title: Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.
abstract: The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.
authors.affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Turjeman
authors.affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yaelle
authors.initials: Y
authors.lastname: Bavli
authors.affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Pablo
authors.initials: P
authors.lastname: Kizelsztein
authors.affiliation: The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.
authors.forename: Yaelle
authors.initials: Y
authors.lastname: Schilt
authors.affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Nahum
authors.initials: N
authors.lastname: Allon
authors.affiliation: BioImage MRI Research & Consulting, Tel Aviv, Israel.
authors.forename: Tamar Blumenfeld
authors.initials: TB
authors.lastname: Katzir
authors.affiliation: BioImage MRI Research & Consulting, Tel Aviv, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Sasson
authors.affiliation: The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Raviv
authors.affiliation: Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Ovadia
authors.affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry*; D008776:Methylprednisolone Hemisuccinate / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D003497:Cyclic N-Oxides; D008081:Liposomes; D011355:Prodrugs; C015527:4-amino-TEMPO; D008776:Methylprednisolone Hemisuccinate