Beyine İlaç Hedeflendirme Stratejileri

Yıl 2013, Sayı: 2, 231 - 250, 01.06.2013

Selin S. Doğan Seçil Çaban Yılmaz Çapan

Öz

Santral Sinir Sistemi SSS bozukluklarında kullanılmak üzere yeni ilaç molekülleri ve tedavilerin geliştirilmesi, beyin mikrodamarlarında bulunan sıkı kavşakların oluşturduğu Kan-Beyin Engeli KBE tarafından kısıtlanmaktadır. KBE, beyni toksik ve zararlı bileşiklerden korurken aynı zamanda çok sayıda ilaç molekülü için de engel teşkil etmektedir. Bu sebeple şizofreni, depresyon ve insomniayı kapsayan küçük bir grup dışındaki SSS hastalıkları KBE sebebiyle tedavi edilememektedir. SSS için ilaç geliştirilmesinde geri kalınmasının nedeni, yeni ilaç keşfi ve hedeflendirmenin iki ayrı disiplin olarak düşünülmesidir. Diğer alanlarda olduğu gibi gelişmenin yakalanabilmesi için temel yaklaşım, yeni ilaç molekülü ve hedeflendirme araştırmalarının beraber yürütülmesidir. Beyne ilaç hedeflendirme stratejileri, kimyasal ve biyoloji temelli disiplinlere dayanan iki gruba ayrılabilir. Geçmiş yıllarda, KBE’ye ilaç hedeflendirmede yapılan çalışmalar kimyasal yaklaşımlar alanında yoğunlaşmaktadır. Ancak günümüzde, biyolojik stratejilere dayanan, beyin kapiller endotel hücrelerindeki spesifik reseptörlere hedeflendirilmiş nanopartiküler sistemlerle umut verici çalışmalar yürütülmektedir. Bu derlemenin amacı, yeni stratejileri daha iyi anlayabilmek için, yürütülmüş önceki çalışmaların izlenmesine ek olarak yeni sistemlerin temellerinin incelenmesidir.

Anahtar Kelimeler

İlaç hedeflendirme, kan-beyin engeli, reseptör aracılı transport

Brain Drug Targeting

Öz

The development of new drug candidates and cures for Central Nervous System CNS disorders is restricted owing to the Blood-Brain Barrier BBB formed by the endothelial tight junctions within the brain microvasculature. The BBB protects brain from toxic and harmful compounds, but it also represents an obstacle for a large number of drugs. Thus, there are number of Central Nervous System CNS diseases that cannot be treated owing to the BBB problem, except the small group of CNS disorders including schizophrenia, depression and insomnia. The lag in CNS drug development is due to the fact that drug discovering and drug targeting are conducted as two separate disciplines. The major point to catch up with the progress in any other developing area is to carry on the researches for new drug development and targeting together. The brain drug targeting strategies can be divided into two groups derived from either chemistry based or biology-based disciplines. For the past decades, there has been a research interest in the area of chemical approaches for BBB targeting. But nowadays, promising applications of brain drug targeting have been done based on biologic strategies by nanoparticulate systems targeting specific receptors expressed in brain capillary endothelial cells. Therefore, the aim of this present review is to follow the time line of previous approaches to access to the CNS for better understanding of the new strategies as well as the basis of novel targeting systems.

