title: Lipid nanoparticles for brain targeting III. Long-term stability and in vivo toxicity.
abstract: OBJECTIVE
  The aim of the work was to assess the long-term stability and the safety of lipid nanoparticles intended for brain drug delivery.
  
  
  METHODS
  Lipid nanoparticles, prepared by high pressure homogenization, were stored at room temperature and 4°C and monitored for their mean hydrodynamic diameter and Gaussian distribution width over time. Cetylpalmitate and polysorbate(®) 80 chemical integrity were investigated by nuclear magnetic resonance on diagnostic signals. Nanoparticle toxicity was assessed in chicken embryos by chorioallantoic membrane assay and in rodents by brain histological evaluation.
  
  
  RESULTS
  Data showed nanoparticle stability at 4°C over a period of time of 4 years with only a limited particle size increase while at room temperature destabilization was observed after 9 months. Nuclear magnetic resonance investigation confirmed the absence (<5%) of chemical degradation of the lipid matrix and the surfactant after 4 years of storage at 4°C. Chorioallantoic membrane assay and rat brain histology showed the absence of acute toxicity corroborating previously published data.
  
  
  CONCLUSIONS
  Cetylpalmitate nanoparticle long-term physical and chemical stability, together with the in vivo safety, corroborate the existing evidences of the high value of colloidal lipids as parenteral formulations and carriers for brain drug delivery.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, University of Perugia, via del Liceo 1, 06123 Perugia, Italy. kaolino@unipg.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Blasi
authors.forename: Aurélie
authors.initials: A
authors.lastname: Schoubben
authors.forename: Giovanna
authors.initials: G
authors.lastname: Traina
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Lanfranco
authors.initials: L
authors.lastname: Barberini
authors.forename: Paolo Francesco
authors.initials: PF
authors.lastname: Alberti
authors.forename: Carlo
authors.initials: C
authors.lastname: Cirotto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ricci
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002626:Chemistry, Pharmaceutical; D002642:Chick Embryo; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000187:drug effects* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D053758:Nanoparticles; D036103:Nanotechnology; D010169:Palmitic Acids / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D010316:Particle Size; D011136:Polysorbates / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011312:Pressure; D017208:Rats, Wistar; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D013997:Time Factors
chemical_list: D010169:Palmitic Acids; D011136:Polysorbates
keywords: (1)H NMR; (1)H nuclear magnetic resonance; Acute toxicity; BBB; CAM; CP; Chorioallantoic membrane (CAM) assay; LDL; Long-term stability; NP; NPs; Nanoparticles (NPs); P80; PCS; PVDF; SDS; SLN; Solid lipid nanoparticles (SLN); TEM; TMS; blood–brain barrier; cetylpalmitate; chorioallantoic membrane; low density lipoprotein; nanoparticle; nanoparticles; photon correlation spectroscopy; polysorbate 80; polyvinylidene fluoride; sodium dodecyl sulfate; solid lipid nanoparticles; tetramethylsilane; transmission electron microscopy