title: In vivo and in vitro toxicity and anti-inflammatory properties of gold nanoparticle bioconjugates to the vascular system.
abstract: Gold nanoparticle (AuNP) bioconjugates have been used as therapeutic and diagnostic tools; however, in vivo biocompatibility and cytotoxicity continue to be two fundamental issues. The effect of AuNPs (20 nm) conjugated with antibody [immunoglobulin G (IgG)], albumin, protein A, PEG4000, and citrate (cit) were evaluated in vitro using primary human cells of the vascular system. AuNP bioconjugates did not cause lysis of human erythrocytes, apoptosis or necrosis of human leukocytes, and endothelial cells in vitro, although AuNPs had been internalized and detected in the cytoplasm. Moreover, the influence of AuNPs on rheological parameters, blood and vessel wall characteristics was investigated in vivo by intravital microscopy assay using male Wistar rats mesentery microcirculation as model. Intravenous injection of AuNP-IgG or cit-AuNP did not cause hemorrhage, hemolysis or thrombus formation, instead suppressed the leukocyte adhesion to postcapillary vessel walls, an early stage of an inflammatory process. Furthermore, AuNP-IgG abrogated the expression of platelet-endothelial cell adhesion molecule-1, chemotaxis, and oxidative burst activation on neutrophils after leukotriene B4 stimulation, a membrane receptor-dependent stimulus, thus confirming their anti-inflammatory effects in vitro. The expression of oxidative burst activation was also suppressed after stimulating AuNP-IgG-treated neutrophils with lipid-soluble phorbol myristate acetate (PMA), confirming the direct intracellular action of AuNP-IgG on the inflammatory process in vitro. Our in vitro and in vivo experimental approaches highlighted the great potentiality of AuNP bioconjugates for therapeutic and diagnostic applications by parenteral routes.
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Mayara Klimuk
authors.initials: MK
authors.lastname: Uchiyama
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Daiana Kotra
authors.initials: DK
authors.lastname: Deda
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Stephen Fernandes de Paula
authors.initials: SF
authors.lastname: Rodrigues
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Carine Cristiane
authors.initials: CC
authors.lastname: Drewes
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Simone Marques
authors.initials: SM
authors.lastname: Bolonheis
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Pedro Kunihiko
authors.initials: PK
authors.lastname: Kiyohara
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Simone Perche de
authors.initials: SP
authors.lastname: Toledo
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Walter
authors.initials: W
authors.lastname: Colli
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil koiaraki@iq.usp.br.
authors.forename: Koiti
authors.initials: K
authors.lastname: Araki
authors.affiliation: *Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, 05508-000, Sao Paulo, Brazil, Department of General Physics, Institute of Physics, University of Sao Paulo, 05508-090, Sao Paulo, Brazil and Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000, Sao Paulo, Brazil.
authors.forename: Sandra Helena Poliselli
authors.initials: SH
authors.lastname: Farsky
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D001783:Blood Flow Velocity / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006046:Gold / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D006461:Hemolysis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010316:Particle Size; D017208:Rats, Wistar; D013499:Surface Properties
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001672:Biocompatible Materials; D007074:Immunoglobulin G; D006046:Gold
keywords: cytoviva; erythrocytes; human leukocytes; intravital microscopy; leukocyte-endothelial interactions; neutrophils