Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models
This study aimed to develop redox-sensitive and CD44-targeted liposomes to improve chemotherapy of osteosarcoma. Cationic liposomes were prepared and stabilized with a novel detachable polyethylene glycol (PEG2000) conjugated with cholesterol through a bio-reducible disulfide linker (Chol-SS-mPEG)....
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| Veröffentlicht in: | Journal of controlled release 2017-09, Vol.261, p.113-125 |
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| creator | Chi, Yingying Yin, Xuelei Sun, Kaoxiang Feng, Shuaishuai Liu, Jinhu Chen, Daquan Guo, Chuanyou Wu, Zimei |
| description | This study aimed to develop redox-sensitive and CD44-targeted liposomes to improve chemotherapy of osteosarcoma. Cationic liposomes were prepared and stabilized with a novel detachable polyethylene glycol (PEG2000) conjugated with cholesterol through a bio-reducible disulfide linker (Chol-SS-mPEG). Hyaluronic acid (HA, MW 20–40kDa), a ligand to CD44, was non-covalently coated on the cationic liposomes. Doxorubicin (DOX) was actively loaded in the liposomes as a model drug. The roles of HA and Chol-SS-mPEG on intracellular drug delivery efficiency, and antitumor efficacy were studied. The structure of Chol-SS-mPEG was confirmed with Fourier-transform infrared and nuclear magnetic resonance (1H NMR). The liposomes, Chol-SS-mPEG/HA-L had a mean diameter of 165nm, zeta potential −28.9mV, and destabilized in reducing or acidic (pH5–6) conditions. In vitro release of DOX was well-controlled at physiological conditions, but a burst release of 60% was observed in the presence of 10mM glutathione (GSH), in contrast to non-redox sensitive liposomes (Chol-mPEG/HA-L and Chol-mPEG-L). MTT cell viability assay showed that the dual-functional Chol-SS-mPEG/HA-L with a drug loading of 15.0% (w/w) had significantly higher cytotoxicity to MG63 osteosarcoma cells compared with non-reduction sensitive or non-HA coated liposomes (p10-fold. In a MG63 xenograft mouse model, Chol-SS-mPEG/HA-L showed the most effective tumor suppression with minimal uptake by the liver compared with other liposomes. All animals treated with liposomal formulations survived, in contrast to those free-DOX treated. In conclusion, the easily prepared Chol-SS-mPEG/HA-L was demonstrated as an excellent CD44-mediated intracellular delivery system capable of long-circulation and GSH-triggered cytoplasmic drug release. Further translational and multidisciplinary research is required to make it real clinical benefits to cancer patients.
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| doi_str_mv | 10.1016/j.jconrel.2017.06.027 |
| 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.2017.06.027</identifier><identifier>PMID: 28666726</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Antibiotics, Antineoplastic - administration & dosage ; Antibiotics, Antineoplastic - pharmacokinetics ; Antibiotics, Antineoplastic - pharmacology ; Bone Neoplasms - drug therapy ; CD44 ; Cytoplasm - metabolism ; Doxorubicin - administration & dosage ; Doxorubicin - pharmacokinetics ; Doxorubicin - pharmacology ; Drug Delivery Systems ; Flow Cytometry ; GSH-responsive ; Humans ; Hyaluronan Receptors - metabolism ; Hyaluronic acid (HA) ; Hyaluronic Acid - chemistry ; Intracellular delivery ; Liposomes ; Liver - metabolism ; Long-circulation ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microscopy, Confocal ; Osteosarcoma ; Osteosarcoma - drug therapy ; Osteosarcoma - metabolism ; Oxidation-Reduction ; PEG-detachment ; Polyethylene Glycols - chemistry ; Rats ; Rats, Sprague-Dawley ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of controlled release, 2017-09, Vol.261, p.113-125</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017. Published by Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c468t-4f0c117d239fe282e172b14477019f0be710c7e68c092bfdb1f36eaaec02b99c3</citedby><cites>FETCH-LOGICAL-c468t-4f0c117d239fe282e172b14477019f0be710c7e68c092bfdb1f36eaaec02b99c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0168365917306922$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28666726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chi, Yingying</creatorcontrib><creatorcontrib>Yin, Xuelei</creatorcontrib><creatorcontrib>Sun, Kaoxiang</creatorcontrib><creatorcontrib>Feng, Shuaishuai</creatorcontrib><creatorcontrib>Liu, Jinhu</creatorcontrib><creatorcontrib>Chen, Daquan</creatorcontrib><creatorcontrib>Guo, Chuanyou</creatorcontrib><creatorcontrib>Wu, Zimei</creatorcontrib><title>Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>This study aimed to develop redox-sensitive and CD44-targeted liposomes to improve chemotherapy of osteosarcoma. Cationic liposomes were prepared and stabilized with a novel detachable polyethylene glycol (PEG2000) conjugated with cholesterol through a bio-reducible disulfide linker (Chol-SS-mPEG). Hyaluronic acid (HA, MW 20–40kDa), a ligand to CD44, was non-covalently coated on the cationic liposomes. Doxorubicin (DOX) was actively loaded in the liposomes as a model drug. The roles of HA and Chol-SS-mPEG on intracellular drug delivery efficiency, and antitumor efficacy were studied. The structure of Chol-SS-mPEG was confirmed with Fourier-transform infrared and nuclear magnetic resonance (1H NMR). The liposomes, Chol-SS-mPEG/HA-L had a mean diameter of 165nm, zeta potential −28.9mV, and destabilized in reducing or acidic (pH5–6) conditions. In vitro release of DOX was well-controlled at physiological conditions, but a burst release of 60% was observed in the presence of 10mM glutathione (GSH), in contrast to non-redox sensitive liposomes (Chol-mPEG/HA-L and Chol-mPEG-L). MTT cell viability assay showed that the dual-functional Chol-SS-mPEG/HA-L with a drug loading of 15.0% (w/w) had significantly higher cytotoxicity to MG63 osteosarcoma cells compared with non-reduction sensitive or non-HA coated liposomes (p<0.01), consistent with the cellular uptake and intracellular trafficking studies using confocal microscopy and flow cytometry. Furthermore, the HA-coated GSH-responsive liposomes preferentially internalized to MG63 over human liver cells LO2. In rats, liposomes stabilized with either Chol-SS-mPEG or Chol-mPEG, with or without HA, increased the half-life of DOX by >10-fold. In a MG63 xenograft mouse model, Chol-SS-mPEG/HA-L showed the most effective tumor suppression with minimal uptake by the liver compared with other liposomes. All animals treated with liposomal formulations survived, in contrast to those free-DOX treated. In conclusion, the easily prepared Chol-SS-mPEG/HA-L was demonstrated as an excellent CD44-mediated intracellular delivery system capable of long-circulation and GSH-triggered cytoplasmic drug release. Further translational and multidisciplinary research is required to make it real clinical benefits to cancer patients.
