Nanomedicine. 2014 Apr;9(5):709-22. doi: 10.2217/nnm.14.27.

Targeting nanoparticles across the blood-brain barrier with monoclonal antibodies.

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



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



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.

 fig1 Figure 1. Mechanisms of transport of molecules into the brain through the blood–brain barrier.

The blood–brain barrier (BBB), anatomically defined as the cerebral microvascular endothelium, limits severely the delivery of molecules to the brain. The BBB is different from all other vascular beds as it has tight cell-cell junctions and few alternate transport pathways. The brain endothelial cells have also extra degrading enzymes and additionally express high levels of active influx/efflux membrane transport proteins (e.g. P-glycoprotein). Most molecules are forced to cross the BBB via the transcellular route owing to the tight junction between adjacent endothelial cells (Figure 1).

Targeting drugs to the brain can be achieved by utilizing antibodies for receptors that are overexpressed on the surface of the brain endothelial cells such as the transferrin and insulin receptors.

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).

  fig2 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).

 fig3a fig3r
Figure 3. Cellular uptake by porcine brain capillary endothelial cells (graph on the left) and cryo-sections of rat brains 2h after intravenous administration (images on the right) of pegylated liposomes (gray bars and left image) and pegylated liposomes coupled to antibodies against transferrin receptors and amyloid beta-peptide (violet bar and right image).


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.



  1. Rocha S. Targeted drug delivery across the blood brain barrier in Alzheimer’s disease. Curr. Pharm. Des. 2013;19(37):6635-46.


Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann