Zebrafish as a Predictive Screening Model to Assess Macrophage Clearance of Liposomes In Vivo

Authors: S. Sieber, P. Grossen, P. Uhl, P. Detampel, W. Mier, D. Witzigmann, J. Huwyler

Journal: Nanomedicine: Nanotechnology, Biology and MEdicine

DOI: 10.1016/j.nano.2018.11.017

Publication - Summary

January 17, 2019


The Witzigmann and Huwyler labs at the University of Basel examined the in vivo clearance of previously approved liposome formulations in zebrafish embryos and rats to demonstrate that zebrafish embryos provide similar results while being are a cheaper and faster to study. They compared the in vivo clearance of formulations containing Polyethylene glycol lipids (PEG-lipids) with different PEG molecular weights and molar quantities. PEG content in such formulations however have a strong effect on liposome size and size distribution (polydispersity index), which in turn affects in vivo fate. Hence, to make fair comparisons between PEG length and density, they used the NanoAssemblr Benchtop to tune liposome size to be similar across formulations. This would otherwise be very difficult to control through other methods of liposome production. They found liposome clearance behaved similarly in zebrafish embryos and rats, making zebrafish embryos a cheaper and faster model in which to study biodistribution and clearance while maintaining representative results. The paper is available online and will appear in print in the April 2019 volume of Nanomedicine: Nanotechnology, Biology and Medicine.


Macrophage recognition of nanoparticles is highly influenced by particle size and surface modification. Due to the lack of appropriate in vivo screening models, it is still challenging and time-consuming to characterize and optimize nanomedicines regarding this undesired clearance mechanism. Therefore, we validate zebrafish embryos as an emerging vertebrate screening tool to assess the macrophage sequestration of surface modified particulate formulations with varying particle size under realistic biological conditions. Liposomes with different PEG molecular weights (PEG350-PEG5000) at different PEG densities (3.0-10.0 mol%) and particle sizes between 60 and 120 nm were used as a well-established reference system showing various degrees of macrophage uptake. The results of in vitro experiments, zebrafish embryos, and in vivo rodent biodistribution studies were consistent, highlighting the validity of the newly introduced zebrafish macrophage clearance model. We hereby present a strategy for efficient, systematic and rapid nanomedicine optimization in order to facilitate the preclinical development of nanotherapeutics.

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