Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug

Miles A. Miller, Yao-Rong Zheng, Suresh Gadde, Christina Pfirschke, Harshal Zope, Camilla Engblom, Rainer H. Kohler, Yoshiko Iwamoto, Katherine S. Yang, Bjorn Askevold, Nagesh Kolishetti, Mikael Pittet, Stephen J. Lippard, Omid C. Farokhzad and Ralph Weissleder ()
Additional contact information
Miles A. Miller: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
Yao-Rong Zheng: Massachusetts Institute of Technology (MIT)
Suresh Gadde: Laboratory of Nanomedicine and Biomaterials, Brigham and Women’s Hospital (BWH), Harvard Medical School
Christina Pfirschke: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
Harshal Zope: Laboratory of Nanomedicine and Biomaterials, Brigham and Women’s Hospital (BWH), Harvard Medical School
Camilla Engblom: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
Rainer H. Kohler: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
Yoshiko Iwamoto: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
Katherine S. Yang: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
Bjorn Askevold: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
Nagesh Kolishetti: Laboratory of Nanomedicine and Biomaterials, Brigham and Women’s Hospital (BWH), Harvard Medical School
Mikael Pittet: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
Stephen J. Lippard: Massachusetts Institute of Technology (MIT)
Omid C. Farokhzad: Laboratory of Nanomedicine and Biomaterials, Brigham and Women’s Hospital (BWH), Harvard Medical School
Ralph Weissleder: Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms9692

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