Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases

PLoS One. 2015 Jul 6;10(7):e0130442. doi: 10.1371/journal.pone.0130442. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • Apolipoproteins E / metabolism
  • Cyclic N-Oxides / chemistry
  • Cyclic N-Oxides / pharmacokinetics
  • Cyclic N-Oxides / pharmacology
  • Disease Models, Animal
  • Drug Delivery Systems / methods
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Liposomes / chemistry*
  • Methylprednisolone Hemisuccinate / chemistry
  • Methylprednisolone Hemisuccinate / pharmacokinetics
  • Methylprednisolone Hemisuccinate / pharmacology
  • Mice
  • Multiple Sclerosis / drug therapy
  • Multiple Sclerosis / metabolism
  • Nanoparticles / chemistry*
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / metabolism
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Tissue Distribution

Substances

  • Amyloid beta-Peptides
  • Anti-Inflammatory Agents
  • Apolipoproteins E
  • Cyclic N-Oxides
  • Liposomes
  • Prodrugs
  • 4-amino-TEMPO
  • Methylprednisolone Hemisuccinate

Grant support

This study was supported in part by the Barenholz Fund. The Barenholz Fund is a fund established by Professor Barenholz from royalties that the Hebrew University and Professor Barenholz get from various patents which are dedicated to support research in his lab. There are no connections between the patents for which he gets the royalties and this research, so it is basically a research fund. The other support was the Hebrew University regular support system. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors TBK and ES are employed by BioImage MRI Research & Consulting. The company was hired to perform the MRI and to process the data obtained but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.