Site-Directed Nanotherapeutics to Abrogate RRMS and Promote Remyelination Repair
Abstract
Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the human central nervous system. 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)-4/7 inhibitors can prevent injury-induced reductions of cAMP as well as facilitate tissue protection, anatomical repair, and functional recovery. PDE inhibitor containing nanoparticles (NP), surface modified with peptides that recognize proteins extravasated at sites of vascular disruption (clotting factors, ECM), can accumulate at regions of CNS demyelination, reducing tissue injury and promoting remyelination repair at very low drug doses. Characterization of non-functionalized polymeric (poly(ethylene glycol-b- -caprolactone)) NP demonstrated a size range of 28-42nm, no surface charge and a low polydispersity index. Size varied depending on amount of aminated PEG-b-PCL+peptide incorporated. NP allowed inclusion of fluorescent dyes (DiI, DiO) and the PDE-inhibitors Rolipram and BRL50481. 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 37C, after which NP started to aggregate/disassemble. Functionalization of the NP with peptides (i.e. NQEQVSP, DPEAAE and NIDPNAV) improved adherence in fibrin gels (blood clots) or tissue sections of the injured spinal cord (contusion type injury, explanted 1 week after injury).
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2012
- Accession Number
- ADA575578
Entities
People
- Damien D Pearse
- Mousumi Ghosh
- Paul Dalton
- Tobias Fuehrmann
Organizations
- Queensland University of Technology