title: Clozapine-Loaded Polysorbate-Coated Polymeric Nanocapsules: Physico-Chemical Characterization and Toxicity Evaluation in Caenorhabditis elegans Model.
abstract: The aim of this work was to develop and characterize clozapine loaded polysorbate-coated polymeric nanocapsules and assess their toxicity in Caenorhabditis elegans, an invertebrate animal model. Formulations were prepared by nanoprecipitation method and characterized by particle size, zeta potential, pH, drug loading, entrapment efficiency and in vitro drug release. All nanocapsules prepared presented diameter around 140 nm, pH slightly acid and negative zeta potential. In vitro studies showed biphasic drug release from nanocapsules with decreasing of the release rate on nanoencapsulation. The t(1/2)beta of clozapine was 7.23 +/- 0.73 and 2.23 +/- 0.97 h for nanoencapsulated and free drug, respectively (p < 0.05), in pH 1.2 medium. Similar results were obtained in pH 6.8 buffer. Regarding toxicity evaluation, worms exposed to clozapine-loaded nanocapsules did not show the same mortality rate compared to others formulations, as the survival was significantly higher than the free drug treated-group. In addition, we observed that free clozapine decreased egg laying at the first reproductive day, whereas nanoencapsulated clozapine did not depict significant change of this parameter. Longevity assay showed no significant difference, demonstrating that the toxicological effects of clozapine observed in C. elegans are acute. In addition, we proved that free and nanoencapsulated clozapine were orally uptake by the worms, as determined by fluorescein-labeled nanocapsules. Then, the use of nanocapsules delayed the drug release and minimized the toxic effects of clozapine in worms, which can be used as a new animal model to evaluate the nanotoxicity of drug delivery systems.
authors.forename: BarbraKatyúscya Sanches
authors.initials: BS
authors.lastname: Moraes
authors.forename: Simone Machado
authors.initials: SM
authors.lastname: Vieira
authors.forename: Willian Goulart
authors.initials: WG
authors.lastname: Salgueiro
authors.forename: Luana Roberta
authors.initials: LR
authors.lastname: Michels
authors.forename: Letícia Marques
authors.initials: LM
authors.lastname: Colomé
authors.forename: Daiana Silva
authors.initials: DS
authors.lastname: Avila
authors.forename: Sandra Elisa
authors.initials: SE
authors.lastname: Haas
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D003024:Clozapine / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D053769:Nanocapsules / Q000737:chemistry*; D010316:Particle Size
chemical_list: D003692:Delayed-Action Preparations; D053769:Nanocapsules; D003024:Clozapine