Zebrafish as a preclinical in vivo screening model for nanomedicines

Sieber, Sandro; Grossen, Philip; Bussmann, Jeroen; Campbell, Frederick; Kros, Alexander; Witzigmann, Dominik; Huwyler, Jörg

doi:10.1016/j.addr.2019.01.001

Cited by 122 publications

(109 citation statements)

References 233 publications

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“…The zebrafish embryo is rapidly becoming an attractive tool for screening nanoparticles . This transparent vertebrate system develops rapidly, and already after 48 h a beating heart and robust blood circulation are readily observable under a stereomicroscope .…”

Section: Introductionmentioning

confidence: 99%

Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle–Cell Interactions

Dal

Kocere

Wohlmann

et al. 2020

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The zebrafish embryo is a vertebrate well suited for visualizing nanoparticles at high resolution in live animals. Its optical transparency and genetic versatility allow noninvasive, real‐time observations of vascular flow of nanoparticles and their interactions with cells throughout the body. As a consequence, this system enables the acquisition of quantitative data that are difficult to obtain in rodents. Until now, a few studies using the zebrafish model have only described semiquantitative results on key nanoparticle parameters. Here, a MACRO dedicated to automated quantitative methods is described for analyzing important parameters of nanoparticle behavior, such as circulation time and interactions with key target cells, macrophages, and endothelial cells. Direct comparison of four nanoparticle (NP) formulations in zebrafish embryos and mice reveals that data obtained in zebrafish can be used to predict NPs' behavior in the mouse model. NPs having long or short blood circulation in rodents behave similarly in the zebrafish embryo, with low circulation times being a consequence of NP uptake into macrophages or endothelial cells. It is proposed that the zebrafish embryo has the potential to become an important intermediate screening system for nanoparticle research to bridge the gap between cell culture studies and preclinical rodent models such as the mouse.

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Section: Introductionmentioning

confidence: 99%

Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle–Cell Interactions

Dal

Kocere

Wohlmann

et al. 2020

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“…In addition, it shares high degree of genetic conservation which makes it have additional advantages over traditional animal models (Crawford et al, 2008;Jia et al, 2019). Moreover, one major advantage is that malformation and organogenesis toxicity induced by chemicals can be readily and directly observed under stereo-or fluorescencemicroscope at the early developmental stage of zebrafish (Heideman et al, 2005;Sieber et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Developmental Toxicity Induced by E804 in Zebrafish Embryos

et al. 2020

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E804, a derivative of indirubin, have multi-biological activities such as anticancer and antiinflammatory activities, but little is known about its developmental toxicity. In this study, we investigated the toxicity of E804 on the developments of zebrafish embryos. Our results showed that E804 treatment caused a significant increase of the malformation rate compared with the control groups. Pericardial edema and curved body shape were the most morphological abnormalities observed in E804-treated group. The hatching rates and body length of the zebrafish larvae was significantly decreased in E804-treated groups. E804 also affect the development of heart, liver, phagocytes and vascular formation. Further studies showed that the level of reactive oxygen species was significantly increased. The activity of total superoxide dismutase decreased and the concentration of malondialdehyde were increased. Much more apoptotic cells were detected in E804-treated group, compared with the control. In addition, geneexpression results showed that the pathways of oxidative stress and apoptosis were provoked in E804 treated groups. Taken together, our findings will be helpful to understanding E804-induced developmental toxicity and the underlying mechanism.

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“…In order to study the pharmacokinetics of liposomes with different surface modifications, we selected the zebrafish model as a validated in vivo tool to assess circulation properties and macrophage clearance …”

Section: Introductionmentioning

confidence: 99%

Poly(Sarcosine) Surface Modification Imparts Stealth‐Like Properties to Liposomes

Bleher

Buck

Muhl

et al. 2019

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Thereby, one of the main goals of liposomes is to protect the entrapped drug while also reducing its off-site toxicity, as shown for multiple formulations. [5][6][7][8] To this end, increasing on-target tissue concentration is a key aspect which can be achieved both by nontargeted and targeted liposomes. [9][10][11][12] In this regard, a crucial point is the prolongation of systemic circulation lifetime. It is well-known that upon injection the majority of conventional (plain) liposomes are cleared rapidly from the blood stream by cells of the mononuclear phagocyte system. [13][14][15] To enhance circulation times, a variety of approaches to modify the surface of liposomes emerged, [16][17][18] yet ultimately polyethylene glycol (PEG) established itself as gold standard in the early 1990s aiming at decreasing opsonization. [19][20][21] PEGylation not only reduces but also alternates the recognition of nanoparticles by complement factors and opsonins, resulting in a decreased nanoparticle recognition and clearance by macrophages. [22,23] Manipulating opsonization, including the reduction of complement activation thus is one of the main goals in preventing rapid clearance.Today, surface modifications of liposomes are mostly realized with amphiphilic lipid-polymer conjugates like 1,2-distearoyl-snglycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-mPEG2k). [24,25] Despite the benefits and being considered mostly nonimmunogenic, phospholipid-PEG conjugates have also demonstrated some drawbacks over the Circulation lifetime is a crucial parameter for a successful therapy with nanoparticles. Reduction and alteration of opsonization profiles by surface modification of nanoparticles is the main strategy to achieve this objective. In clinical settings, PEGylation is the most relevant strategy to enhance blood circulation, yet it has drawbacks, including hypersensitivity reactions in some patients treated with PEGylated nanoparticles, which fuel the search for alternative strategies. In this work, lipopolysarcosine derivatives (BA-pSar, bisalkyl polysarcosine) with precise chain lengths and low polydispersity indices are synthesized, characterized, and incorporated into the bilayer of preformed liposomes via a post insertion technique. Successful incorporation of BA-pSar can be realized in a clinically relevant liposomal formulation. Furthermore, BA-pSar provides excellent surface charge shielding potential for charged liposomes and renders their surface neutral. Pharmacokinetic investigations in a zebrafish model show enhanced circulation properties and reduction in macrophage recognition, matching the behavior of PEGylated liposomes. Moreover, complement activation, which is a key factor in hypersensitivity reactions caused by PEGylated liposomes, can be reduced by modifying the surface of liposomes with an acetylated BA-pSar derivative. Hence, this study presents an alternative surface modification strategy with similar benefits as the established PEGylation of nanoparticles, but with the potential...

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Zebrafish as a preclinical in vivo screening model for nanomedicines

Cited by 122 publications

References 233 publications

Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle–Cell Interactions

Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle–Cell Interactions

Evaluation of the Developmental Toxicity Induced by E804 in Zebrafish Embryos

Poly(Sarcosine) Surface Modification Imparts Stealth‐Like Properties to Liposomes

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