| Summary: |
The current research is oriented to design drug delivery systems able to cross the blood-brain barrier (BBB). The concept will be applied to Alzheimer's disease (AD) drugs. The aim is to develop liposomes, functionalized with BBB antibodies, for amyloid disrupting molecules. Beta-sheet breaker peptides and fluorinated compounds prevent aggregation and toxicity of amyloid beta-peptide (Abeta), the main constituent of AD deposits. Recently, we have developed a polyethylene glycol (PEG) conjugate of one of the most promising beta-sheet breaker peptides to improve its stability. However the BBB limits the brain penetration of peptides and of the majority of AD drug candidates as they lack of the molecular characteristics required for BBB transport: lipid-miscibility and MW below the 400 Da threshold. Delivery of neuropeptides is further complicated by their metabolic lability. Certain hydrophilic macromolecules as monoclonal antibodies (mAb) are able to cross the BBB by receptor-mediated transport. These antibodies can be used as molecular Trojan horses to carry hydrophilic and/or large molecules across the BBB. The idea within this project is to combine pegylation to antibody functionalization for delivering drugs to the brain. The innovation proposed here is to use mAb for BBB endogenous receptors and for Abeta oligomers. If PEG-derivatized lipids or polymers are inserted within the liposomes, their half-life is prolonged considerably in the blood circulation system. The antibodies that will target the liposomes will be conjugated at the terminus of the PEG chains that are used as spacer. Coupling liposomes to receptor-specific targeting ligands will trigger the activation of receptors followed by transcytosis across the BBB. Particular focus will be given to toxicity evaluation of the systems. A systematic study to examine the role of surface functionalization versus encapsulation in reducing toxicity will be performed. The project will contribute to a  |
Summary
The current research is oriented to design drug delivery systems able to cross the blood-brain barrier (BBB). The concept will be applied to Alzheimer's disease (AD) drugs. The aim is to develop liposomes, functionalized with BBB antibodies, for amyloid disrupting molecules. Beta-sheet breaker peptides and fluorinated compounds prevent aggregation and toxicity of amyloid beta-peptide (Abeta), the main constituent of AD deposits. Recently, we have developed a polyethylene glycol (PEG) conjugate of one of the most promising beta-sheet breaker peptides to improve its stability. However the BBB limits the brain penetration of peptides and of the majority of AD drug candidates as they lack of the molecular characteristics required for BBB transport: lipid-miscibility and MW below the 400 Da threshold. Delivery of neuropeptides is further complicated by their metabolic lability. Certain hydrophilic macromolecules as monoclonal antibodies (mAb) are able to cross the BBB by receptor-mediated transport. These antibodies can be used as molecular Trojan horses to carry hydrophilic and/or large molecules across the BBB. The idea within this project is to combine pegylation to antibody functionalization for delivering drugs to the brain. The innovation proposed here is to use mAb for BBB endogenous receptors and for Abeta oligomers. If PEG-derivatized lipids or polymers are inserted within the liposomes, their half-life is prolonged considerably in the blood circulation system. The antibodies that will target the liposomes will be conjugated at the terminus of the PEG chains that are used as spacer. Coupling liposomes to receptor-specific targeting ligands will trigger the activation of receptors followed by transcytosis across the BBB. Particular focus will be given to toxicity evaluation of the systems. A systematic study to examine the role of surface functionalization versus encapsulation in reducing toxicity will be performed. The project will contribute to advancing delivery systems that are able to cross the BBB and reach brain areas affected by AD. |