title: Charge effect of a liposomal delivery system encapsulating simvastatin to treat experimental ischemic stroke in rats.
abstract: OBJECTIVE
  Although the beneficial effects of statins on stroke have been widely demonstrated both in experimental studies and in clinical trials, the aim of this study is to prepare and characterize a new liposomal delivery system that encapsulates simvastatin to improve its delivery into the brain.
  
  
  METHODS
  In order to select the optimal liposome lipid composition with the highest capacity to reach the brain, male Wistar rats were submitted to sham or transitory middle cerebral arterial occlusion (MCAOt) surgery and treated (intravenous [IV]) with fluorescent-labeled liposomes with different net surface charges. Ninety minutes after the administration of liposomes, the brain, blood, liver, lungs, spleen, and kidneys were evaluated ex vivo using the Xenogen IVIS(®) Spectrum imaging system to detect the load of fluorescent liposomes. In a second substudy, simvastatin was assessed upon reaching the brain, comparing free and encapsulated simvastatin (IV) administration. For this purpose, simvastatin levels in brain homogenates from sham or MCAOt rats at 2 hours or 4 hours after receiving the treatment were detected through ultra-high-protein liquid chromatography.
  
  
  RESULTS
  Whereas positively charged liposomes were not detected in brain or plasma 90 minutes after their administration, neutral and negatively charged liposomes were able to reach the brain and accumulate specifically in the infarcted area. Moreover, neutral liposomes exhibited higher bioavailability in plasma 4 hours after being administered. The detection of simvastatin by ultra-high-protein liquid chromatography confirmed its ability to cross the blood-brain barrier, when administered either as a free drug or encapsulated into liposomes.
  
  
  CONCLUSIONS
  This study confirms that liposome charge is critical to promote its accumulation in the brain infarct after MCAOt. Furthermore, simvastatin can be delivered after being encapsulated. Thus, simvastatin encapsulation might be a promising strategy to ensure that the drug reaches the brain, while increasing its bioavailability and reducing possible side effects.
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona.
authors.forename: Mireia
authors.initials: M
authors.lastname: Campos-Martorell
authors.affiliation: Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and The Barcelona Institute of Science and Technology, Universitat Autònoma de Barcelona, Barcelona.
authors.forename: Mary
authors.initials: M
authors.lastname: Cano-Sarabia
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona.
authors.forename: Alba
authors.initials: A
authors.lastname: Simats
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona.
authors.forename: Mar
authors.initials: M
authors.lastname: Hernández-Guillamon
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosell
authors.affiliation: Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and The Barcelona Institute of Science and Technology, Universitat Autònoma de Barcelona, Barcelona; Institució Catalana de Recerca i Estudis Avançats (ICREA).
authors.forename: Daniel
authors.initials: D
authors.lastname: Maspoch
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona; Neurovascular Unit, Department of Neurology, Universitat Autònoma de Barcelona, Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
mesh_terms: D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy; D016503:Drug Delivery Systems / Q000379:methods*; D020244:Infarction, Middle Cerebral Artery; D007668:Kidney / Q000187:drug effects; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D017208:Rats, Wistar; D019821:Simvastatin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy*; D014018:Tissue Distribution
chemical_list: D008081:Liposomes; D019821:Simvastatin
keywords: brain; delivery; liposomes; rat; simvastatin; stroke