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Transport system smuggles medicines into brain

 

Dutch researcher Corine Visser investigated a new way of transporting medicines into the brain. Her approach made use of an iron transport system located on the blood-brain barrier. The smaller the medicine, the more easily it penetrates the brain.

A special barrier between the blood and the brain, the so-called blood-brain barrier (BBB), protects the brain from toxic substances. It only lets through important nutrients for the brain such as iron, glucose and oxygen. Visser allowed larger molecules, such as medicines, to pass through the blood-brain barrier by attaching these to the iron-containing protein transferrin. This technique allowed the medicines to 'hitch a lift' and pass unnoticed though the BBB. How much medicine reaches the brain depends on the size of the molecule attached to the transferrin.

Much of the BBB is made up of capillary endothelial cells, the cells which line the walls of blood vessels. In the brain, unlike other parts of the body, these cells are closely packed together. This makes it almost impossible for substances to pass between the cells. Further in the brain, few substances can pass through the endothelial cells.

Transferrin is a protein in the blood that contains two iron atoms. On reaching the BBB it binds to transferrin receptors on the endothelial cells. Once the transferrin has bound to the receptor, a vesicle in the cell completely engulfs it. The transferrin then releases the iron atoms, which are brought to the brain by another protein. A major advantage of this transport system with vesicles is that larger molecules can pass through the BBB. The vesicle has a diameter of about 120 nanometres.

Conjugation

In three stages, Visser investigated how medicines can enter the brain via the transferrin receptor. In the first stage she demonstrated the presence of the receptor in her BBB model by using radioactively-labelled transferrin. She then conjugated an enzyme to the transferrin. With the enzyme attached, the transferrin also bound to the receptor and was taken up in the cells of the BBB.

Finally, Visser attached a tiny fat bubble (liposome) containing small molecules, such as medicines, to the transferrin. She discovered that the transferrin with the liposome attached was also taken up by the cell. However, the cell subsequently broke down the liposomal content, because the liposomes were significantly bigger than the previously linked enzyme. Liposomes have a diameter of 100 nanometres and the enzyme a diameter of 3 to 4 nanometres. Therefore a liposome or a direct conjugation can be chosen, dependent on the intracellular destination of the medicine.

The research was funded by the Netherlands Organisation for Scientific Research.

For further information please contact:

Dr Corine Visser (LACDR - Leiden/Amsterdam Center for Drug Research, Leiden University)
t: +31 (0)71 527 6269
ccvisser@freeler.nl

or Dr A.G. de Boer (Leiden University), t:+31 (0)71 527 6215 (assistent supervisor)

The doctoral thesis was defended on 18 January 2005
Supervisor Prof M. Danhof (Leiden University) and Prof D.J.A. Crommelin (Utrecht University)

Reference URL
http://www.nwo.nl/nwohome.nsf/pages/NWOP_68HBWN_Eng


This story has been adapted from a news release -
Diese Meldung basiert auf einer Pressemitteilung -
Deze tekst is gebaseerd op een nieuwsbericht -


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