|Ph.D Student||Kahana Meygal|
|Subject||Targeting of Therapeutic Agents to the Brain Based on|
Liposomes: a Treatment Paradigm to Control and
Improve the Symptoms of Parkinson's
|Department||Department of Medicine||Supervisor||Professor Emeritus Moshe Gavish|
|Full Thesis text|
Targeting drugs to specific organs without risking unwanted scattering in the body or causing severe side effects is an innovative and promising approach. In the brain the permeability problem is greater compared to peripheral organs due to the blood brain barrier (BBB). Its tight junction structure restricts the penetration of drugs through the BBB into the brain thus making it difficult to treat brain diseases in this manner. We created a brain-targeting drug system based on liposomes that are attached to an APP-targeted peptide (6 amino acids selected from the amyloid beta precursor protein sequence), identified by specific transporters in the BBB. This enables delivery of the medication over the BBB into the brain. Liposomes are the most common carriers, formed naturally by adding a mixture of phospholipids to an aquatic solution. This results in a two-layer stable global sphere. This trans-BBB, brain-directed liposomal system was developed to be used in the treatment of Parkinson's disease (PD). PD is a neurodegenerative disease of the central nervous system caused by degeneration of the dopaminergic neurons in the brain's striatum. It is practically incurable and is associated with low quality of life. The symptoms may be alleviated by replenishing dopamine in the striatum with external administration of the dopamine precursor L-DOPA. Dopamine (DA) cannot be used in PD treatment since it does not penetrate the BBB. L-DOPA on the other hand, manages to penetrate it, but only minimally, namely only a small percentage crosses the BBB. Long-term use of L-DOPA results in a reduction in drug effectiveness. We adapted our liposomal system to carry DA. A single treatment with liposomes, loaded with DA in the hydrophilic phase at a much lower concentration than that of the currently used L-DOPA, will be able to provide DA to the brain in an easy, safe and continuous release process with minimal side effects. Our targeted liposomes are characterized by their small size (~100 nm) and negative zeta potential -30mv which allows for the permeability through the BBB and prevents adhesion of the liposomes to each other and thus prevents the formation of aggregates.
We demonstrated a significant increase of DA in the striatum compared to the controls in both functional and pharmacokinetic experiments. We demonstrated that the targeted liposomal system can penetrate the BBB in a variety of animal models. This delivery system is versatile and can be modified for various drugs thus making it useful for treating a large number of brain diseases. This novel approach has the potential to open a window to directing drugs at specific brain regions by using the brain transport systems as carrier and avoiding invasive treatments and large drug doses that may result in severe side effects.