Delivery to the Brain

In general, the blood-brain barrier (BBB) is only permeable to lipophilic molecules of molecular weight 600 Da, while even small water-soluble molecules generally cannot be transported [21]. This would preclude the direct delivery of ASO to the brain from the systemic circulation without the assistance of specialized drug delivery systems. 

Boado et al. [28] devised delivery systems based on conjugates of streptavidin and the 0X26 monoclonal antibody directed to the transferrin receptor as a carrier for the transport of ASO. These delivery systems were found to transport peptide nucleic acid antisense molecules, but not ASO, across the BBB. These authors attributed this difference to preferential binding of phosphorothioate oligonucleotide to plasma protein instead of the antibody complex, which reduced their transport. 

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W. M. Pardridge, Peptide Drug Delivery to the Brain, Raven Press, New York, 1991. 

Pardridge WM. Drug delivery to the brain. J Cereb Blood Flow Metab 1997 17 713-31. 

Lemaire, M. and Desrayaud, S. (2005) The priorities/needs of the pharmaceutical industry in drug delivery to the brain. International Congress Series, 2005, 32 6. 

Sadeque, A.J., Wandel, C., He, H., Shah, S., and Wood, A.J. (2000) Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 68 231-237. 

Penichet ML, et al. An antibody-avidin fusion protein specific for the transferrin receptor serves as a delivery vehicle for effective brain targeting initial applications in anti-HIV antisense drug delivery to the brain. J Immunol 1999 163(8) 4421—4426. 

Oldendorf, W.H., Some relationships between addiction and drug delivery to the brain, NIDA Res. Mon., 120, 13, 1992. 

Pardridge, W.M. 1999. Vector-mediated drug delivery to the brain. Adv Drug Deliv Rev 36 299. 

Halmos, T., et al. 1997. Synthesis of O-methylsulfonyl derivatives of D-glucose as potential alkylating agents for targeted drug delivery to the brain. Evaluation of their interaction with the human erythrocyte GLUT1 hexose transporter. Carbohydr Res 299 15. 

Terasaki, T., and A. Tsuji. 1994. Drug delivery to the brain utilizing blood-brain barrier transport systems. J Control Release 29 163. 

Several active transport systems also exist on the blood-brain barrier that are responsible for removing drugs and toxins from the brain.6,11 That is, certain drugs can enter the brain easily via diffusion or another process, but these drugs are then rapidly and efficiently transported out of the brain and back into the systemic circulation.6,13 This effect creates an obvious problem because these drugs will not reach therapeutic levels within the CNS, and won t be beneficial. Hence, the blood-brain barrier has many structural and functional characteristics that influence CNS drugs, and researchers continue to explore ways that these characteristics can be modified to ensure adequate drug delivery to the brain and spinal cord.15,23... 

T. Ishikura, T. Senou, H. Ishihara, T. Kato, and T. Ito, Drug delivery to the brain. DOPA prodrugs based on a ring-closure reaction to quaternary thiazolium compounds, Int. J. Pharm. 116 51 (1995). 

G. Somogyi, S. Nishitani, D. Nomi, P. Buchwald, L. Prokai, and N. Bodor, Targeted drug delivery to the brain via phosphonate derivatives. I. Design, synthesis, and evaluation of an anionic chemical delivery system for testosterone, Int. J. Pharm. 166 15 (1998). 

Polymer-Based Drug Delivery to the Brain, Science and Medicine, 3 2-11 (1996). 

Outline the physiological factors affecting drag delivery to the brain. 

Figure 16.2 Dihydropyridine-pyridinium salt redox system for site-specific and sustained delivery to the brain. The prodrug A is delivered directly to the brain, where it is oxidized and trapped as the prodrug B. The quaternary ammonium salt is slowly cleaved by chemical/enzymatic action with sustained release of the biologically active phenylethylamine C and the facile elimination of the carrier molecule D. Elimination of the drug from the general circulation is by comparison accelerated, either as A or B or as cleavage products...

Pardridge, W.M. (2002) Drag and gene delivery to the brain the vascular route. Neuron 36,555-558. 

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