jessie L.-S.</creatorcontrib><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>AGRICOLA</collection><collection>AGRICOLA - Academic</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>Wang, Jin</au><au>Yeung, Bertrand Z.</au><au>Cui, Minjian</au><au>Peer, Cody J.</au><au>Lu, Ze</au><au>Figg, William D.</au><au>Guillaume Wientjes, M.</au><au>Woo, Sukyung</au><au>Au, Jessie L.-S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exosome is a mechanism of intercellular drug transfer: Application of quantitative pharmacology</atitle><jtitle>Journal of controlled release</jtitle><addtitle>J Control Release</addtitle><date>2017-12-28</date><risdate>2017</risdate><volume>268</volume><spage>147</spage><epage>158</epage><pages>147-158</pages><issn>0168-3659</issn><eissn>1873-4995</eissn><abstract>Exosomes are small membrane vesicles (30–100nm in diameter) secreted by cells into extracellular space. The present study evaluated the effect of chemotherapeutic agents on exosome production and/or release, and quantified the contribution of exosomes to intercellular drug transfer and pharmacodynamics.
Human cancer cells (breast MCF7, breast-to-lung metastatic LM2, ovarian A2780 and OVCAR4) were treated with paclitaxel (PTX, 2–1000nM) or doxorubicin (DOX, 20–1000nM) for 24–48h. Exosomes were isolated from the culture medium of drug-treated donor cells (Donor cells) using ultra-centrifugation, and analyzed for acetylcholinesterase activity, total proteins, drug concentrations, and biological effects (cytotoxicity and anti-migration) on drug-naïve recipient cells (Recipient cells). These results were used to develop computational predictive quantitative pharmacology models.
Cells in exponential growth phase released ~220 exosomes/cell in culture medium. PTX and DOX significantly promoted exosome production and/or release in a dose- and time-dependent manner, with greater effects in ovarian cancer cells than in breast cancer cells. Exosomes isolated from Donor cells contained appreciable drug levels (2–7pmole/106 cells after 24h treatment with 100–1000nM PTX), and caused cytotoxicity and inhibited migration of Recipient cells. Quantitative pharmacology models that integrated cellular PTX pharmacokinetics with PTX pharmacodynamics successfully predicted effects of exosomes on intercellular drug transfer, cytotoxicity of PTX on Donor cells and cytotoxicity of PTX-containing exosomes on Recipient cells. Additional model simulations indicate that within clinically achievable PTX concentrations, the contribution of exosomes to active drug efflux increased with drug concentration and exceeded the p-glycoprotein efflux when the latter was saturated.
Our results indicate (a) chemotherapeutic agents stimulate exosome production or release, and (b) exosome is a mechanism of intercellular drug transfer that contributes to pharmacodynamics of neighboring cells.
[Display omitted]</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>29054369</pmid><doi>10.1016/j.jconrel.2017.10.020</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | acetylcholinesterase Antineoplastic Agents - pharmacology Biological Transport breast neoplasms breasts Cell Line, Tumor Cell Survival - drug effects Chemoresistance culture media cytotoxicity developmental stages doxorubicin Doxorubicin - pharmacology drug therapy enzyme activity Exocytosis Exosome exosomes Exosomes - metabolism extracellular space Humans Intercellular drug transfer metastasis Models, Biological neoplasm cells ovarian neoplasms P-glycoproteins paclitaxel Paclitaxel - pharmacology pharmacodynamics pharmacokinetics Pharmacology Quantitative pharmacology simulation models |
| title | Exosome is a mechanism of intercellular drug transfer: Application of quantitative pharmacology |
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