Determination of an optimal dosing schedule for combining Irinophore C™ and temozolomide in an orthotopic model of glioblastoma
Our laboratory reported that Irinophore C™ (IrC™; a lipid-based nanoparticulate formulation of irinotecan) is effective against an orthotopic model of glioblastoma (GBM) and that treatment with IrC™ was associated with vascular normalization within the tumor. Here, the therapeutic effects of IrC™ wh...
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| creator | Verreault, M. Wehbe, M. Strutt, D. Masin, D. Anantha, M. Walker, D. Chu, F. Backstrom, I. Kalra, J. Waterhouse, D. Yapp, D.T. Bally, M.B. |
| description | Our laboratory reported that Irinophore C™ (IrC™; a lipid-based nanoparticulate formulation of irinotecan) is effective against an orthotopic model of glioblastoma (GBM) and that treatment with IrC™ was associated with vascular normalization within the tumor. Here, the therapeutic effects of IrC™ when used in combination with temozolomide (TMZ) in concurrent and sequential treatment schedules were tested. It was anticipated that IrC™ engendered vascular normalization would increase the delivery of TMZ to the tumor and that this would be reflected by improved treatment outcomes. The approach compared equally efficacious doses of irinotecan (IRN; 50mg/kg) and IrC™ (25mg/kg) in order to determine if there was a unique advantage achieved when combining TMZ with IrC™. The TMZ sensitive U251MGO cell line (null expression of O-6-methylguanine-DNA methyltransferase (MGMT)) modified to express the fluorescent protein mKate2 was inoculated orthotopically into NOD.CB17-SCID mice and treatment was initiated 14days later. Our results demonstrated that IrC™ and TMZ administered concurrently resulted in optimal treatment outcomes, with 50% long term survivors (>180days) in comparison to 17% long term survivors in animals treated with IRN and TMZ or TMZ alone. Indeed, the different treatments resulted in a 353%, 222% and 280% increase in median survival time (MST) compared to untreated animals for, respectively, IrC™ combined with TMZ, IRN combined with TMZ, and TMZ alone. When TMZ was administered after completion of IRN or IrC™ dosing, an increase in median survival time of 167–174% was observed compared to untreated animals and of 67% and 74%, respectively, when IRN (50mg/kg) and IrC™ (25mg/kg) were given as single agents. We confirmed in these studies that after completion of the Q7D×3 dosing of IrC™, but not IRN, the tumor-associated vascular was normalized as compared to untreated tumors. Specifically, reductions in the fraction of collagen IV-free CD31 staining (p |
| doi_str_mv | 10.1016/j.jconrel.2015.10.053 |
| 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.2015.10.053</identifier><identifier>PMID: 26528901</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject><![CDATA[Angiogenesis Inhibitors - administration & dosage ; Angiogenesis Inhibitors - chemistry ; Animals ; Antineoplastic Agents, Alkylating - administration & dosage ; Antineoplastic Agents, Alkylating - chemistry ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Biomarkers, Tumor - metabolism ; Brain Neoplasms - blood supply ; Brain Neoplasms - drug therapy ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Camptothecin - administration & dosage ; Camptothecin - analogs & derivatives ; Camptothecin - chemistry ; Cancer ; Dacarbazine - administration & dosage ; Dacarbazine - analogs & derivatives ; Dacarbazine - chemistry ; Drug Administration Schedule ; Drug Compounding ; Drug delivery ; Glioblastoma ; Glioblastoma - blood supply ; Glioblastoma - drug therapy ; Glioblastoma - metabolism ; Glioblastoma - pathology ; Humans ; Irinotecan ; Liposomes ; Mice, Inbred NOD ; Mice, SCID ; Neovascularization, Pathologic ; Time Factors ; Tumor Burden - drug effects ; Tumor-associated vasculature ; Xenograft Model Antitumor Assays]]></subject><ispartof>Journal of controlled release, 2015-12, Vol.220 (Pt A), p.348-357</ispartof><rights>2015 Elsevier B.V.