[Display omitted]</description><subject>Animals</subject><subject>Antibiotics, Antineoplastic - administration & dosage</subject><subject>Antibiotics, Antineoplastic - pharmacokinetics</subject><subject>Antibiotics, Antineoplastic - pharmacology</subject><subject>Bone Neoplasms - drug therapy</subject><subject>CD44</subject><subject>Cytoplasm - metabolism</subject><subject>Doxorubicin - administration & dosage</subject><subject>Doxorubicin - pharmacokinetics</subject><subject>Doxorubicin - pharmacology</subject><subject>Drug Delivery Systems</subject><subject>Flow Cytometry</subject><subject>GSH-responsive</subject><subject>Humans</subject><subject>Hyaluronan Receptors - metabolism</subject><subject>Hyaluronic acid (HA)</subject><subject>Hyaluronic Acid - chemistry</subject><subject>Intracellular delivery</subject><subject>Liposomes</subject><subject>Liver - metabolism</subject><subject>Long-circulation</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Microscopy, Confocal</subject><subject>Osteosarcoma</subject><subject>Osteosarcoma - drug therapy</subject><subject>Osteosarcoma - metabolism</subject><subject>Oxidation-Reduction</subject><subject>PEG-detachment</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Xenograft Model Antitumor Assays</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>eNqFkE1v3CAQhlHVqtkk_QmtOPZiB7AXzCmqouZDihQpas8Iw9CywrAFO8q2fz6sdtNrTnN55n1nHoQ-U9JSQvnFpt2YFDOElhEqWsJbwsQ7tKKD6JpeyvV7tKrc0HR8LU_QaSkbQsi668VHdMIGzrlgfIX-PYJNz02BWPzsnwDraPHvnQ5LTtEbrI232C3RzD5FHfxfsDj4bSppgoJdytjs5rQNukyVtnn5hS2EGpR3eE44lRlS0dmkSWMfa7qfdMBTqlA5Rx-cDgU-HecZ-nn9_cfVbXP_cHN39e2-MT0f5qZ3xFAqLOukAzYwoIKNtO-FIFQ6MoKgxAjggyGSjc6O1HUctAZD2Cil6c7Q10PuNqc_C5RZTb4YCEFHSEtRVNK9F0m6iq4PqMmplAxObXO9OO8UJWrvXW3U0bvae1eEq-q97n05VizjBPb_1qvoClwegPo3PHnIqhgP0YD1GcysbPJvVLwAleCaWg</recordid><startdate>20170910</startdate><enddate>20170910</enddate><creator>Chi, Yingying</creator><creator>Yin, Xuelei</creator><creator>Sun, Kaoxiang</creator><creator>Feng, Shuaishuai</creator><creator>Liu, Jinhu</creator><creator>Chen, Daquan</creator><creator>Guo, Chuanyou</creator><creator>Wu, Zimei</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></search><sort><creationdate>20170910</creationdate><title>Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models</title><author>Chi, Yingying ; Yin, Xuelei ; Sun, Kaoxiang ; Feng, Shuaishuai ; Liu, Jinhu ; Chen, Daquan ; Guo, Chuanyou ; Wu, Zimei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c468t-4f0c117d239fe282e172b14477019f0be710c7e68c092bfdb1f36eaaec02b99c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antibiotics, Antineoplastic - administration & dosage</topic><topic>Antibiotics, Antineoplastic - pharmacokinetics</topic><topic>Antibiotics, Antineoplastic - pharmacology</topic><topic>Bone Neoplasms - drug therapy</topic><topic>CD44</topic><topic>Cytoplasm - metabolism</topic><topic>Doxorubicin - administration & dosage</topic><topic>Doxorubicin - pharmacokinetics</topic><topic>Doxorubicin - pharmacology</topic><topic>Drug Delivery Systems</topic><topic>Flow Cytometry</topic><topic>GSH-responsive</topic><topic>Humans</topic><topic>Hyaluronan Receptors - metabolism</topic><topic>Hyaluronic acid (HA)</topic><topic>Hyaluronic Acid - chemistry</topic><topic>Intracellular delivery</topic><topic>Liposomes</topic><topic>Liver - metabolism</topic><topic>Long-circulation</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Microscopy, Confocal</topic><topic>Osteosarcoma</topic><topic>Osteosarcoma - drug therapy</topic><topic>Osteosarcoma - metabolism</topic><topic>Oxidation-Reduction</topic><topic>PEG-detachment</topic><topic>Polyethylene Glycols - chemistry</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chi, Yingying</creatorcontrib><creatorcontrib>Yin, Xuelei</creatorcontrib><creatorcontrib>Sun, Kaoxiang</creatorcontrib><creatorcontrib>Feng, Shuaishuai</creatorcontrib><creatorcontrib>Liu, Jinhu</creatorcontrib><creatorcontrib>Chen, Daquan</creatorcontrib><creatorcontrib>Guo, Chuanyou</creatorcontrib><creatorcontrib>Wu, Zimei</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><jtitle>Journal