Tumour-associated Macrophages Act as a Slow-Release Reservoir of Nano-Therapeutic Pt(IV) Pro-Drug

Nat Commun. 2015 Oct 27;6:8692. doi: 10.1038/ncomms9692.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics*
  • Cell Line, Tumor
  • Drug Delivery Systems / methods*
  • Female
  • Humans
  • Macrophages / chemistry
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Nanoparticles / chemistry
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Platinum / chemistry
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics*

Substances

  • Antineoplastic Agents
  • Prodrugs
  • Platinum