Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors
The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment w...
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2016
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| Online Access: | http://hdl.handle.net/1721.1/105476 https://orcid.org/0000-0002-0930-302X https://orcid.org/0000-0003-2599-2774 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0002-1293-2097 |
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| author | Scherz-Shouval, R. Galie, P. A. Whitesell, L. Chen, C. S. Bagley, Alexander F Zhang, Angela Q. Wyckoff, Jeffrey Lindquist, Susan Bhatia, Sangeeta N |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Scherz-Shouval, R. Galie, P. A. Whitesell, L. Chen, C. S. Bagley, Alexander F Zhang, Angela Q. Wyckoff, Jeffrey Lindquist, Susan Bhatia, Sangeeta N |
| author_sort | Scherz-Shouval, R. |
| collection | MIT |
| description | The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrated potential to enhance drug delivery in preclinical models. Here, we investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer. We observed a temperature-dependent increase in the transport of diagnostic nanoparticles into tumors. However, a transient, reversible reduction in this enhanced transport was seen upon reexposure to heating, consistent with the development of vascular thermotolerance. Harnessing these observations, we designed an improved treatment protocol combining plasmonic nanoantennae with diffusion-limited chemotherapies. Using a microfluidic endothelial model and genetic tools to inhibit the heat-shock response, we found that the ability of thermal preconditioning to limit heat-induced cytoskeletal disruption is an important component of vascular thermotolerance. This work, therefore, highlights the clinical relevance of cellular adaptations to nanomaterials and identifies molecular pathways whose modulation could improve the exposure of tumors to therapeutic agents. |
| first_indexed | 2024-09-23T10:30:21Z |
| format | Article |
| id | mit-1721.1/105476 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:30:21Z |
| publishDate | 2016 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/1054762022-09-27T09:50:15Z Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors Scherz-Shouval, R. Galie, P. A. Whitesell, L. Chen, C. S. Bagley, Alexander F Zhang, Angela Q. Wyckoff, Jeffrey Lindquist, Susan Bhatia, Sangeeta N Massachusetts Institute of Technology. Institute for Medical Engineering & Science Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Bagley, Alexander F Zhang, Angela Q. Wyckoff, Jeffrey Lindquist, Susan Bhatia, Sangeeta N The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrated potential to enhance drug delivery in preclinical models. Here, we investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer. We observed a temperature-dependent increase in the transport of diagnostic nanoparticles into tumors. However, a transient, reversible reduction in this enhanced transport was seen upon reexposure to heating, consistent with the development of vascular thermotolerance. Harnessing these observations, we designed an improved treatment protocol combining plasmonic nanoantennae with diffusion-limited chemotherapies. Using a microfluidic endothelial model and genetic tools to inhibit the heat-shock response, we found that the ability of thermal preconditioning to limit heat-induced cytoskeletal disruption is an important component of vascular thermotolerance. This work, therefore, highlights the clinical relevance of cellular adaptations to nanomaterials and identifies molecular pathways whose modulation could improve the exposure of tumors to therapeutic agents. National Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. Support Grant P30-CA14051) National Institute of Environmental Health Sciences (Core Center Grant P30-ES002109) Marie D. and Pierre Casimir-Lambert Fund National Institutes of Health (U.S.) (Grants UH3 EB017103, R01 EB000262 and U54CA151884) MIT-Harvard Center of Cancer Nanotechnology Excellence National Institute of General Medical Sciences (U.S.) (MSTP Grant T32GM007753) Harvard Medical School. Harvard-MIT MD-PhD Program 2016-11-30T16:36:40Z 2016-11-30T16:36:40Z 2015-08 Article http://purl.org/eprint/type/JournalArticle 0008-5472 1538-7445 http://hdl.handle.net/1721.1/105476 Bagley, A. F. et al. “Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors.” Cancer Research 75.16 (2015): 3255–3267. https://orcid.org/0000-0002-0930-302X https://orcid.org/0000-0003-2599-2774 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0002-1293-2097 en_US http://dx.doi.org/10.1158/0008-5472.CAN-15-0325 Cancer Research Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Association for Cancer Research PMC |
| spellingShingle | Scherz-Shouval, R. Galie, P. A. Whitesell, L. Chen, C. S. Bagley, Alexander F Zhang, Angela Q. Wyckoff, Jeffrey Lindquist, Susan Bhatia, Sangeeta N Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors |
| title | Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors |
| title_full | Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors |
| title_fullStr | Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors |
| title_full_unstemmed | Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors |
| title_short | Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors |
| title_sort | endothelial thermotolerance impairs nanoparticle transport in tumors |
| url | http://hdl.handle.net/1721.1/105476 https://orcid.org/0000-0002-0930-302X https://orcid.org/0000-0003-2599-2774 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0002-1293-2097 |
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