Targeted liposomes for drug delivery across the blood-brain barrier

Abstract

Our brain is protected by the blood-brain barrier (BBB). This barrier is formed by specialized endothelial cells of the brain vasculature and prevents toxic substances from entering the brain. The downside of this barrier is that many drugs that have been developed to cure brain diseases cannot cross this barrier and do not reach the brain in therapeutic concentrations. An innovative way to help these drugs to reach the brain is by encapsulating them into nanoparticles (e.g. liposomes). A targeting ligand on the outside of the particle induces specific uptake of the drug-loaded particle into the endothelial cells of the BBB, after which the drug can be released into the brain. In this thesis, liposomes were coupled to brain-targeting ligands and the potential of these liposomes to reach the brain was studied. Several of the targeting ligands that were used were already described in literature for their brain-targeting potential. These ligands were compared to each other to identify which one was the best. In vivo experiments showed that an anti-transferrin receptor antibody was the best targeting ligand in our studies. Next to these already existing targeting ligands, a new brain-targeting ligand was identified in this thesis by using the technique of phage display. In vitro studies showed that this ligand could significantly enhance the binding of liposomes to brain endothelial cells after it had been fused to a phage coat protein. Therefore, this ligand has the potential to facilitate the brain uptake of therapeutics, and could benefit the treatment of severe brain diseases such as Alzheimer’s disease, brain cancer, or psychotic disorders.