of controlled release</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chi, Yingying</au><au>Yin, Xuelei</au><au>Sun, Kaoxiang</au><au>Feng, Shuaishuai</au><au>Liu, Jinhu</au><au>Chen, Daquan</au><au>Guo, Chuanyou</au><au>Wu, Zimei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models</atitle><jtitle>Journal of controlled release</jtitle><addtitle>J Control Release</addtitle><date>2017-09-10</date><risdate>2017</risdate><volume>261</volume><spage>113</spage><epage>125</epage><pages>113-125</pages><issn>0168-3659</issn><eissn>1873-4995</eissn><abstract>This study aimed to develop redox-sensitive and CD44-targeted liposomes to improve chemotherapy of osteosarcoma. Cationic liposomes were prepared and stabilized with a novel detachable polyethylene glycol (PEG2000) conjugated with cholesterol through a bio-reducible disulfide linker (Chol-SS-mPEG). Hyaluronic acid (HA, MW 20–40kDa), a ligand to CD44, was non-covalently coated on the cationic liposomes. Doxorubicin (DOX) was actively loaded in the liposomes as a model drug. The roles of HA and Chol-SS-mPEG on intracellular drug delivery efficiency, and antitumor efficacy were studied. The structure of Chol-SS-mPEG was confirmed with Fourier-transform infrared and nuclear magnetic resonance (1H NMR). The liposomes, Chol-SS-mPEG/HA-L had a mean diameter of 165nm, zeta potential −28.9mV, and destabilized in reducing or acidic (pH5–6) conditions. In vitro release of DOX was well-controlled at physiological conditions, but a burst release of 60% was observed in the presence of 10mM glutathione (GSH), in contrast to non-redox sensitive liposomes (Chol-mPEG/HA-L and Chol-mPEG-L). MTT cell viability assay showed that the dual-functional Chol-SS-mPEG/HA-L with a drug loading of 15.0% (w/w) had significantly higher cytotoxicity to MG63 osteosarcoma cells compared with non-reduction sensitive or non-HA coated liposomes (p<0.01), consistent with the cellular uptake and intracellular trafficking studies using confocal microscopy and flow cytometry. Furthermore, the HA-coated GSH-responsive liposomes preferentially internalized to MG63 over human liver cells LO2. In rats, liposomes stabilized with either Chol-SS-mPEG or Chol-mPEG, with or without HA, increased the half-life of DOX by >10-fold. In a MG63 xenograft mouse model, Chol-SS-mPEG/HA-L showed the most effective tumor suppression with minimal uptake by the liver compared with other liposomes. All animals treated with liposomal formulations survived, in contrast to those free-DOX treated. In conclusion, the easily prepared Chol-SS-mPEG/HA-L was demonstrated as an excellent CD44-mediated intracellular delivery system capable of long-circulation and GSH-triggered cytoplasmic drug release. Further translational and multidisciplinary research is required to make it real clinical benefits to cancer patients.
[Display omitted]</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>28666726</pmid><doi>10.1016/j.jconrel.2017.06.027</doi><tpages>13</tpages></addata></record> |
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| subjects | Animals Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - pharmacokinetics Antibiotics, Antineoplastic - pharmacology Bone Neoplasms - drug therapy CD44 Cytoplasm - metabolism Doxorubicin - administration & dosage Doxorubicin - pharmacokinetics Doxorubicin - pharmacology Drug Delivery Systems Flow Cytometry GSH-responsive Humans Hyaluronan Receptors - metabolism Hyaluronic acid (HA) Hyaluronic Acid - chemistry Intracellular delivery Liposomes Liver - metabolism Long-circulation Male Mice Mice, Inbred BALB C Mice, Nude Microscopy, Confocal Osteosarcoma Osteosarcoma - drug therapy Osteosarcoma - metabolism Oxidation-Reduction PEG-detachment Polyethylene Glycols - chemistry Rats Rats, Sprague-Dawley Xenograft Model Antitumor Assays |
| title | Redox-sensitive and hyaluronic acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models |
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