A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways
Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2014
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| Online Access: | http://hdl.handle.net/1721.1/91686 https://orcid.org/0000-0002-4954-8443 https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0003-1727-5732 https://orcid.org/0000-0003-3988-0837 |
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| author | Morton, Stephen Winford Lee, Michael J. Deng, Zhou J. Siouve, Elise Shopsowitz, Kevin Shah, Nisarg J. Dreaden, Erik Yaffe, Michael B Hammond, Paula T |
| author2 | Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies |
| author_facet | Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies Morton, Stephen Winford Lee, Michael J. Deng, Zhou J. Siouve, Elise Shopsowitz, Kevin Shah, Nisarg J. Dreaden, Erik Yaffe, Michael B Hammond, Paula T |
| author_sort | Morton, Stephen Winford |
| collection | MIT |
| description | Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models. |
| first_indexed | 2024-09-23T12:39:22Z |
| format | Article |
| id | mit-1721.1/91686 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:39:22Z |
| publishDate | 2014 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/916862022-10-01T10:17:04Z A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways Morton, Stephen Winford Lee, Michael J. Deng, Zhou J. Siouve, Elise Shopsowitz, Kevin Shah, Nisarg J. Dreaden, Erik Yaffe, Michael B Hammond, Paula T Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies 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 Morton, Stephen Winford Lee, Michael J. Deng, Zhou J. Dreaden, Erik Christopher Siouve, Elise Shopsowitz, Kevin Shah, Nisarg J. Yaffe, Michael B. Hammond, Paula T. Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models. National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. P30-CA14051) National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. U54-CA151884) National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. U54-CA112967) National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. R01-ES015339) National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. R21-ES020466) Breast Cancer Alliance (Exceptional Project Grant) National Science Foundation (U.S.) (Graduate Research Fellowship) National Health and Medical Research Council (Australia) (CJ Martin Fellowship) National Institutes of Health (U.S.) (Kirschstein NRSA 1F32EB017614-01) Natural Sciences and Engineering Research Council of Canada (post-doctoral fellowship) Kathy and Curt Marble Cancer Research Fund David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Frontier Research Program) 2014-11-21T20:28:45Z 2014-11-21T20:28:45Z 2014-05 Article http://purl.org/eprint/type/JournalArticle 1945-0877 1937-9145 http://hdl.handle.net/1721.1/91686 Morton, S. W., M. J. Lee, Z. J. Deng, E. C. Dreaden, E. Siouve, K. E. Shopsowitz, N. J. Shah, M. B. Yaffe, and P. T. Hammond. “A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways.” Science Signaling 7, no. 325 (May 13, 2014): ra44–ra44. p.1-11. https://orcid.org/0000-0002-4954-8443 https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0003-1727-5732 https://orcid.org/0000-0003-3988-0837 en_US http://dx.doi.org/10.1126/scisignal.2005261 Science Signaling Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Morton, Stephen Winford Lee, Michael J. Deng, Zhou J. Siouve, Elise Shopsowitz, Kevin Shah, Nisarg J. Dreaden, Erik Yaffe, Michael B Hammond, Paula T A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways |
| title | A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways |
| title_full | A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways |
| title_fullStr | A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways |
| title_full_unstemmed | A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways |
| title_short | A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways |
| title_sort | nanoparticle based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways |
| url | http://hdl.handle.net/1721.1/91686 https://orcid.org/0000-0002-4954-8443 https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0003-1727-5732 https://orcid.org/0000-0003-3988-0837 |
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