</rights><rights>Copyright © 2015 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c365t-a56cbfc0ae47b8381875ed43398cd291e8dc0ae13e1394667553cbe69aed39b63</citedby><cites>FETCH-LOGICAL-c365t-a56cbfc0ae47b8381875ed43398cd291e8dc0ae13e1394667553cbe69aed39b63</cites><orcidid>0000-0001-6708-7698</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jconrel.2015.10.053$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26528901$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Verreault, M.</creatorcontrib><creatorcontrib>Wehbe, M.</creatorcontrib><creatorcontrib>Strutt, D.</creatorcontrib><creatorcontrib>Masin, D.</creatorcontrib><creatorcontrib>Anantha, M.</creatorcontrib><creatorcontrib>Walker, D.</creatorcontrib><creatorcontrib>Chu, F.</creatorcontrib><creatorcontrib>Backstrom, I.</creatorcontrib><creatorcontrib>Kalra, J.</creatorcontrib><creatorcontrib>Waterhouse, D.</creatorcontrib><creatorcontrib>Yapp, D.T.</creatorcontrib><creatorcontrib>Bally, M.B.</creatorcontrib><title>Determination of an optimal dosing schedule for combining Irinophore C™ and temozolomide in an orthotopic model of glioblastoma</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>Our laboratory reported that Irinophore C™ (IrC™; a lipid-based nanoparticulate formulation of irinotecan) is effective against an orthotopic model of glioblastoma (GBM) and that treatment with IrC™ was associated with vascular normalization within the tumor. Here, the therapeutic effects of IrC™ when used in combination with temozolomide (TMZ) in concurrent and sequential treatment schedules were tested. It was anticipated that IrC™ engendered vascular normalization would increase the delivery of TMZ to the tumor and that this would be reflected by improved treatment outcomes. The approach compared equally efficacious doses of irinotecan (IRN; 50mg/kg) and IrC™ (25mg/kg) in order to determine if there was a unique advantage achieved when combining TMZ with IrC™. The TMZ sensitive U251MGO cell line (null expression of O-6-methylguanine-DNA methyltransferase (MGMT)) modified to express the fluorescent protein mKate2 was inoculated orthotopically into NOD.CB17-SCID mice and treatment was initiated 14days later. Our results demonstrated that IrC™ and TMZ administered concurrently resulted in optimal treatment outcomes, with 50% long term survivors (>180days) in comparison to 17% long term survivors in animals treated with IRN and TMZ or TMZ alone. Indeed, the different treatments resulted in a 353%, 222% and 280% increase in median survival time (MST) compared to untreated animals for, respectively, IrC™ combined with TMZ, IRN combined with TMZ, and TMZ alone. When TMZ was administered after completion of IRN or IrC™ dosing, an increase in median survival time of 167–174% was observed compared to untreated animals and of 67% and 74%, respectively, when IRN (50mg/kg) and IrC™ (25mg/kg) were given as single agents. We confirmed in these studies that after completion of the Q7D×3 dosing of IrC™, but not IRN, the tumor-associated vascular was normalized as compared to untreated tumors. Specifically, reductions in the fraction of collagen IV-free CD31 staining (p<0.05) and reductions in tumor vessel diameter were observed in tumors from IrC™-treated animals when compared to tumors from untreated or IRN treated animals. Analysis by transmission electron microscopy of the ultra-structure of tumors from IrC™-treated and untreated animals revealed that tumor-associated vessels from treated animals were smaller, more organized and exhibited a morphology comparable to normal blood vessels. In conclusion, optimal treatment outcomes were achieved when IrC™ and TMZ were administered concurrently, whereas IrC™ followed by TMZ treatment given sequentially did not confer any therapeutic advantage.
