title: Magnetic nanoparticles for drug targeting: from design to insights into systemic toxicity. Preclinical evaluation of hematological, vascular and neurobehavioral toxicology.
abstract: A simple two-step drug encapsulation method was developed to obtain biocompatible magnetic nanocarriers for the potential targeted treatment of diverse diseases. The nanodevice consists of a magnetite core coated with chitosan (Chit@MNPs) as a platform for diclofenac (Dic) loading as a model drug (Dic-Chit@MNPs). Mechanistic and experimental conditions related to drug incorporation and quantification are further addressed. This multi-disciplinary study aims to elucidate the toxicological impact of the MNPs at hematological, vascular, neurological and behavioral levels. Blood compatibility assays revealed that MNPs did not affect either erythrosedimentation rates or erythrocyte integrity at the evaluated doses (1, 10 and 100 μg mL-1). A microscopic evaluation of blood smears indicated that MNPs did not induce morphological changes in blood cells. Platelet aggregation was not affected by MNPs either and just a slight diminution was observed with Dic-Chit@MNPs, an effect possibly due to diclofenac. The examined formulations did not exert cytotoxicity on rat aortic endothelial cells and no changes in cell viability or their capacity to synthesize NO were observed. Behavioral and functional nervous system parameters in a functional observational battery were assessed after a subacute treatment of mice with Chit@MNPs. The urine pools of the exposed group were decreased. Nephritis and an increased number of megakaryocytes in the spleen were observed in the histopathological studies. Sub-acute exposure to Chit@MNPs did not produce significant changes in the parameters used to evaluate neurobehavioral toxicity. The aspects focused on within this manuscript are relevant at the pre-clinical level providing new and novel knowledge concerning the biocompatibility of magnetic nanodevices for biomedical applications.
authors.affiliation: INQUISUR, Departamento de Química, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Argentina. magotegaray@uns.edu.ar.
authors.forename: Mariela A
authors.identifier: http://orcid.org/0000-0002-0206-306X
authors.initials: MA
authors.lastname: Agotegaray
authors.affiliation: Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET)-UNS Dpto. de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: Adrián E
authors.initials: AE
authors.lastname: Campelo
authors.affiliation: CONICET - Centro Atómico Bariloche, Instituto Balseiro, S.C. de Bariloche, Argentina.
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Zysler
authors.affiliation: Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET)-UNS Dpto. de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Gumilar
authors.affiliation: Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET)-UNS Dpto. de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bras
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB-CONICET)-UNS Dpto. de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: Ariel
authors.initials: A
authors.lastname: Gandini
authors.affiliation: Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET)-UNS Dpto. de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Minetti
authors.affiliation: Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET)-UNS Dpto. de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Massheimer
authors.affiliation: INQUISUR, Departamento de Química, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca, Argentina. magotegaray@uns.edu.ar.
authors.forename: Verónica L
authors.initials: VL
authors.lastname: Lassalle
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D048271:Chitosan / Q000737:chemistry / Q000633:toxicity*; D004008:Diclofenac / Q000008:administration & dosage*; D004337:Drug Carriers / Q000737:chemistry / Q000633:toxicity*; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D058185:Magnetite Nanoparticles / Q000737:chemistry / Q000633:toxicity* / Q000648:ultrastructure; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004337:Drug Carriers; D058185:Magnetite Nanoparticles; D004008:Diclofenac; D009569:Nitric Oxide; D048271:Chitosan