In this work we show the zebrafish embryo can be used to identify the mechanisms which determine nanoparticle fate in vivo. Through this approach, we discovered that many administered liposomes – as well as other nanoparticles commonly used for drug delivery - are cleared from circulation by a specialized endothelial cell type, previously unknown within the zebrafish embryo. Importantly, we show these cells are homologous to mammalian liver sinusoidal endothelial cells (LSECs) and can therefore be defined as scavenging endothelial cells (SECs). Having identified this cell type, we are able to show, for the first time, SEC differentiation during early embryonic development. In mammals, up to 99% of the injected nanoparticle dose is cleared by the liver. The current paradigm is that within the liver, nanoparticles are cleared by the mononuclear phagocyte system (MPS). Our results direct challenge this paradigm and show SECs are a complementary cell-type critical for clearance of nanoparticles. So far, mechanistic studies have focused on nanoparticle clearance by the MPS. In this work, we uncover the biological mechanism underpinning nanoparticle-SEC interactions in zebrafish, revealing nanoparticle binding and uptake is dominated by a single scavenger receptor, stabilin-2. In mammals, this receptor is selectively expressed by LSECs. With this knowledge, we are able to not only exploit nanoparticle-SEC interactions to demonstrate SEC-specific drug delivery and selective deletion of a single blood vessel in the zebrafish embryo but also prevent these interactions through injection of a competitive Stabilin-2 inhibitor. This method radically alters nanoparticle biodistribution in vivo and provides a novel rationale for minimising off-target nanoparticle interactions with the human liver. Targeting inefficiencies of reported nanoparticle-based drug delivery systems have recently come under scrutiny. In the vast majority of cases, failure to efficiently target specific cells and tissues is compounded by nanoparticle-liver interactions. By revealing a key interaction between administered nanoparticles and the SECs of the mammalian liver, this work is of fundamental interest to all those wishing to apply nanotechnologies in vivo.

Selective blood vessel deletion using nanoparticle-mediated drug delivery in zebrafish embryos

255th National Meeting (2018)

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