Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells
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Author(s)
Abraham, Wuhbet
Zheng, Yiran
Huang, Bonnie
Bustamante Lopez, Sandra C
Irvine, Darrell J
Luo, Samantha
Date Issued
June 2015
Journal
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Citation
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.
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Author's final manuscript
Abstract
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.
MIT Department
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
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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.
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DOI of Published Version
https://doi.org/10.1126/scitranslmed.aaa5447
