title: Nanoparticle toxicity assessment using an in vitro 3-D kidney organoid culture model.
abstract: Nanocarriers and nanoparticles remain an intense pharmaceutical and medical imaging technology interest. Their entry into clinical use is hampered by the lack of reliable in vitro models that accurately predict in vivo toxicity. This study evaluates a 3-D kidney organoid proximal tubule culture to assess in vitro toxicity of the hydroxylated generation-5 PAMAM dendrimer (G5-OH) compared to previously published preclinical in vivo rodent nephrotoxicity data. 3-D kidney proximal tubule cultures were created using isolated murine proximal tubule fractions suspended in a biomedical grade hyaluronic acid-based hydrogel. Toxicity in these cultures to neutral G5-OH dendrimer nanoparticles and gold nanoparticles in vitro was assessed using clinical biomarker generation. Neutral PAMAM nanoparticle dendrimers elicit in vivo-relevant kidney biomarkers and cell viability in a 3-D kidney organoid culture that closely reflect toxicity markers reported in vivo in rodent nephrotoxicity models exposed to this same nanoparticle.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA.
authors.forename: Anna I
authors.initials: AI
authors.lastname: Astashkina
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA.
authors.forename: Clint F
authors.initials: CF
authors.lastname: Jones
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112-5820, USA.
authors.forename: Giridhar
authors.initials: G
authors.lastname: Thiagarajan
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT 84112-5820, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Kurtzeborn
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112-5820, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112-5820, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Ghandehari
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Brooks
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112-5820, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112-5820, USA. Electronic address: david.grainger@utah.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Grainger
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D050091:Dendrimers / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000633:toxicity*; D009940:Organoids / Q000187:drug effects*; D046509:Tissue Culture Techniques / Q000379:methods*; D018675:Toxicity Tests
chemical_list: D015415:Biomarkers; D016207:Cytokines; D050091:Dendrimers; C104700:PAMAM Starburst
keywords: 3-D cell culture; Gold nanoparticles; In vitro–in vivo correlations; Nephrotoxicity; PAMAM dendrimers; Proximal tubules