Anahtar Kelimeler

Drug targeting, blood-brain barrier, receptor mediated transport

Kaynakça

• Pardridge, W.M. Blood-brain barrier delivery. Drug Discov Today, 12 (1-2), 54-61 (2007).
• Pardridge, W.M. The blood-brain barrier: bottleneck in brain drug development. Neu- roRx, 2 (1), 3-14 (2005).
• Pardridge, W.M. Re-engineering biopharmaceuticals for delivery to brain with molecu- lar Trojan horses. Bioconjug Chem, 19 (7), 1327-1338 (2008).
• Pardridge, W.M. Molecular Trojan horses for blood-brain barrier drug delivery. Curr Opin Pharmacol, 6 (5), 494-500 (2006).
• Pardridge, W.M. William Pardridge discusses the lack of BBB research. Interview by Rebecca N. Lawrence. Drug Discov Today, 7 (4), 223-226 (2002).
• Beduneau, A., Saulnier, P., Benoit, J.P. Active targeting of brain tumors using nanocar- riers. Biomaterials, 28 (33), 4947-4967 (2007).
• Abbott, N.J., Ronnback, L., Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci, 7 (1), 41-53 (2006).
• Begley, D.J. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther, 104 (1), 29-45 (2004).
• Pardridge, W.M. BBB-Genomics: creating new openings for brain-drug targeting. Drug Discov Today, 6 (8), 381-383 (2001).
• Syvänen S., X.R., Sahin S., Hammarlund-Udenaes M. Pharmacokinetic Consequences of Active Drug Efflux at the Blood–Brain Barrier. Pharmaceutical Research, 23, 705- 717 (2006).
• Pardridge, W.M. (2001). Brain Drug Targeting: The Future of Brain Drug Development: Cambridge University Press.
• Pardridge, W.M. Drug delivery to the brain. Journal of cerebral blood flow and metabo- lism: official journal of the International Society of Cerebral Blood Flow and Metabo- lism, 17 (7), 713-731 (1997).
• Pardridge, W.M. Drug targeting to the brain. Pharm Res, 24 (9), 1733-1744 (2007).
• Pardridge, W.M. Blood-brain barrier drug targeting: the future of brain drug develop- ment. Mol Interv, 3 (2), 90-105, 151 (2003).
• Oldendorf, W.H., Hyman, S., Braun, L., and Ordendorf, S.Z. Blood-brain barrier pen- etration of morphine, codeine, heroin, and methadone after carotid injection. . Science, 178, 984–986 (1973).
• Trauble, H. Movement of Molecules across Lipid Membranes - Molecular Theory. Jour- nal of Membrane Biology, 4 (2), 193-& (1971).
• Wade, L.A., Katzman, R. Rat brain regional uptake and decarboxylation of L-DOPA fol- lowing carotid injection. The American journal of physiology, 228 (2), 352-359 (1975).
• L. A. Wade, R.K. Synthetic Amino Acids and the Nature of L-Dopa Transport at the Blood-Brain Barrier. Journal of Neurochemistry, 25 (6), 837-842 (1975).
• Cornford E.M., H.S. Localization of Brain Endothelial Luminal and Abluminal Trans- porters with Immunogold Electron Microscopy. NeuroRX, 2 (1), 27-43 (2005).
• Tamai I., T.A. Transporter-Mediated Permeation of Drugs Across the Blood–Brain Bar- rier. Journal of Pharmaceutical Sciences, 89 (11), 1371-1388 (2000).
• Tsuji, A., Tamai, I.I. Carrier-mediated or specialized transport of drugs across the blood-brain barrier. Adv Drug Deliv Rev, 36 (2-3), 277-290 (1999).
• Uchino, H., Kanai, Y., Kim, D.K., Wempe, M.F., Chairoungdua, A., Morimoto, E. ve diğerleri. Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): Insights into the mechanisms of substrate recognition. Molecular Pharmacology, 61 (4), 729-737 (2002).
• Persidsky, Y., Ramirez, S.H., Haorah, J., Kanmogne, G.D. Blood-brain barrier: struc- tural components and function under physiologic and pathologic conditions. J Neuro- immune Pharmacol, 1 (3), 223-236 (2006).
• Yong-Eun Lee Koo, G.R.R., Mahaveer Bhojani,, Randy Schneider, M.A.P., Alnawaz Rehemtulla,,Brian D. Ross, R.K. Brain cancer diagnosis and therapy with nanoplat- forms. Advanced Drug Delivery Reviews, 58, 1556-1577 (2006).
• Pardridge, W.M. Vector-mediated drug delivery to the brain. Advanced Drug Delivery Reviews, 36 (2-3), 299-321 (1999).
• Jones, A.R., Shusta, E.V. Blood-brain barrier transport of therapeutics via receptor- mediation. Pharm Res, 24 (9), 1759-1771 (2007).
• Li H., S.H., Qian Z.M. The role of the transferrin–transferrin-receptor system in drug delivery and targeting. Trends in Pharmacological Sciences, 23 (5), 206-209 (2002).
• Shin, S.U., Friden, P., Moran, M., Olson, T., Kang, Y.S., Pardridge, W.M. ve diğerleri. Transferrin-antibody fusion proteins are effective in brain targeting. Proceedings of the National Academy of Sciences of the United States of America, 92 (7), 2820-2824 (1995).
• Mishra, V., Mahor, S., Rawat, A., Gupta, P.N., Dubey, P., Khatri, K. ve diğerleri. Tar- geted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles. Journal of drug targeting, 14 (1), 45-53 (2006).
• Sumbria, R.K., Boado, R.J., Pardridge, W.M. Combination stroke therapy in the mouse with blood-brain barrier penetrating IgG-GDNF and IgG-TNF decoy receptor fusion proteins. Brain research, 1507, 91-96 (2013).
• Bickel, U., Yoshikawa, T., Pardridge, W.M. Delivery of peptides and proteins through the blood-brain barrier. Adv Drug Deliv Rev, 46 (1-3), 247-279 (2001).
• Boado, R.J., Hui, E.K., Lu, J.Z., Sumbria, R.K.,Pardridge, W.M. Blood-brain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkey. Bioconjugate Chemistry, 24 (10), 1741-1749 (2013).
• Pardridge, W.M. shRNA and siRNA delivery to the brain. Adv Drug Deliv Rev, 59 (2-3), 141-152 (2007).
• Pardridge, W.M. Blood–brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses. Journal of Controlled Release, 122, 345-348 (2007).
• Fu, A., Hui, E.K., Lu, J.Z., Boado, R.J., Pardridge, W.M. Neuroprotection in stroke in the mouse with intravenous erythropoietin-Trojan horse fusion protein. Brain Res, , 203-207 (2011).