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Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip

Natalia Feiner-Gracia, View ORCID ProfileAdrianna Glinkowska Mares, Marina Buzhor, Romen Rodriguez-Trujillo, Josep Samitier, View ORCID ProfileRoey J. Amir, Silvia Pujals, View ORCID ProfileLorenzo Albertazzi
doi: https://doi.org/10.1101/2020.03.08.978783
Natalia Feiner-Gracia
1Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology (BIST), Carrer Baldiri Reixac 15-21, 08024 Barcelona, Spain
2Department of Biomedical Engineering, Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5612AZ Eindhoven, The Netherlands
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Adrianna Glinkowska Mares
1Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology (BIST), Carrer Baldiri Reixac 15-21, 08024 Barcelona, Spain
2Department of Biomedical Engineering, Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5612AZ Eindhoven, The Netherlands
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  • ORCID record for Adrianna Glinkowska Mares
Marina Buzhor
3Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel
4Tel Aviv University Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 6997801, Israel
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Romen Rodriguez-Trujillo
1Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology (BIST), Carrer Baldiri Reixac 15-21, 08024 Barcelona, Spain
6Department of Electronic and Biomedical Engineering, Faculty of Physics, University of Barcelona, Carrer Martí I Franquès 1, 08028 Barcelona, Spain
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Josep Samitier
1Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology (BIST), Carrer Baldiri Reixac 15-21, 08024 Barcelona, Spain
6Department of Electronic and Biomedical Engineering, Faculty of Physics, University of Barcelona, Carrer Martí I Franquès 1, 08028 Barcelona, Spain
7Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
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Roey J. Amir
3Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel
4Tel Aviv University Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 6997801, Israel
5BLAVATNIK CENTER for Drug Discovery, Tel-Aviv University, Tel-Aviv 6997801, Israel
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  • For correspondence: l.albertazzi@tue.nl amirroey@tauex.tau.ac.il
Silvia Pujals
1Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology (BIST), Carrer Baldiri Reixac 15-21, 08024 Barcelona, Spain
6Department of Electronic and Biomedical Engineering, Faculty of Physics, University of Barcelona, Carrer Martí I Franquès 1, 08028 Barcelona, Spain
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Lorenzo Albertazzi
1Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology (BIST), Carrer Baldiri Reixac 15-21, 08024 Barcelona, Spain
2Department of Biomedical Engineering, Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5612AZ Eindhoven, The Netherlands
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  • ORCID record for Lorenzo Albertazzi
  • For correspondence: l.albertazzi@tue.nl amirroey@tauex.tau.ac.il
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ABSTRACT

The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by confronting different barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix and eventually cancer cell membranes. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is a key factor for the rational design of these systems. One of the key challenges is that current 2D in vitro models do not provide exhaustive information, as they do not fully recapitulate the 3D tumor microenvironment. This deficiency of the 2D models complexity is the main reason for the differences observed in vivo when testing the performance of supramolecular nanocarriers. Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic tumor-on-a-chip. The combination of advanced imaging and a reliable organ-on-a-chip model allow us to track micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation followed during the crossing of barriers by spectral imaging, revealing the interplay between carrier structure, micellar stability and extravasation. Integrating the ability of the micelles to change their fluorescent properties when disassembled, spectral confocal imaging and 3D microfluidic tumor blood vessel-on-a-chip, resulted in the establishment of a robust testing platform, suitable for real-time imaging and evaluation of supramolecular drug delivery carrier’s stability.

  • ABBREVIATIONS

    DDS
    drug delivery systems
    DMEM
    Dulbecco’s Modified Eagle Medium
    EB
    endothelial barrier
    ECs
    Endothelial Cells
    ECM
    extracellular matrix
    EPR
    Endothelial Permeability and Retention effect
    (FRET)
    Förster Resonance Energy Transfer
    HUVEC
    Human Umbilical Vein Endothelial Cells
    NPs
    nanoparticles
    TME
    Tumor Microenvironment
  • Copyright 
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    Posted March 09, 2020.
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    Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip
    Natalia Feiner-Gracia, Adrianna Glinkowska Mares, Marina Buzhor, Romen Rodriguez-Trujillo, Josep Samitier, Roey J. Amir, Silvia Pujals, Lorenzo Albertazzi
    bioRxiv 2020.03.08.978783; doi: https://doi.org/10.1101/2020.03.08.978783
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    Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip
    Natalia Feiner-Gracia, Adrianna Glinkowska Mares, Marina Buzhor, Romen Rodriguez-Trujillo, Josep Samitier, Roey J. Amir, Silvia Pujals, Lorenzo Albertazzi
    bioRxiv 2020.03.08.978783; doi: https://doi.org/10.1101/2020.03.08.978783

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