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

Author

Listed:
  • 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
    Present address: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Canada K1H 8M5.)

  • 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
    King Abdulaziz University)

  • Ralph Weissleder

    (Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School
    Harvard Medical School)

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.

Suggested Citation

  • 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 & M, 2015. "Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug," Nature Communications, Nature, vol. 6(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9692
    DOI: 10.1038/ncomms9692
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