5 research outputs found
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.National Cancer Institute (U.S.) (Grant RO1-CA034992
A Ruthenium Hydrido Dinitrogen Core Conserved across Multielectron/Multiproton Changes to the Pincer Ligand Backbone
A series
of ruthenium(II) hydrido dinitrogen complexes supported by pincer
ligands in different formal oxidation states have been prepared and
characterized. Treating a ruthenium dichloride complex supported by
the pincer ligand bis(di-<i>tert</i>-butylphosphinoethyl)amine
(H-PNP) with reductant or base generates new five-coordinate <i>cis</i>-hydridodinitrogen ruthenium complexes each containing
different forms of the pincer ligand. Further ligand transformations
provide access to the first isostructural set of complexes featuring
all six different forms of the pincer ligand. The conserved <i>cis</i>-hydridodinitrogen structure facilitates characterization
of the π-donor, π-acceptor, and/or σ-donor properties
of the ligands and assessment of the impact of ligand-centered multielectron/multiproton
changes on N<sub>2</sub> activation. Crystallographic studies, infrared
spectroscopy, and <sup>15</sup>N NMR spectroscopy indicate that N<sub>2</sub> remains weakly activated in all cases, providing insight
into the donor properties of the different pincer ligand states. Ramifications
on applications of (pincer)Ru species in catalysis are considered
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Tumor 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 behavior. Model TNPs comprised of 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 tumor 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 neighboring tumor 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