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Biotechnol J. 2019 Apr;14(4):e1800413. doi: 10.1002/biot.201800413. Epub 2018 Nov 23.

Cell-Nanoparticle Interactions at (Sub)-Nanometer Resolution Analyzed by Electron Microscopy and Correlative Coherent Anti-Stokes Raman Scattering.

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Drug Research Program, Division of Pharmaceutical Chemistry and , University of Helsinki, Viikinkaari 5 E (PO Box 56), 00014 Helsinki, Finland.
Pharmaceutical Institute Department of Pharmaceutics and Biopharmaceutics, Faculty of Mathematics and Natural Sciences, Kiel University, Grasweg 9a, 24118 Kiel, Germany.
Institute of Biotechnology, Electron Microscopy Unit, University of Helsinki, Viikinkaari 9 (PO Box 56), 00014 Helsinki, Finland.
Dodd-Walls Centre, Department of Chemistry, University of Otago, PO Box 56, 9056 Dunedin, New Zealand.
Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Viikinkaari 5 E (PO Box 56), 00014 Helsinki, Finland.
Biomedicum Imaging Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8 (PO Box 63), 00014 Helsinki, Finland.


A wide variety of nanoparticles are playing an increasingly important role in drug delivery. Label-free imaging techniques are especially desirable to follow the cellular uptake and intracellular fate of nanoparticles. The combined correlative use of different techniques, each with unique advantages, facilitates more detailed investigation about such interactions. The synergistic use of correlative coherent anti-Stokes Raman scattering and electron microscopy (C-CARS-EM) imaging offers label-free, chemically-specific, and (sub)-nanometer spatial resolution for studying nanoparticle uptake into cells as demonstrated in the current study. Coherent anti-Stokes Raman scattering (CARS) microscopy offers chemically-specific (sub)micron spatial resolution imaging without fluorescent labels while transmission electron microscopy (TEM) offers (sub)-nanometer scale spatial resolution and thus visualization of precise nanoparticle localization at the sub-cellular level. This proof-of-concept imaging platform with unlabeled drug nanocrystals and macrophage cells revealed good colocalization between the CARS signal and electron dense nanocrystals in TEM images. The correlative TEM images revealed subcellular localization of nanocrystals inside membrane bound vesicles, showing multivesicular body (MVB)-like morphology typical for late endosomes (LEs), endolysosomes, and phagolysosomes. C-CARS-EM imaging has much potential to study the interactions between a wide range of nanoparticles and cells with high precision and confidence.


cell imaging; cellular nanoparticle uptake; coherent anti-Stokes Raman scattering (CARS) microscopy; drug nanocrystals; non-linear imaging


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