Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis
Agnese Kocere,
Julien Resseguier,
Jens Wohlmann,
Frode Miltzow Skjeldal,
Shanawaz Khan,
Martin Speth,
Nils-Jørgen Knudsen Dal,
Matthew Yoke Wui Ng,
Noelia Alonso-Rodriguez,
Edoardo Scarpa,
Loris Rizzello,
Giuseppe Battaglia,
Gareth Griffiths,
Federico Fenaroli
Affiliations
Agnese Kocere
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Julien Resseguier
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Jens Wohlmann
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Frode Miltzow Skjeldal
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Shanawaz Khan
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Martin Speth
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Nils-Jørgen Knudsen Dal
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Matthew Yoke Wui Ng
University of Oslo, Domus Medica, Sognsvannsveien 9, 0317 Oslo, Norway
Noelia Alonso-Rodriguez
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Edoardo Scarpa
University College London, Department of Chemistry, 20 Gordon Street, WC1H 0AJ London, United Kingdom
Loris Rizzello
University of Milan, Department of Pharmaceutical Sciences, via Mangiagalli 25, 20133 Milan (Italy); Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona (Spain)
Giuseppe Battaglia
University College London, Department of Chemistry, 20 Gordon Street, WC1H 0AJ London, United Kingdom; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona (Spain); Institute for the Physics of Living Systems, University College London, Gower Street, London, WC1E 6BT, London, United Kingdom; Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 2308010 Barcelona, Spain
Gareth Griffiths
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway
Federico Fenaroli
University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway; Corresponding author.
Background: The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells. Methods: Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles. Findings: Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells. Interpretation: The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells. Funding: We received funding from the Norwegian research council and the Norwegian cancer society
