Special Issue "Drug Delivery to Brain"
A special issue of Pharmaceutics (ISSN 1999-4923).
Deadline for manuscript submissions: closed (31 March 2015)
Drug delivery to the brain remains one of the biggest challenges in modern pharmacotherapy. Many drug candidates for therapy of CNS diseases fail during development because they are not able to overcome the blood brain barrier (BBB) and to achieve therapeutically relevant concentrations within brain tissue. Modern drug discovery has evolved to optimize target affinity, but a parallel maturation of effective CNS drug delivery strategies is lacking. More than 98% of CNS drug development is devoted to drug discovery and only <2% is devoted to CNS drug delivery. Except for lipid-soluble molecules, which have a molecular weight under a 400-600 Da threshold, virtually all drugs that originate from either biotechnology or classical small molecule pharmacology exhibit negligible transport across the BBB.
This barrier is formed by endothelial cells of brain microvessels being connected by extremely tight junctions and surrounded by parricides, a basal membrane and astrocytes, which form—together with neurons—the so called neurovascular unit. The capillary network has impressive dimensions: the total length of capillaries in the human brain is approximate 600 km with a surface area of 20 m2, which means, in fact, that almost every neuron is perfused by its own capillary. A peculiarity of the endothelial cells is the high expression of export proteins including p-glycoprotein, breast cancer resistance protein and Mrp proteins, which act as active efflux systems for a variety of drugs. In addition, endothelial cells are equipped with a battery of other transport proteins such as a glucose transporter, amino acid transporters, organic anion transport proteins as well as with distinct receptors, e.g., transferring receptor, insulin receptor or low-density lipoprotein receptor related protein-1 (LRP or LDL like receptor). During recent years these receptors have become interesting as targets for drug
delivery using colloidal carrier systems like liposomes, polymeric nanoparticles or solid lipid nanoparticles. Specific surface modification (vector technology) enables these carriers systems to be recognized by the respective receptors, which subsequently undergo transcytosis and release their cargo at the brain side of the endothelial wall. Whereas application of normal colloidal carriers yielded more or less disillusioning results in clinical trials within the last 25 years, this vector technology offers promising tools for new therapeutic areas. Thus, the idea of unfailing “magic bullets”, which was originally developed by Paul Ehrlich at the beginning of the 20th century, appears to come closer to reality.
This special issue “Drug Delivery to Brain" will address new biological, pharmacological and technological approaches to overcome the BBB, which might help to satisfy one of the biggest therapeutic needs of the present time.
Prof. Dr. Gert Fricker
Dr. Anne Mahringer
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