Session Speaker
Drug Delivery to the Brain by Polymeric Nanoparticles
Gert Fricker, Isolde Reimold
Germany


Delivery of drugs across the blood-brain barrier (BBB) is a critical issue in the therapy of CNS diseases. Many drugs may cross the BBB because they are too hydrophilic or because they are substrates of the ABC-export pumps, such as P-glycoprotein, located in the luminal membrane of endothelial cells. A promising approach to overcome this problem is the incorporation of drugs into polymeric nanoparticles, which use cytotic pathways for permeation across the BBB.

Here, we tried to explore and extend the application potential of poly(n-butylcyanoacrylate) (PBCA) nanoparticles to cross the BBB and to deliver their content into the central nervous system (1). PBCA particles were prepared by a new and efficient mini-emulsion method with high yield and reproducibility. Nanoparticles were loaded with 1.5% (w/v) FITC-dextran, 1.5 % rhodamine-123 or 7.3% doxorubicin. They were characterized by dynamic light scattering determining particle size, polydispersity index and zeta-potential. Particles were coated with 10% w/v polysorbate-80 and administered to rats. Cryosections of the excised brain were prepared and time dependent distribution of fluorescence was studied.

After administration of polysorbate-80 coated particles by carotic injection FITC-dextran and rhodamine123, respectively, related fluorescence could first be detected in capillary lumens with a progressive shift to capillary endothelial cells at 30 minutes and a rather evenly spread distribution of fluorescence across the brain tissue was observed at 1-3 hours after administration. Sixty minutes after administration into the tail vein fluorescent particles could be assigned to endothelial cells, whereas after 2 hours also a rather evenly spread distribution across brain tissue was seen.

Identical results were obtained with doxorubicin loaded nanoparticles. In parallel, looking at the body distribution of doxorubicin, a significantly decreased accumulation of the drug in cardiac tissue was observed, which may be a major therapeutic benefit during chemotherapy, as cardiotoxicity is one major unwanted side effect of doxorubicin.
The present observations indicate that surface coated PBCA nanoparticles are able to cross the blood brain barrier efficiently and to serve as a drug delivery system to the central nervous system.


Reference
1. Reimold I., Domke D., Bender J., Seyfried C. A., Radunz H.-E., Fricker G. A nanoscaled approach to target the central nervous system. Eur. J. Pharm. Biopharm 70: 627-632 (2008).