title: Zebrafish as a model system for characterization of nanoparticles against cancer.
abstract: Therapeutic nanoparticles (NPs) have great potential to deliver drugs against human diseases. Encapsulation of drugs in NPs protects them from being metabolized, while they are delivered specifically to a target site, thereby reducing toxicity and other side-effects. However, non-specific tissue accumulation of NPs, for example in macrophages, especially in the spleen and liver is a general problem with many NPs being developed for cancer therapy. To address the problem of non-specific tissue accumulation of NPs we describe the development of the zebrafish embryo as a transparent vertebrate system for characterization of NPs against cancer. We show that injection of human cancer cells results in tumor-like structures, and that subsequently injected fluorescent NPs, either made of polystyrene or liposomes can be imaged in real-time. NP biodistribution and general in vivo properties can be easily monitored in embryos having selective fluorescent labeling of specific tissues. We demonstrate in vitro, by using optical tweezer micromanipulation, microscopy and flow cytometry that polyethylene glycol (PEG) coating of NPs decreases the level of adhesion of NPs to macrophages, and also to cancer cells. In vivo in zebrafish embryos, PEG coating resulted in longer NP circulation times, decreased macrophage uptake, and reduced adhesion to the endothelium. Importantly, liposomes were observed to accumulate passively and selectively in tumor-like structures comprised of human cancer cells. These results show that zebrafish embryo is a powerful system for microscopy-based screening of NPs on the route to preclinical testing.
authors.affiliation: Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway. g.w.griffiths@ibv.uio.no.
authors.forename: Lasse
authors.initials: L
authors.lastname: Evensen
authors.affiliation: Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway. g.w.griffiths@ibv.uio.no.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Johansen
authors.affiliation: Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway. g.w.griffiths@ibv.uio.no.
authors.forename: Gerbrand
authors.initials: G
authors.lastname: Koster
authors.affiliation: Department of Chemistry, University of Oslo, Sem Sælands vei 26, 0371, Oslo, Norway.
authors.forename: Kaizheng
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Herfindal
authors.affiliation: Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway. g.w.griffiths@ibv.uio.no.
authors.forename: Martin
authors.initials: M
authors.lastname: Speth
authors.affiliation: Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway. g.w.griffiths@ibv.uio.no.
authors.forename: Federico
authors.initials: F
authors.lastname: Fenaroli
authors.affiliation: Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway. g.w.griffiths@ibv.uio.no.
authors.forename: Jon
authors.initials: J
authors.lastname: Hildahl
authors.affiliation: Department of Chemistry, University of Oslo, Sem Sælands vei 26, 0371, Oslo, Norway.
authors.forename: Shahla
authors.initials: S
authors.lastname: Bagherifam
authors.affiliation: Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tulotta
authors.affiliation: Department of Tumour Biology, Oslo University Hospital Radiumhospital, Oslo, Norway.
authors.forename: Lina
authors.initials: L
authors.lastname: Prasmickaite
authors.affiliation: Department of Tumour Biology, Oslo University Hospital Radiumhospital, Oslo, Norway.
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mælandsmo
authors.affiliation: Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Ewa
authors.initials: E
authors.lastname: Snaar-Jagalska
authors.affiliation: Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway. g.w.griffiths@ibv.uio.no.
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry; D008846:Micromanipulation / Q000379:methods*; D008853:Microscopy; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy; D052898:Optical Tweezers; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011137:Polystyrenes / Q000737:chemistry; D014018:Tissue Distribution; D015027:Zebrafish / Q000196:embryology*
chemical_list: D005456:Fluorescent Dyes; D008081:Liposomes; D011108:Polymers; D011137:Polystyrenes; D011092:Polyethylene Glycols