Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles
Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2018
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| Online Access: | http://hdl.handle.net/1721.1/116978 https://orcid.org/0000-0002-9801-5037 https://orcid.org/0000-0003-1468-8275 https://orcid.org/0000-0002-9547-3251 |
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| author | Vu Han, Tu-Lan Balkanska-Sinclair, Elena Floyd, Scott R Lam, Fred Chiu-Lai Morton, Stephen Winford Wyckoff, Jeffrey Vu-Han, Tu-Lan Hwang, Mun Kyung Maffa, Amanda Yaffe, Michael B Hammond, Paula T |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Vu Han, Tu-Lan Balkanska-Sinclair, Elena Floyd, Scott R Lam, Fred Chiu-Lai Morton, Stephen Winford Wyckoff, Jeffrey Vu-Han, Tu-Lan Hwang, Mun Kyung Maffa, Amanda Yaffe, Michael B Hammond, Paula T |
| author_sort | Vu Han, Tu-Lan |
| collection | MIT |
| description | Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5-to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors. |
| first_indexed | 2024-09-23T08:48:01Z |
| format | Article |
| id | mit-1721.1/116978 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:48:01Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1169782022-09-23T14:38:50Z Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles Vu Han, Tu-Lan Balkanska-Sinclair, Elena Floyd, Scott R Lam, Fred Chiu-Lai Morton, Stephen Winford Wyckoff, Jeffrey Vu-Han, Tu-Lan Hwang, Mun Kyung Maffa, Amanda Yaffe, Michael B Hammond, Paula T Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Lam, Fred Chiu-Lai Morton, Stephen Winford Wyckoff, Jeffrey Vu-Han, Tu-Lan Hwang, Mun Kyung Maffa, Amanda Yaffe, Michael B Hammond, Paula T Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5-to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors. National Institutes of Health (U.S.) (Grant R01-ES015339) National Institutes of Health (U.S.) (Grant R35-ES028374) National Cancer Institute (U.S.) (Grant P30-CA14051) 2018-07-13T16:22:43Z 2018-07-13T16:22:43Z 2018-05 2017-07 2018-07-13T13:58:58Z Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/116978 Lam, Fred C. et al. “Enhanced Efficacy of Combined Temozolomide and Bromodomain Inhibitor Therapy for Gliomas Using Targeted Nanoparticles.” Nature Communications 9, 1 (May 2018): 1991 © 2018 The Author(s) https://orcid.org/0000-0002-9801-5037 https://orcid.org/0000-0003-1468-8275 https://orcid.org/0000-0002-9547-3251 http://dx.doi.org/10.1038/s41467-018-04315-4 Nature Communications Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature |
| spellingShingle | Vu Han, Tu-Lan Balkanska-Sinclair, Elena Floyd, Scott R Lam, Fred Chiu-Lai Morton, Stephen Winford Wyckoff, Jeffrey Vu-Han, Tu-Lan Hwang, Mun Kyung Maffa, Amanda Yaffe, Michael B Hammond, Paula T Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles |
| title | Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles |
| title_full | Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles |
| title_fullStr | Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles |
| title_full_unstemmed | Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles |
| title_short | Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles |
| title_sort | enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles |
| url | http://hdl.handle.net/1721.1/116978 https://orcid.org/0000-0002-9801-5037 https://orcid.org/0000-0003-1468-8275 https://orcid.org/0000-0002-9547-3251 |
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