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

• Published in: Nature communications Vol. 6; no. 1; p. 8692
• Main Authors: Miller, Miles A., 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-10-2015; Nature Publishing Group
• Subjects: 14/1; 14/19; 14/28; 14/34; 14/35; 14/56; 14/63; 59; 631/1647/350/354; 631/61/54/152; 631/67/1059; 631/92/436/108; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Cancer; Cell Line, Tumor; DNA damage; Drug Delivery Systems - methods; Female; Humanities and Social Sciences; Humans; Macrophages - chemistry; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Nude; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Neoplasms - drug therapy; Neoplasms - metabolism; Permeability; Platinum - chemistry; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Science; Science (multidisciplinary); Tumors; United States > US; Massachusetts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9692

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.
Drug-loaded nanoparticles allow controlled release and enhanced delivery, yet understanding
in vivo
behavior has been difficult. Here, the authors develop a platinum prodrug coupled to a polymer platform, and use intravital imaging to show that the nanoparticle accumulates in macrophages, from the which drug redistributes to neighboring tumour cells.