title: Nanotoxicity of poly(n-butylcyano-acrylate) nanoparticles at the blood-brain barrier, in human whole blood and in vivo.
abstract: Therapy of diseases of the central nervous system is a major challenge since drugs have to overcome the blood-brain barrier (BBB). A powerful strategy to enhance cerebral drug concentration is administration of drug-loaded poly(n-butylcyano-acrylate) (PBCA) nanoparticles coated with polysorbate 80 (PS80). This study evaluates the toxicity of PBCA-nanoparticles at the BBB, representing the target organ, the inflammatory response in human whole blood, as the site of administration and in a rat model in vivo. PBCA-nanoparticles were prepared by a mini-emulsion method and characterized concerning size, surface charge, shape and PS80-adsorption. The influence on metabolic activity, cell viability and integrity of the BBB was analyzed in an in vitro model of the BBB. In ex vivo experiments in human whole blood the release of 12 inflammatory cytokines was investigated. In addition, the inflammatory response was studied in vivo in rats and complemented with the analysis of different organ toxicity parameters. PBCA-nanoparticles showed time- and concentration-dependent effects on metabolic activity, cell viability and BBB integrity. No cell death or loss of metabolic activity was observed for nanoparticle-concentrations ≤500μg/ml up to 3h of treatment. Within 12 tested inflammatory cytokines, only interleukin-8 displayed a significant release after nanoparticle exposure in human blood. No severe inflammatory processes or organ damages were identified in rats in vivo. Thus, PBCA-nanoparticles are a promising drug delivery system to overcome the BBB since they showed hardly any cytotoxic or inflammatory effect at therapeutic concentrations and incubation times.
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany. Electronic address: kolter@uni-heidelberg.de.
authors.forename: Marise
authors.initials: M
authors.lastname: Kolter
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hauer
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Isolde
authors.initials: I
authors.lastname: Reimold
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany. Electronic address: gert.fricker@uni-hd.de.
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
mesh_terms: D000327:Adsorption; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004659:Enbucrilate / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D010078:Oxazines / Q000378:metabolism; D011136:Polysorbates / Q000737:chemistry; D017208:Rats, Wistar; D013552:Swine; D014966:Xanthenes / Q000378:metabolism
chemical_list: D016207:Cytokines; D010078:Oxazines; D011136:Polysorbates; D014966:Xanthenes; C005843:resazurin; D007770:L-Lactate Dehydrogenase; D004659:Enbucrilate
keywords: Blood–brain barrier; Cytokine; Human blood; Nanoparticle; PBCA; Toxicity