[Display omitted]</description><subject>Angiogenesis Inhibitors - administration & dosage</subject><subject>Angiogenesis Inhibitors - chemistry</subject><subject>Animals</subject><subject>Antineoplastic Agents, Alkylating - administration & dosage</subject><subject>Antineoplastic Agents, Alkylating - chemistry</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Brain Neoplasms - blood supply</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Camptothecin - administration & dosage</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - chemistry</subject><subject>Cancer</subject><subject>Dacarbazine - administration & dosage</subject><subject>Dacarbazine - analogs & derivatives</subject><subject>Dacarbazine - chemistry</subject><subject>Drug Administration Schedule</subject><subject>Drug Compounding</subject><subject>Drug delivery</subject><subject>Glioblastoma</subject><subject>Glioblastoma - blood supply</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - pathology</subject><subject>Humans</subject><subject>Irinotecan</subject><subject>Liposomes</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Neovascularization, Pathologic</subject><subject>Time Factors</subject><subject>Tumor Burden - drug effects</subject><subject>Tumor-associated vasculature</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM2OFCEUhYnROO3oI2hYuqkWmqKqWBnT_k0yiRtdEwpuTdOBuiXQJroz8Ul8NJ9Eym7dmhBILufck_MR8pSzLWe8e3HcHi3OCcJ2x7issy2T4h7Z8KEXTauUvE82VTc0opPqijzK-chYlbT9Q3K16-RuUIxvyPfXUCBFP5vicaY4UVPvpfhoAnWY_XxHsz2AOwWgEyZqMY5-Xsc3yc-4HDAB3f_68bMaHS0Q8RsGjN4B9fOfZakcsODiLY3oIKwZd8HjGEwuGM1j8mAyIcOTy3tNPr1983H_vrn98O5m_-q2sbVBaYzs7DhZZqDtx0EMtacE1wqhBut2isPg1k8u6lFt1_VSCjtCpww4ocZOXJPn571Lws8nyEVHny2EYGbAU9a8l5wrKXhfpfIstQlzTjDpJVUg6avmTK_09VFf6OuV_jquaKvv2SXiNEZw_1x_cVfBy7MAatEvHpLO1sNswfkEtmiH_j8RvwGL85xp</recordid><startdate>20151228</startdate><enddate>20151228</enddate><creator>Verreault, M.</creator><creator>Wehbe, M.</creator><creator>Strutt, D.</creator><creator>Masin, D.</creator><creator>Anantha, M.</creator><creator>Walker, D.</creator><creator>Chu, F.</creator><creator>Backstrom, I.</creator><creator>Kalra, J.</creator><creator>Waterhouse, D.</creator><creator>Yapp, D.T.</creator><creator>Bally, M.B.</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/0000-0001-6708-7698</orcidid></search><sort><creationdate>20151228</creationdate><title>Determination of an optimal dosing schedule for combining Irinophore C™ and temozolomide in an orthotopic model of glioblastoma</title><author>Verreault, M. ; Wehbe, M. ; Strutt, D. ; Masin, D. ; Anantha, M. ; Walker, D. ; Chu, F. ; Backstrom, I. ; Kalra, J. ; Waterhouse, D. ; Yapp, D.T. ; Bally, M.B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c365t-a56cbfc0ae47b8381875ed43398cd291e8dc0ae13e1394667553cbe69aed39b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Angiogenesis Inhibitors - administration & dosage</topic><topic>Angiogenesis Inhibitors - chemistry</topic><topic>Animals</topic><topic>Antineoplastic Agents, Alkylating - administration & dosage</topic><topic>Antineoplastic Agents, Alkylating - chemistry</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Brain Neoplasms - blood supply</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - pathology</topic><topic>Camptothecin - administration & dosage</topic><topic>Camptothecin - analogs & derivatives</topic><topic>Camptothecin - chemistry</topic><topic>Cancer</topic><topic>Dacarbazine - administration & dosage</topic><topic>Dacarbazine - analogs & derivatives</topic><topic>Dacarbazine - chemistry</topic><topic>Drug Administration Schedule</topic><topic>Drug Compounding</topic><topic>Drug delivery</topic><topic>Glioblastoma</topic><topic>Glioblastoma - blood supply</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - metabolism</topic><topic>Glioblastoma - pathology</topic><topic>Humans</topic><topic>Irinotecan</topic><topic>Liposomes</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Neovascularization, Pathologic</topic><topic>Time Factors</topic><topic>Tumor Burden - drug effects</topic><topic>Tumor-associated vasculature</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Verreault, M.</creatorcontrib><creatorcontrib>Wehbe, M.</creatorcontrib><creatorcontrib>Strutt, D.</creatorcontrib><creatorcontrib>Masin, D.</creatorcontrib><creatorcontrib>Anantha, M.</creatorcontrib><creatorcontrib>Walker, D.</creatorcontrib><creatorcontrib>Chu, F.</creatorcontrib><creatorcontrib>Backstrom, I.</creatorcontrib><creatorcontrib>Kalra, J.</creatorcontrib><creatorcontrib>Waterhouse, D.</creatorcontrib><creatorcontrib>Yapp, D.T.</creatorcontrib><creatorcontrib>Bally, M.B.</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>Verreault, M.</au><au>Wehbe, M.</au><au>Strutt, D.</au><au>Masin, D.</au><au>Anantha, M.