Universiteit Leiden

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Research project

Exploring the mechanism of targeted nanoparticle-mediated drug delivery using the zebrafish model

Exploring the mechanism of targeted nanoparticle-mediated drug delivery using the zebrafish model

Wim Jiskoot

Nanoparticle-mediated drug delivery promises to reduce side effects while improving therapeutic efficacy of drugs through increased concentration at the site of disease1. Multiple methods have been developed that aim to achieve this: in passive targeting, particles accumulate at sites of increased vascular permeability and reduced lymphatic drainage – most prominently in solid tumors2. Responsive nanoparticles can accumulate through application of external stimuli. Finally, in active targeting, nanoparticles contain a targeting ligand that binds to membrane receptors on pathologic cells, and ideally release the therapeutic agent intracellularly (for example, by inducing receptor-mediated endocytosis3). Although this provides an optimal concept for diseased cell-specific drug delivery, translation to patients has so far been limited. Therefore, we propose to study active targeting of nanoparticles using a simple model system – the zebrafish embryo – in order to define the critical steps that are required to achieve truly cell-specific drug delivery. The zebrafish model has several important advantages over traditional animal models. Their transparent embryos allow direct visualization of nanoparticle distribution in vivo4. By using CRISPR/Cas9 technology, we can knock out the targeted receptor in zebrafish and observe the actively targeted nanoparticle’s biodistribution in mutant and wild type zebrafish directly. Finally, a range of genetic tools exist that allow the visualization of nanoparticle-cell interaction and intracellular trafficking in vivo5. Together, this projecte aims to provide general principles for cell-specific drug delivery to improve clinical translation of actively targeted drug delivery

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