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 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.
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Miles A
MA
Miller
Department of Chemistry, Massachusetts Institute of Technology (MIT), 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Yao-Rong
YR
Zheng
Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital (BWH), Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
Suresh
http://orcid.org/0000-0001-9102-3029
S
Gadde
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Christina
C
Pfirschke
Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital (BWH), Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
Harshal
H
Zope
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Camilla
C
Engblom
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Rainer H
http://orcid.org/0000-0001-6269-6590
RH
Kohler
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Yoshiko
Y
Iwamoto
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Katherine S
KS
Yang
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Bjorn
B
Askevold
Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital (BWH), Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
Nagesh
http://orcid.org/0000-0001-5574-673X
N
Kolishetti
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Mikael
M
Pittet
Department of Chemistry, Massachusetts Institute of Technology (MIT), 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Stephen J
SJ
Lippard
Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital (BWH), Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.|King Abdulaziz University, Jeddah, Saudi Arabia.
Omid C
OC
Farokhzad
Center for Systems Biology, Massachusetts General Hospital (MGH), Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Ralph
R
Weissleder
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010984:Platinum / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D011355:Prodrugs; D010984:Platinum