Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes
In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30–35%) with tumors exhibiting methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. In order to allow more patients to benefit from this treatment, we ex...
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| Veröffentlicht in: | Journal of controlled release 2019-02, Vol.295, p.130-139 |
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| creator | Papachristodoulou, Alexandros Signorell, Rea Deborah Werner, Beat Brambilla, Davide Luciani, Paola Cavusoglu, Mustafa Grandjean, Joanes Silginer, Manuela Rudin, Markus Martin, Ernst Weller, Michael Roth, Patrick Leroux, Jean-Christophe |
| description | In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30–35%) with tumors exhibiting methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. In order to allow more patients to benefit from this treatment, we explored magnetic resonance image-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) to transiently open the blood-brain barrier and deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O6-(4-bromothenyl)guanine (O6BTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomide in vitro. Furthermore, we report that image-guided LIFU mediates the delivery of the stable liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo. Treatment with this new liposomal MGMT inactivator facilitated by LIFU-mediated blood-brain barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.
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•A novel therapeutic liposomal agent inactivates MGMT in glioblastoma•MRI-guided LIFU opens the BBB to deploy nanotherapeutics in targeted regions•LIFU-driven delivery of liposomal MGMT inactivators reverses glioma chemoresistance |
| doi_str_mv | 10.1016/j.jconrel.2018.12.009 |
| format | Article |
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[Display omitted]
•A novel therapeutic liposomal agent inactivates MGMT in glioblastoma•MRI-guided LIFU opens the BBB to deploy nanotherapeutics in targeted regions•LIFU-driven delivery of liposomal MGMT inactivators reverses glioma chemoresistance</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2018.12.009</identifier><identifier>PMID: 30537486</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject><![CDATA[Animals ; Antineoplastic Agents, Alkylating - administration & dosage ; Antineoplastic Agents, Alkylating - therapeutic use ; Brain Neoplasms - diagnostic imaging ; Brain Neoplasms - drug therapy ; Brain Neoplasms - metabolism ; Cell Line, Tumor ; Dacarbazine - administration & dosage ; Dacarbazine - therapeutic use ; Drug Delivery Systems - methods ; Enzyme Inhibitors - administration & dosage ; Enzyme Inhibitors - therapeutic use ; Focused ultrasound ; Glioblastoma ; Glioblastoma - diagnostic imaging ; Glioblastoma - drug therapy ; Glioblastoma - metabolism ; Guanine - administration & dosage ; Guanine - analogs & derivatives ; Guanine - therapeutic use ; Image-guided targeting ; Liposomes ; Liposomes - administration & dosage ; Liposomes - therapeutic use ; Magnetic Resonance Imaging - methods ; Methylguanine-DNA methyltransferase inactivation ; Mice ; O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors ; O-Methylguanine-DNA Methyltransferase - metabolism ; Temozolomide resistance ; Ultrasonic Waves]]></subject><ispartof>Journal of controlled release, 2019-02, Vol.295, p.130-139</ispartof><rights>2018 Elsevier B.V.</rights><rights>Copyright © 2018 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c515t-eee09b429edb82dd6d3f9f03ea9e51f9f40cf1a1d4250b13c545384f46fff9093</citedby><cites>FETCH-LOGICAL-c515t-eee09b429edb82dd6d3f9f03ea9e51f9f40cf1a1d4250b13c545384f46fff9093</cites><orcidid>0000-0001-8488-7785</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0168365918307041$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30537486$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Papachristodoulou, Alexandros</creatorcontrib><creatorcontrib>Signorell, Rea Deborah</creatorcontrib><creatorcontrib>Werner, Beat</creatorcontrib><creatorcontrib>Brambilla, Davide</creatorcontrib><creatorcontrib>Luciani, Paola</creatorcontrib><creatorcontrib>Cavusoglu, Mustafa</creatorcontrib><creatorcontrib>Grandjean, Joanes</creatorcontrib><creatorcontrib>Silginer, Manuela</creatorcontrib><creatorcontrib>Rudin, Markus</creatorcontrib><creatorcontrib>Martin, Ernst</creatorcontrib><creatorcontrib>Weller, Michael</creatorcontrib><creatorcontrib>Roth, Patrick</creatorcontrib><creatorcontrib>Leroux, Jean-Christophe</creatorcontrib><title>Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30–35%) with tumors exhibiting methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. In order to allow more patients to benefit from this treatment, we explored magnetic resonance image-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) to transiently open the blood-brain barrier and deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O6-(4-bromothenyl)guanine (O6BTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomide in vitro. Furthermore, we report that image-guided LIFU mediates the delivery of the stable liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo. Treatment with this new liposomal MGMT inactivator facilitated by LIFU-mediated blood-brain barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.
