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

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

Nature communications (2015-10-28)
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, Ralph Weissleder
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA Mn 15,000, lactide:glycolide 80:20
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 2,000, PLGA Mn 3,000, lactide:glycolide 50:50
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA Mn 10,000, lactide:glycolide 50:50
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA Mn 5,000, lactide:glycolide 50:50
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA Mn 20,000, lactide:glycolide 50:50
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA Mn 15,000, lactide:glycolide 50:50
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA average Mn 10,000, lactide:glycolide 80:20
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA average Mn 5,000, lactide:glycolide 80:20
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 2,000, PLGA average Mn 10,000, lactide:glycolide 50:50
Sigma-Aldrich
Folate-poly(ethylene glycol)-b-poly(lactide-co-glycolide), PEG average Mn 2,000, PLGA average Mn 10,000, lactide:glycolide 50:50
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide)(85/15)-b-poly(ethylene glycol)-carboxylic acid, 5k-13k
Sigma-Aldrich
Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG average Mn 2,000, PLGA average Mn 10,000, lactide:glycolide 80:20
Sigma-Aldrich
Carboxylic acid-poly(ethylene glycol)-b-poly(lactide-co-glycolide), PEG average Mn 5,000, PLGA average Mn 20,000, lactide:glycolide 50:50
Sigma-Aldrich
Biotin-poly(ethylene glycol)-b-poly(lactide-co-glycolide), PEG average Mn 2,000, PLGA average Mn 10,000, lactide:glycolide 50:50
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide)(50:50)-b-poly(ethylene glycol), 10k-2k