Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells
Tumor cells disseminate into compartments that are poorly accessible from circulation, which necessitates high doses of systemic chemotherapy. However, the effectiveness of many drugs, such as the potent topoisomerase I poison SN-38, is hampered by poor pharmacokinetics. To deliver SN-38 to lymphoma...
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108108 https://orcid.org/0000-0003-0817-0525 |
| _version_ | 1826196263319633920 |
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| author | Abraham, Wuhbet Zheng, Yiran Huang, Bonnie Bustamante Lopez, Sandra C Irvine, Darrell J Luo, Samantha |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Abraham, Wuhbet Zheng, Yiran Huang, Bonnie Bustamante Lopez, Sandra C Irvine, Darrell J Luo, Samantha |
| author_sort | Abraham, Wuhbet |
| collection | MIT |
| description | Tumor cells disseminate into compartments that are poorly accessible from circulation, which necessitates high doses of systemic chemotherapy. However, the effectiveness of many drugs, such as the potent topoisomerase I poison SN-38, is hampered by poor pharmacokinetics. To deliver SN-38 to lymphoma tumors in vivo, we took advantage of the fact that healthy lymphocytes can be programmed to phenocopy the biodistribution of the tumor cells. In a murine model of disseminated lymphoma, we expanded autologous polyclonal T cells ex vivo under conditions that retained homing receptors mirroring lymphoma cells, and functionalized these T cells to carry SN-38–loaded nanocapsules on their surfaces. Nanocapsule-functionalized T cells were resistant to SN-38 but mediated efficient killing of lymphoma cells in vitro. Upon adoptive transfer into tumor-bearing mice, these T cells served as active vectors to deliver the chemotherapeutic into tumor-bearing lymphoid organs. Cell-mediated delivery concentrated SN-38 in lymph nodes at levels 90-fold greater than free drug systemically administered at 10-fold higher doses. The live T cell delivery approach reduced tumor burden significantly after 2 weeks of treatment and enhanced survival under conditions where free SN-38 and SN-38–loaded nanocapsules alone were ineffective. These results suggest that tissue-homing lymphocytes can serve as specific targeting agents to deliver nanoparticles into sites difficult to access from the circulation, and thus improve the therapeutic index of chemotherapeutic drugs with unfavorable pharmacokinetics. |
| first_indexed | 2024-09-23T10:23:46Z |
| format | Article |
| id | mit-1721.1/108108 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:23:46Z |
| publishDate | 2017 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1081082022-09-26T17:36:36Z Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells Abraham, Wuhbet Zheng, Yiran Huang, Bonnie Bustamante Lopez, Sandra C Irvine, Darrell J Luo, Samantha Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Materials Science and Engineering Ragon Institute of MGH, MIT and Harvard Koch Institute for Integrative Cancer Research at MIT Abraham, Wuhbet Zheng, Yiran Huang, Bonnie Bustamante Lopez, Sandra C Luo, Samantha S. Irvine, Darrell J Tumor cells disseminate into compartments that are poorly accessible from circulation, which necessitates high doses of systemic chemotherapy. However, the effectiveness of many drugs, such as the potent topoisomerase I poison SN-38, is hampered by poor pharmacokinetics. To deliver SN-38 to lymphoma tumors in vivo, we took advantage of the fact that healthy lymphocytes can be programmed to phenocopy the biodistribution of the tumor cells. In a murine model of disseminated lymphoma, we expanded autologous polyclonal T cells ex vivo under conditions that retained homing receptors mirroring lymphoma cells, and functionalized these T cells to carry SN-38–loaded nanocapsules on their surfaces. Nanocapsule-functionalized T cells were resistant to SN-38 but mediated efficient killing of lymphoma cells in vitro. Upon adoptive transfer into tumor-bearing mice, these T cells served as active vectors to deliver the chemotherapeutic into tumor-bearing lymphoid organs. Cell-mediated delivery concentrated SN-38 in lymph nodes at levels 90-fold greater than free drug systemically administered at 10-fold higher doses. The live T cell delivery approach reduced tumor burden significantly after 2 weeks of treatment and enhanced survival under conditions where free SN-38 and SN-38–loaded nanocapsules alone were ineffective. These results suggest that tissue-homing lymphocytes can serve as specific targeting agents to deliver nanoparticles into sites difficult to access from the circulation, and thus improve the therapeutic index of chemotherapeutic drugs with unfavorable pharmacokinetics. United States. Department of Defense (W81XWH-10-1-0290) National Institutes of Health (U.S.) (CA140476 and CA172164) National Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. Support (Core) Grant P30-CA14051) 2017-04-13T16:16:00Z 2017-04-13T16:16:00Z 2015-06 2014-12 Article http://purl.org/eprint/type/JournalArticle 1946-6234 1946-6242 http://hdl.handle.net/1721.1/108108 Huang, B., W. D. Abraham, Y. Zheng, S. C. Bustamante Lopez, S. S. Luo, and D. J. Irvine. “Active Targeting of Chemotherapy to Disseminated Tumors Using Nanoparticle-Carrying T Cells.” Science Translational Medicine 7, no. 291 (June 10, 2015): 291ra94–291ra94. https://orcid.org/0000-0003-0817-0525 en_US http://dx.doi.org/10.1126/scitranslmed.aaa5447 Science Translational Medicine 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 the Advancement of Science (AAAS) PMC |
| spellingShingle | Abraham, Wuhbet Zheng, Yiran Huang, Bonnie Bustamante Lopez, Sandra C Irvine, Darrell J Luo, Samantha Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells |
| title | Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells |
| title_full | Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells |
| title_fullStr | Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells |
| title_full_unstemmed | Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells |
| title_short | Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells |
| title_sort | active targeting of chemotherapy to disseminated tumors using nanoparticle carrying t cells |
| url | http://hdl.handle.net/1721.1/108108 https://orcid.org/0000-0003-0817-0525 |
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