title: Imidazole-stabilized gold nanoparticles induce neuronal apoptosis: an in vitro and in vivo study.
abstract: Gold nanoparticles are increasingly being employed in innovative biological applications thanks to their advantages of material- and size-dependent physics and chemical interactions with the cellular systems. On the other hand, growing concern has emerged on the toxicity which would render gold-based nanoparticles harmful to cell cultures, animals, and humans. Emerging attention is focused on the interaction of gold nanoparticles with nervous system, especially regarding the ability to overcome the blood-brain barrier (BBB) which represents the major impediment to the delivery of therapeutics into the brain. We synthesized highly stable 2-mercapto-1-methylimidazole-stabilized gold-nanoparticles (AuNPs)-mmi to investigate their entry, accumulation, and toxicity in vitro (SH-SY5Y human neuroblastoma cells) and in vivo (brain of C57BL/6 mice) through optical and electron microscopy. After incubation in the cell culture medium at the lowest dose of 0.1 mg/mL the (AuNPs)-mmi nanoparticles were found compacted and recruited into endosome/lysosomes (1 h) before their fusion (2 h) and the onset of neuronal death by apoptosis (4 h) as proved by terminal-transferase-mediated dUTP nick end labeling assay and caspase-3 immunoreactivity. The ability of (AuNPs)-mmi to cross the BBB was assessed by injection in the caudal vein of C57BL/6 mice. Among different brain regions, the nanoparticles were found in the CaudatoPutamen area, mainly in the striatal neurons 4 h after injection. These neurons showed the typical hallmarks of apoptosis. Our findings provide, for the first time, the dynamic of 2-mercapto-1-methylimidazole nanogold uptake. The molecular mechanism which underlies the nanogold-driven apoptotic event is analyzed and discussed in order to take into account when designing nanomaterials to interface with biological structures.
authors.affiliation: Institute of Biomolecular Chemistry, CNR of Pozzuoli, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Imperatore
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Carotenuto
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Di Grazia
authors.forename: Ida
authors.initials: I
authors.lastname: Ferrandino
authors.forename: Letizia
authors.initials: L
authors.lastname: Palomba
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mariotti
authors.forename: Emilia
authors.initials: E
authors.lastname: Vitale
authors.forename: Sergio
authors.initials: S
authors.lastname: De Nicola
authors.forename: Angela
authors.initials: A
authors.lastname: Longo
authors.forename: Luigia
authors.initials: L
authors.lastname: Cristino
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D006046:Gold / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D007093:Imidazoles; D006046:Gold; C029899:imidazole
keywords: apoptosis; blood-brain barrier; cytotoxicity; neuroblastoma; thiolato ligands