Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug
Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their hete...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2015
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| Online Access: | http://hdl.handle.net/1721.1/100507 https://orcid.org/0000-0002-2693-4982 |
| _version_ | 1826202024581005312 |
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| author | Miller, Miles Aaron Zheng, Yao-Rong Gadde, Suresh Pfirschke, Christina Zope, Harshal Engblom, Camilla Kohler, Rainer H. Iwamoto, Yoshiko Yang, Katherine S. Askevold, Bjorn Kolishetti, Nagesh Pittet, Mikael Lippard, Stephen J. Farokhzad, Omid C. Weissleder, Ralph |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Miller, Miles Aaron Zheng, Yao-Rong Gadde, Suresh Pfirschke, Christina Zope, Harshal Engblom, Camilla Kohler, Rainer H. Iwamoto, Yoshiko Yang, Katherine S. Askevold, Bjorn Kolishetti, Nagesh Pittet, Mikael Lippard, Stephen J. Farokhzad, Omid C. Weissleder, Ralph |
| author_sort | Miller, Miles Aaron |
| collection | MIT |
| description | Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials. |
| first_indexed | 2024-09-23T12:00:50Z |
| format | Article |
| id | mit-1721.1/100507 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:00:50Z |
| publishDate | 2015 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1005072022-10-01T07:37:08Z Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug Miller, Miles Aaron Zheng, Yao-Rong Gadde, Suresh Pfirschke, Christina Zope, Harshal Engblom, Camilla Kohler, Rainer H. Iwamoto, Yoshiko Yang, Katherine S. Askevold, Bjorn Kolishetti, Nagesh Pittet, Mikael Lippard, Stephen J. Farokhzad, Omid C. Weissleder, Ralph Massachusetts Institute of Technology. Department of Chemistry Zheng, Yao-Rong Lippard, Stephen J. Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials. National Cancer Institute (U.S.) (Grant RO1-CA034992) 2015-12-23T18:22:19Z 2015-12-23T18:22:19Z 2015-10 2014-12 Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/100507 Miller, Miles A., Yao-Rong Zheng, Suresh Gadde, Christina Pfirschke, Harshal Zope, Camilla Engblom, Rainer H. Kohler, et al. “Tumour-Associated Macrophages Act as a Slow-Release Reservoir of Nano-Therapeutic Pt(IV) Pro-Drug.” Nat Comms 6 (October 27, 2015): 8692. © 2015 Macmillan Publishers Limited https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1038/ncomms9692 Nature Communications Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature Publishing Group |
| spellingShingle | Miller, Miles Aaron Zheng, Yao-Rong Gadde, Suresh Pfirschke, Christina Zope, Harshal Engblom, Camilla Kohler, Rainer H. Iwamoto, Yoshiko Yang, Katherine S. Askevold, Bjorn Kolishetti, Nagesh Pittet, Mikael Lippard, Stephen J. Farokhzad, Omid C. Weissleder, Ralph Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug |
| title | Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug |
| title_full | Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug |
| title_fullStr | Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug |
| title_full_unstemmed | Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug |
| title_short | Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug |
| title_sort | tumour associated macrophages act as a slow release reservoir of nano therapeutic pt iv pro drug |
| url | http://hdl.handle.net/1721.1/100507 https://orcid.org/0000-0002-2693-4982 |
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