[Display omitted]
•A novel therapeutic liposomal agent inactivates MGMT in glioblastoma•MRI-guided LIFU opens the BBB to deploy nanotherapeutics in targeted regions•LIFU-driven delivery of liposomal MGMT inactivators reverses glioma chemoresistance</description><subject>Animals</subject><subject>Antineoplastic Agents, Alkylating - administration & dosage</subject><subject>Antineoplastic Agents, Alkylating - therapeutic use</subject><subject>Brain Neoplasms - diagnostic imaging</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Dacarbazine - administration & dosage</subject><subject>Dacarbazine - therapeutic use</subject><subject>Drug Delivery Systems - methods</subject><subject>Enzyme Inhibitors - administration & dosage</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Focused ultrasound</subject><subject>Glioblastoma</subject><subject>Glioblastoma - diagnostic imaging</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - metabolism</subject><subject>Guanine - administration & dosage</subject><subject>Guanine - analogs & derivatives</subject><subject>Guanine - therapeutic use</subject><subject>Image-guided targeting</subject><subject>Liposomes</subject><subject>Liposomes - administration & dosage</subject><subject>Liposomes - therapeutic use</subject><subject>Magnetic Resonance Imaging - methods</subject><subject>Methylguanine-DNA methyltransferase inactivation</subject><subject>Mice</subject><subject>O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors</subject><subject>O-Methylguanine-DNA Methyltransferase - metabolism</subject><subject>Temozolomide resistance</subject><subject>Ultrasonic Waves</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1v1DAQhq0K1C5tf0JRjlwS_JmNT6ha0YJUiUs5W449pt468WI7lba_Hi-79MppRqNn5tU8CN0Q3BFM-s_bbmvinCB0FJOhI7TDWJ6hFRnWrOVSindoVbmhZb2QF-hDzluMsWB8fY4uWG3WfOhX6HnzBFMsT5D0bt9kmLMv_lUXH-cmuuZX8HEMOpc46WbcNy6aJYNtllCSznGZbTuB9brUmYXgXyDtD3vHg7AUb5rgdzHHCfIVeu90yHB9qpfo593Xx8239uHH_ffN7UNrBBGlBQAsR04l2HGg1vaWOekwAy1BkNpybBzRxHIq8EiYEVywgTveO-ckluwSfTre3aX4e4Fc1OSzgRD0DHHJihIhSE-HnlZUHFGTYs4JnNolP-m0VwSrg2e1VSfP6uBZEarw34iPp4hlrALetv6JrcCXIwD10RcPSWXjYTZVVgJTlI3-PxF_AMLylR4</recordid><startdate>20190210</startdate><enddate>20190210</enddate><creator>Papachristodoulou, Alexandros</creator><creator>Signorell, Rea Deborah</creator><creator>Werner, Beat</creator><creator>Brambilla, Davide</creator><creator>Luciani, Paola</creator><creator>Cavusoglu, Mustafa</creator><creator>Grandjean, Joanes</creator><creator>Silginer, Manuela</creator><creator>Rudin, Markus</creator><creator>Martin, Ernst</creator><creator>Weller, Michael</creator><creator>Roth, Patrick</creator><creator>Leroux, Jean-Christophe</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><orcidid>https://orcid.org/0000-0001-8488-7785</orcidid></search><sort><creationdate>20190210</creationdate><title>Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes</title><author>Papachristodoulou, Alexandros ; Signorell, Rea Deborah ; Werner, Beat ; Brambilla, Davide ; Luciani, Paola ; Cavusoglu, Mustafa ; Grandjean, Joanes ; Silginer, Manuela ; Rudin, Markus ; Martin, Ernst ; Weller, Michael ; Roth, Patrick ; Leroux, Jean-Christophe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c515t-eee09b429edb82dd6d3f9f03ea9e51f9f40cf1a1d4250b13c545384f46fff9093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antineoplastic Agents, Alkylating - administration & dosage</topic><topic>Antineoplastic Agents, Alkylating - therapeutic use</topic><topic>Brain Neoplasms - diagnostic imaging</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Dacarbazine - administration & dosage</topic><topic>Dacarbazine - therapeutic use</topic><topic>Drug Delivery Systems - methods</topic><topic>Enzyme Inhibitors - administration & dosage</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Focused ultrasound</topic><topic>Glioblastoma</topic><topic>Glioblastoma - diagnostic imaging</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - metabolism</topic><topic>Guanine - administration & dosage</topic><topic>Guanine - analogs & derivatives</topic><topic>Guanine - therapeutic use</topic><topic>Image-guided targeting</topic><topic>Liposomes</topic><topic>Liposomes - administration & dosage</topic><topic>Liposomes - therapeutic use</topic><topic>Magnetic Resonance Imaging - methods</topic><topic>Methylguanine-DNA methyltransferase inactivation</topic><topic>Mice</topic><topic>O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors</topic><topic>O-Methylguanine-DNA Methyltransferase - metabolism</topic><topic>Temozolomide resistance</topic><topic>Ultrasonic Waves</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Papachristodoulou, Alexandros</creatorcontrib><creatorcontrib>Signorell, Rea Deborah</creatorcontrib><creatorcontrib>Werner, Beat</creatorcontrib><creatorcontrib>Brambilla, Davide</creatorcontrib><creatorcontrib>Luciani, Paola</creatorcontrib><creatorcontrib>Cavusoglu, Mustafa</creatorcontrib><creatorcontrib>Grandjean, Joanes</creatorcontrib><creatorcontrib>Silginer, Manuela</creatorcontrib><creatorcontrib>Rudin, Markus</creatorcontrib><creatorcontrib>Martin, Ernst</creatorcontrib><creatorcontrib>Weller, Michael</creatorcontrib><creatorcontrib>Roth, Patrick</creatorcontrib><creatorcontrib>Leroux, Jean-Christophe</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>Papachristodoulou, Alexandros</au><au>Signorell, Rea Deborah</au><au>Werner, Beat</au><au>Brambilla, Davide</au><au>Luciani, Paola</au><au>Cavusoglu, Mustafa</au><au>Grandjean, Joanes</au><au>Silginer, Manuela</au><au>Rudin, Markus</au><au>Martin, Ernst</au><au>Weller, Michael</au><au>Roth, Patrick</au><au>Leroux, Jean-Christophe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes</atitle><jtitle>Journal of controlled release</jtitle><addtitle>J Control Release</addtitle><date>2019-02-10</date><risdate>2019</risdate><volume>295</volume><spage>130</spage><epage>139</epage><pages>130-139</pages><issn>0168-3659</issn><eissn>1873-4995</eissn><abstract>In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30–35%) with tumors exhibiting methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. In order to allow more patients to benefit from this treatment, we explored magnetic resonance image-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) to transiently open the blood-brain barrier and deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O6-(4-bromothenyl)guanine (O6BTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomide in vitro. Furthermore, we report that image-guided LIFU mediates the delivery of the stable liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo. Treatment with this new liposomal MGMT inactivator facilitated by LIFU-mediated blood-brain barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.
[Display omitted]
•A novel therapeutic liposomal agent inactivates MGMT in glioblastoma•MRI-guided LIFU opens the BBB to deploy nanotherapeutics in targeted regions•LIFU-driven delivery of liposomal MGMT inactivators reverses glioma chemoresistance</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>30537486</pmid><doi>10.1016/j.jconrel.2018.12.009</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-8488-7785</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of controlled release, 2019-02, Vol.295, p.130-139 |
| issn | 0168-3659 1873-4995 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Antineoplastic Agents, Alkylating - administration & dosage Antineoplastic Agents, Alkylating - therapeutic use Brain Neoplasms - diagnostic imaging Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Cell Line, Tumor Dacarbazine - administration & dosage Dacarbazine - therapeutic use Drug Delivery Systems - methods Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - therapeutic use Focused ultrasound Glioblastoma Glioblastoma - diagnostic imaging Glioblastoma - drug therapy Glioblastoma - metabolism Guanine - administration & dosage Guanine - analogs & derivatives Guanine - therapeutic use Image-guided targeting Liposomes Liposomes - administration & dosage Liposomes - therapeutic use Magnetic Resonance Imaging - methods Methylguanine-DNA methyltransferase inactivation Mice O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors O-Methylguanine-DNA Methyltransferase - metabolism Temozolomide resistance Ultrasonic Waves |
| title | Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes |
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