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lüll Macromolecular drug transport into the brain using targeted therapy Lichota J; Skjorringe T; Thomsen LB; Moos TJ Neurochem 2010[Apr]; 113 (1): 1-13The brain forms a vascular barrier system comprised of the blood-brain barrier (BBB) and the blood-CSF barriers. Together they prevent the passage of a number of drugs from the bloodstream into the brain parenchyma, because their molecules are either hydrophilic, too large or both. In many disorders affecting the CNS, these barriers are physically intact, which limits the entry of large molecules with potentially important therapeutic implications. The BBB is the most relevant barrier against drug delivery to the brain as the area of the BBB is about 1000 times larger than that of the blood-CSF barrier. Moreover, the transport through the choroid plexus is directed to the ventricular system, only allowing the transported molecules to access cells near the ventricular and subarachnoid surfaces. This review outlines possible routes for targeted entry of macromolecules like polypeptides, siRNA and cDNA. In the vascular compartment, targeting molecules should interact specifically with proteins expressed exclusively by these barrier cells, and therefore prevent uptake elsewhere in the body. Preferably, the targeting molecule should be conjugated to a drug carrier that allows uptake of a defined cargo. However, evidence for transport of such targetable drug-carrier complexes through the barriers, in particular the BBB, is contentious, and is discussed with emphasis on the different attempts that have evinced transport through the BBB not only from blood-to-endothelium, but also from endothelium-to-brain.|Animals[MESH]|Biological Transport/physiology[MESH]|Blood-Brain Barrier/drug effects/*physiology[MESH]|Brain/*metabolism[MESH]|Central Nervous System Agents/metabolism/pharmacology/therapeutic use[MESH]|Cerebrospinal Fluid/physiology[MESH]|Drug Carriers/metabolism/pharmacology/*therapeutic use[MESH]|Humans[MESH]|Macromolecular Substances/*metabolism[MESH]|Membrane Transport Proteins/metabolism[MESH] |