Site-directed Nanotherapeutics to Abrogate RRMS and Promote Remyelination Repair (Rev)

Abstract

Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the human CNS. The clinical disease course is variable and starts with reversible episodes of neurological disability (remitting relapsing (RR-MS) stage). This transforms into a disease of continuous and irreversible neurological decline. Phosphodiesterase (PDE) inhibitors can prevent injury-induced reductions of cyclic AMP as well as facilitate tissue protection, anatomical repair, and functional recovery. We hypothesized that PDE inhibitor containing nanoparticles (NP), surface modified with peptides that recognize proteins extravasated at sites of vascular disruption (clotting factors, ECM), would accumulate at regions of CNS demyelination, reducing tissue injury and promote remyelination repair at very low drug doses. Initial work for this award focused on the characterization of polymeric (poly(ethylene glycol-b- -caprolactone)) NP size, fluorescent dye or drug incorporation and their functionalization with surface peptides for site-directed targeting. It was demonstrated that peptides (i.e. NQEQVSP, DPEAAE and NIDPNAV) can be conjugated to the aminated PEG-b-PCL and that PEG-b-PCL NPs can readily encapsulate fluorescent dyes (DiI, DiO) and PDE inhibitors (Rolipram and BRL-50481). Whereas the loading efficiency of the fluorescent dyes was high (~45% and 80% respectively), drug loading was low in comparison, but could be improved by using more polymer. The drugs were released slowly over three weeks at 370C, after which the NPs started to aggregate/disassemble. Functionalization of the NP with peptides improved adherence in fibrin gels (blood clots) or onto tissue sections of injured spinal cord.

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Document Details

Document Type
Technical Report
Publication Date
Mar 01, 2013
Accession Number
ADA586059

Entities

People

  • Damien D Pearse
  • Mousumi Ghosh
  • Paul Dalton
  • Tim Dargaville
  • Tobias Fuehrmann

Organizations

  • University of Miami

Tags

Communities of Interest

  • Biomedical

DTIC Thesaurus Topics

  • Alkenes
  • Blood
  • Blood-Brain Barrier
  • Central Nervous System
  • Chemical Synthesis
  • Chemistry
  • Confocal Microscopy
  • Diseases And Disorders
  • Dyes
  • Ethylene Glycol
  • Fluorescent Dyes
  • Medical Personnel
  • Multiple Sclerosis
  • Nervous System
  • Polymers
  • Proteins
  • Spinal Cord

Fields of Study

  • Medicine

Readers

  • Aerial Delivery - Logistics and Supply Chain Management.
  • Immunology and Pathology
  • Molecular Genetics

Technology Areas

  • Biotechnology