</au><au>Walker, D.</au><au>Chu, F.</au><au>Backstrom, I.</au><au>Kalra, J.</au><au>Waterhouse, D.</au><au>Yapp, D.T.</au><au>Bally, M.B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Determination of an optimal dosing schedule for combining Irinophore C™ and temozolomide in an orthotopic model of glioblastoma</atitle><jtitle>Journal of controlled release</jtitle><addtitle>J Control Release</addtitle><date>2015-12-28</date><risdate>2015</risdate><volume>220</volume><issue>Pt A</issue><spage>348</spage><epage>357</epage><pages>348-357</pages><issn>0168-3659</issn><eissn>1873-4995</eissn><abstract>Our laboratory reported that Irinophore C™ (IrC™; a lipid-based nanoparticulate formulation of irinotecan) is effective against an orthotopic model of glioblastoma (GBM) and that treatment with IrC™ was associated with vascular normalization within the tumor. Here, the therapeutic effects of IrC™ when used in combination with temozolomide (TMZ) in concurrent and sequential treatment schedules were tested. It was anticipated that IrC™ engendered vascular normalization would increase the delivery of TMZ to the tumor and that this would be reflected by improved treatment outcomes. The approach compared equally efficacious doses of irinotecan (IRN; 50mg/kg) and IrC™ (25mg/kg) in order to determine if there was a unique advantage achieved when combining TMZ with IrC™. The TMZ sensitive U251MGO cell line (null expression of O-6-methylguanine-DNA methyltransferase (MGMT)) modified to express the fluorescent protein mKate2 was inoculated orthotopically into NOD.CB17-SCID mice and treatment was initiated 14days later. Our results demonstrated that IrC™ and TMZ administered concurrently resulted in optimal treatment outcomes, with 50% long term survivors (>180days) in comparison to 17% long term survivors in animals treated with IRN and TMZ or TMZ alone. Indeed, the different treatments resulted in a 353%, 222% and 280% increase in median survival time (MST) compared to untreated animals for, respectively, IrC™ combined with TMZ, IRN combined with TMZ, and TMZ alone. When TMZ was administered after completion of IRN or IrC™ dosing, an increase in median survival time of 167–174% was observed compared to untreated animals and of 67% and 74%, respectively, when IRN (50mg/kg) and IrC™ (25mg/kg) were given as single agents. We confirmed in these studies that after completion of the Q7D×3 dosing of IrC™, but not IRN, the tumor-associated vascular was normalized as compared to untreated tumors. Specifically, reductions in the fraction of collagen IV-free CD31 staining (p<0.05) and reductions in tumor vessel diameter were observed in tumors from IrC™-treated animals when compared to tumors from untreated or IRN treated animals. Analysis by transmission electron microscopy of the ultra-structure of tumors from IrC™-treated and untreated animals revealed that tumor-associated vessels from treated animals were smaller, more organized and exhibited a morphology comparable to normal blood vessels. In conclusion, optimal treatment outcomes were achieved when IrC™ and TMZ were administered concurrently, whereas IrC™ followed by TMZ treatment given sequentially did not confer any therapeutic advantage.
[Display omitted]</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>26528901</pmid><doi>10.1016/j.jconrel.2015.10.053</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-6708-7698</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0168-3659 |
| ispartof | Journal of controlled release, 2015-12, Vol.220 (Pt A), p.348-357 |
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| subjects | Angiogenesis Inhibitors - administration & dosage Angiogenesis Inhibitors - chemistry Animals Antineoplastic Agents, Alkylating - administration & dosage Antineoplastic Agents, Alkylating - chemistry Antineoplastic Combined Chemotherapy Protocols - pharmacology Biomarkers, Tumor - metabolism Brain Neoplasms - blood supply Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Brain Neoplasms - pathology Camptothecin - administration & dosage Camptothecin - analogs & derivatives Camptothecin - chemistry Cancer Dacarbazine - administration & dosage Dacarbazine - analogs & derivatives Dacarbazine - chemistry Drug Administration Schedule Drug Compounding Drug delivery Glioblastoma Glioblastoma - blood supply Glioblastoma - drug therapy Glioblastoma - metabolism Glioblastoma - pathology Humans Irinotecan Liposomes Mice, Inbred NOD Mice, SCID Neovascularization, Pathologic Time Factors Tumor Burden - drug effects Tumor-associated vasculature Xenograft Model Antitumor Assays |
| title | Determination of an optimal dosing schedule for combining Irinophore C™ and temozolomide in an orthotopic model of glioblastoma |
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