Besides being indispensable for the protection and nutrition of the central nervous
system (CNS), blood-brain barrier (BBB)-forming cerebral endothelial cells (CECs) have a
major role in hampering drugs to reach therapeutically relevant concentrations in the brain.
In this respect, the most important defense systems of CECs are tight junctions (TJs) sealing
the paracellular way of transport, efflux pumps (ABC transporters) and metabolic enzymes.
Here we review current strategies aiming at overcoming the BBB with the purpose of effectively
delivering drugs to the CNS. Besides chemical modification of drug candidates to
improve CNS availability, the main strategies include: bypassing the BBB (intracranial or
nasal routes), reversible opening of TJs (using hyperosmotic mannitol, ultrasounds, peptides
and other physical methods or chemical agents), vector-mediated drug delivery systems
(nanocarriers, exploitation of receptor- and carrier-mediated transport) and inhibition of
efflux transporters. We discuss the main advantages, disadvantages and clinical relevance of
each strategy. Special emphasis will be given to the description of the chemical characteristics of nanoparticles
(lipidic, polymeric, inorganic, etc.) and the main strategies of targeting them to the CNS.