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Targeting nanoparticles across the blood-brain barrier with monoclonal antibodies.
Nanomedicine. 2014 Apr;9(5):709-22. doi: 10.2217/nnm.14.27.
Joana A Loureiro1, Bárbara Gomes1, Manuel AN Coelho1, Maria do Carmo Pereira1 , Sandra Rocha2
1LEPABE, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, Portugal
2Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
sandra.rocha@chalmers.se
Abstract
Development of therapeutics for brain disorders is one of the more difficult challenges to be overcome by the scientific community due to the inability of most molecules to cross the blood–brain barrier (BBB). Antibody-conjugated nanoparticles are drug carriers that can be used to target encapsulated drugs to the brain endothelial cells and have proven to be very promising. They significantly improve the accumulation of the drug in pathological sites and decrease the undesirable side effect of drugs in healthy tissues. We review the systems that have demonstrated promising results in crossing the BBB through receptor-mediated endocytic mechanisms for the treatment of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.
Keywords: Alzheimer’s disease • blood–brain barrier • liposome • monoclonal antibody • Parkinson’s disease • PLGA nanoparticles • targeting
PMID: 24827845
Supplement
Alzheimer’s disease (AD) is the neurodegenerative disorder of the human brain considered the most common form of dementia worldwide. The development of AD drugs is a very active research area and many promising molecules reach the clinical trials but they end up failing. One of the main reasons for that disappointing outcome is the poor blood–brain barrier permeation of the drugs.
Several strategies are being exploited for the delivery of AD drugs through the BBB.1 The approaches based on antibodies against BBB endogenous receptors seem to preserve the integrity of the barrier. They are delineated to deliver the molecules by transcytosis either specific (receptor-mediated transcytosis) or nonspecific (adsorptive-mediated transcytosis).
Liposomes and polymeric nanoparticles are versatile systems that can be used to encapsulate lipophilic, amphiphilic or water-soluble molecules. They are widely used in the preparation of drug delivery system formulations for parenteral administration. Liposomes and polymeric nanoparticles normally do not cross the BBB and are rapidly removed from the bloodstream by cells lining the reticulo-endothelial system but their pharmacological properties can be relatively easily modified. Coating the systems with polyethylene glycol (PEG) increases their half-life in the circulation due to steric stabilization and their BBB permeability can be achieved by coupling antibodies to their surfaces. Multiple conjugation procedures have been developed to bind monoclonal antibodies to nanoparticles. A very common method is the covalent coupling in which the antibody is conjugated to the nanoparticle surface through a functionalized PEG molecule with a chemically reactive end group, e.g. maleimide and biotin (Figure 2).
Figure 2. Two conjugation methods that can be used to couple monoclonal antibodies to pegylated liposomes and pegylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles.
We have developed a system based on liposomes functionalized with two different monoclonal antibodies, against the transferrin receptor and amyloid plaques, to target drugs to areas of the brain affected by amyloid deposits. The antibody against transferrin receptor (OX26) was covalently bound to the pegylated liposomes through the streptavidin-biotin system, whereas the antibody against amyloid deposits (19B8) was coupled through a maleimide group. The cellular uptake of the immunoliposomes by porcine brain capillary endothelial cells, a BBB cell model, is higher than that of liposomes without the monoclonal antibodies. In vivo studies showed that liposomes coupled to the antibodies could reach the cortex of the brain of male Wistar rats after intravenous administration. This study was carried out with liposomes prepared with a lipid labeled with rhodamine B and the results are based on the fluorescence intensity of the dye (Figure 3).
Research on drug delivery systems for targeting the brain is constantly carried out and the results are indeed promising. There is still, however, a huge need for optimization of the systems before they can reach the clinics.
Reference:
- Rocha S. Targeted drug delivery across the blood brain barrier in Alzheimer’s disease. Curr. Pharm. Des. 2013;19(37):6635-46.