Drug Delivery in das ZNS mittels Polymernanopartikel
Final Report Abstract
The endothelial cells of brain microvessels form the blood-brain barrier (BBB), which is impermeable for most drugs and drugs candidates, which are either too large, to hydrophobic and/or substrates of export proteins being highly expressed at the luminal surface of the endothelial cells. One possibility to overcome these drawbacks is the manufacture of nanoparticles, which are surface decorated in such a way, that they are recognized by receptors in the BBB and subsequently undergo transcytosis. In the present project nanoparticles were prepared from poly-butylcyanoacrylate by miniemulsion polymerization and loaded with rhodamin-123, doxorubicin or anti-biotin-IgG. Size, polydispersity index and surface charge of these particles were measured and their morphology was studied by transmission electron microscopy. The residual binding affinity of the IgG was appr. 45 % after disintegration of the nanoparticles. In addition, the shelf-stability of the nanoparticles was determined over a period of 1.5 years, endotoxin con-tent was clearly below the USP-limit of 0.25 EU/ml. Cytotoxicity of the nanoparticles was assessed by determination of metabolic activity (Alamar-Blue-Assay), oxidative stress (Carboxy-H2DCFDA-Assay), endothelial monolayer integrity (transendothelial electrical resistance, capacity, permeation of marker compounds). In summary, the nanoparticles were not toxic in the concentration range used in in vivo experiments in rats. To assess any immune response the release of 12 inflammatory cytokines was determined in endothelial cell cultures and in vivo in rats. No significant adverse reactions could be observed. Determination of blood parameters did not result in any noticeable abnormalities. In summary, the manufactured nanoparticles represent a versatile and promising tool for the delivery of drug across the blood brain barrier.
Publications
- Cytotoxicity of poly(n-butylcyano-acrylate) nanoparticles in brain endothelial cells. Vortrag und Poster, DPhG, Annual Meeting Freiburg, 10/2013
Kolter M., Fricker G.
- Drug Targeting to the CNS by colloidal carriers. Vortrag bei : AAPS Annual Meeting, Chicago, USA, 10/2012
Fricker G
- Drug Transport to the CNS – Methods and novel Strategies, Vortrag bei: BBB-Minisymposium, Odense, DK, 5/2012
Fricker G.
- Drug delivery to the CNS by colloidal carrier systems. EUFPS Conference on CNS Drug discovery and Development, Uppsala, Schweden, 6/2013
Fricker G
- Drug Delivery to the CNS by colloidal carrier systems. Vortrag FIP Pharmaceutical Sciences World Congress, Melbourne, 4/l 2014
Fricker G.
- Nanoparticles as a drug delivery system to overcome the Blood-Brain Barrier – Toxicity Evaluation in Human Blood, AAPS Annual Meeting, San Diego, USA, 11/2014
Kolter M., Fricker G.
- Collodial carriers for CNS drug delivery. AAPS National BioTech Meeting, San Francisco, USA 12/2015
Fricker G., Kolter M., Helm, F. Tremmel R.
- Nanotoxicity of poly-(n-butylcyano-acrylate) nanoparticles at the blood-brain barrier, in human whole blood and in vivo. J Control Release. 2015;197:165-79
Kolter M, Ott M, Hauer C, Reimold I, Fricker G
(See online at https://doi.org/10.1016/j.jconrel.2014.11.005)
