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Accession Number ADA575584
Title Site-Directed Nanotherapeutics to Abrogate RRMS and Promote Remyelination Repair.
Publication Date Sep 2012
Media Count 14p
Personal Author D. D. Pearse M. Ghosh P. Dalton T. Dargaville T. Fuehrmann
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)-4/7 inhibitors can prevent injuryinduced 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 revealed a size range of 28-36 nm when polymer or solvent concentrations were changed. Fixed solvent (28.57%) and polymer concentrations (3 mg) were chosen for further studies. NPs allowed inclusion of fluorescent dyes (DiI, DiO) and aminated PEG-b-PCL. Peptides (i.e. NQEQVSP, DPEAAE and NIDPNAV) can be conjugated to the aminated PEGb- PCL. PEG-b-PCL NPs can readily encapsulate PDE inhibitors (Rolipram and BRL-50481), when the drugs are used alone or in combination with DiI dye and the release kinetics of the NPs in solution show slow release up to 28 days. In an experimental EAE model of RR-MS, we demonstrate that non-functionalized DiI NPs fail to accumulate at sites of EAE lesions following systemic administration, at a time just prior to the appearance of pathological changes and behavioral deficits. In contrast, delivery of DiI laden, laminin- or fibrinogen-functionalized NPs, were found to be sequestered to CNS lesions.
Keywords Behavior
Central nervous system
Clinical medicine
Coagulation
Diseases
Dose rate
Drug delivery
Drugs
Dyes
Ethylene
Factor xiiia
Fibrin (Blood) clot
Fluorescent dyes
Interferon-1a
Irreversible processes
Kinetics
Laminin
Multiple sclerosis
Nanoparticles
Nerve fibers
Nervous system diseases
Neurology
Nidogen
Pathology
Peptides
Phosphodiesterase
Phosphodiesterase inhibitor
Polymers
Proteins
Remyelination repair
Sheaths(Anatomy)
Tenascin c
Tissues(Biology)
Versican
Wounds and injuries

 
Source Agency Non Paid ADAS
NTIS Subject Category 57E - Clinical Medicine
57W - Stress Physiology
Corporate Author Miami Univ., FL.
Document Type Technical report
Title Note Annual rept. 1 Sep 2011-31 Aug 2012.
NTIS Issue Number 1319
Contract Number W81XWH-10-1-0769

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