Drug Delivery to the Brain

Cationic nanocarriers are also promising carrier systems to cross biological membranes. Cationic cyclodextrin nanoparticles were studied for doxorubicin delivery across the blood/brain barrier (BBB). Nanopartieles of 65-85 nm diameter probably passed across the BBB with endoeytosis. Drug-loaded nanoparticles induced a cytotoxic effect on U87 human glioblastoma cells without toxicity on brain microvessel endothelial eells.  

Cationic lipids and cationic polymers are designed as gene delivery systems on the nanoscale. Especially chitosan is under focus as a biodegradable, natural biopolymer, used both as the polyplex and also as a coating material for other polyplexes. Chitosan-coated poly(isohexyl cyanoacrylate) nanoparticles have also been developed for intravenous delivery of siRNA and no evidence of toxicity was observed after intravenous administration for 30 

It is possible to prepare various kinds of nanoparticles with different surface charges and particle sizes depending on the polymer composition and preparation technique. As a result, the particle size of nanoparticles varies from 10 nm to 200 nm and the surface charge - -5 mV to -1-50 mV. In this manner, drug carrier systems can be formed through different routes such as oral, parenteral and other mucosal routes for local or systemic therapy, with high cellular interaction, loading capacity, transfection efficiency and low toxicity. 

Remunan-Lopez, J. L. Vila-Jato and M. J. Alonso, J. AppL Polym. Set, 1997, 63, 125-132. 

Ruponen, S. Yla-Herttuala and A. Urtti, Biochim. Biophys. Acta, 1999, 1415, 331-341. 

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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). 

Sadeque AJM, Wand el C, He H, Shah S, Wood AJJ. Increased drug delivery to the brain... 

General allometric correlations such as these can obscure some interesting and important interspecies differences. Brain size in humans and nonhuman pri-mateS/ for example is considerably larger than would be expected from other mammals. Some implications of this have been discussed with reference to regional drug delivery to the brain (2). 

In conclusion, it may be clear that RMT and CMT are important processes for the influx and efflux of substances to and from the BBB endothelial compartment. Changed activity of these processes due to disease, for example, can have serious consequences for functionality and integrity of the BBB. On one hand, this can result in increased para- and transcellular BBB permeability, and therefore, in changed CNS homeostasis. Ultimately, this can lead to CNS diseases, e.g., Alzheimer s or other neurodegenerative diseases (25-27). On the other hand, this offers opportunities for site-specific or targeted drug delivery to the brain when transport processes are selectively upregulated under disease conditions. 

Hammarlund-Udenaes M, Friden M, Syvanen S, Gupta A (2008) On the rate and extent of drug delivery to the brain. Pharm Res 25(8) 1737-1750... 

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