Receptor-mediated delivery of drugs across the
blood-brain barrier
-
1
BBB technologies BV, Netherlands
In attempts to cure diseases of the central nervous system (CNS), many promising active compounds (mainly biopharmaceuticals) have shown potential therapeutic effect, however over 95% never reach the brain in therapeutically relevant concentrations. These compounds are denied access to the brain by the neuroprotective blood-brain barrier (BBB). This barrier is formed by the endothelial cells in the brain capillaries and is a physical and a metabolic barrier. Many transport systems are present at this sophisticated physiological system to maintain brain homeostasis and allow influx of essential nutrients and metabolites and efflux of potentially harmful substances. Receptor mediated endoand transcytosis is one of the transport systems. This system can be hijacked to use the endogenous uptake-machinery of the BBB to deliver drugs across the BBB. For this application a homing device is used that utilizes endogenous transport mechanisms for site-specific delivery. The main advantages of these systems over other brain delivery methods, like local brain injections or the induction of enhanced BBB permeability, are the safety and the global treatment of the brain. Several approaches have been described and a few companies are developing receptor-targeted drugs. The most commonly used receptors for these approaches are insulin-, transferrin-, scavenger receptor class B- and lipoprotein receptor-related protein receptor. Molecules used to target these receptors can be endogenous ligands like transferrin and insulin, receptor specific antibodies or peptides. The ligands are used directly conjugated to a drug or in combination with delivery systems like liposomes and polyplexes.
At to-BBB, we use the tripeptide glutathione (GSH) as a ligand for brain delivery. Several (active) GSH transporters are described to be present at the CNS and BBB, and GSH is identical from mice to man. GSH is a safe delivery ligand since it is an endogenous tripeptide and an antioxidant that is present in food and used for supportive therapy in cancer and HIV. Liposomes coated with GSH-conjugated PEG for intravenous injections are used by us to mediate safe delivery of drugs to the brain. For technological validation of this approach a microdialysis study in rats with antiviral drug (Ribavirin) containing GSH-PEG liposomes was performed by Brains On-line (Groningen, The Netherlands). Rats received i.v. injections of ribavirin GSH-PEG liposomes at 50 mg/kg ribavirin. The liposomes contained different percentages of GSH on the outside ranging from 0 to 2%. Samples were collected from blood and the microdialysis probe implanted in the medial prefrontal cortex. Brain uptake AUCs and plasma AUCs were calculated and compared. Average plasma half-life of the liposomes was found to be 19 hours. Increasing amounts of GSH resulted in higher amounts of free ribavirin in the brain whereas plasma levels were comparable (figure 1).
In conclusion: The GSH-PEG liposomes can be safely used for drug delivery to the brain and could enable the development of treatments for patients with devastating brains diseases.
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Rip
J,
Appeldoorn
CC,
Manca
FM,
Dorland
R,
Van Kregten
JM and
Gaillard
PJ
(2010). Receptor-mediated delivery of drugs across the
blood-brain barrier.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00025
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Received:
11 Mar 2010;
Published Online:
11 Mar 2010.
*
Correspondence:
Jaap Rip, BBB technologies BV, Leiden, Netherlands, rip@tobbb.com