Small drug molecules analogous to glucose, amino acids, and small intermediate metabolites, for example, reach brain tissue via facilitated transport mediated by specific transport proteins, whereas larger molecules, such as insulin and other protein type therapeutic

agents, are carried across the BBB via receptor-mediated or adsorptive transcytosis. Furthermore, some small molecules with high octanol/water partition coefficients are seemingly blocked. Thorough data analysis suggests that they are actively pumped back into the blood by efflux systems. For instance, members of the adenosine INCB028050 mouse triphosphate-binding cassette family of exporters Inhibitors,research,lifescience,medical are potent energy-dependent transporters. They contribute greatly to the efflux of xenobiotics and due to this protective role impede the delivery of therapeutic agents. Consequently, to develop Inhibitors,research,lifescience,medical effective and efficient methods for drug delivery to the brain through the BBB, it is imperative to control its permeability. This requires understanding the mechanism by which these structural components,

as well as transporters, receptors, efflux pumps and other components at the endothelium and Inhibitors,research,lifescience,medical astrocyte foot processes determine it. Various methods such as intracerebral implantation, microdialysis, convection-enhanced distribution (CED), osmotic shock, and chemical modification of the BBB have been developed for delivering drugs into the brain. However, the applications of these methods are limited and they can only partially keep with the demands of modern therapies. For instance, the efficiency of intracerebral implantation, microdialysis and CED methods are low since their major transport mechanisms are diffusion and convection Inhibitors,research,lifescience,medical of interstitial fluid. For effective treatment of CNS

diseases, an adequate amount of therapeutic agents must reach the specific regions of the brain. As discussed earlier, functionalized target chaperones have this ability. They can directly deliver therapeutic agents via these transporters by closely mimicking their substrates, Inhibitors,research,lifescience,medical or conjugating the drugs to ligands of the specific surface receptors expressed for transcytosis (receptor-mediated transcytosis, RMT-Trojan horse approach). Furthermore, these functionalized target chaperones are used in delivering cationized proteins, peptides, and as nanoparticle carriers for adsorptive mediated transcytosis (AMT). Although the exact mechanisms mafosfamide of RMT are not fully understood, the development of drug delivery protocols using receptor targeting has been successful [46–50]. This physiological approach is often referred to as the molecular Trojan horse approach since the therapeutic compounds are delivered to specific sites for transcytosis by various forms of vector carriers. This approach also improves the drug loading capacity. The technique is very promising, but unfortunately there remain a number of hurdles to overcome [48–50].