The blood-brain barrier: Structure, function and therapeutic approaches to cross it

Molecular Membrane Biology

Volumn 31, Issue 5, 2014, Pages 152-167

  Tajes, Marta ^a   Ramos Fernández, Eva ^a   Weng Jiang, Xian ^a   Bosch Morató, Mònica ^a   Guivernau, Biuse ^a   Eraso Pichot, Abel ^a   Salvador, Bertrán ^a   Fernàndez Busquets, Xavier ^b,c,d   Roquer, Jaume ^e   Muñoz, Francisco J ^a  

^a UNIVERSITAT POMPEU FABRA   (Spain)

^b INSTITUTE FOR BIOENGINEERING OF CATALONIA IBEC   (Spain)

^c UNIVERSITY OF BARCELONA   (Spain)

^d UNIVERSITY OF BARCELONA   (Spain)

^e HOSPITAL DEL MAR   (Spain)

Author keywords

Blood brain barrier; Drug delivery; Membrane transport

Indexed keywords

LIPOSOME;

BLOOD BRAIN BARRIER; BRAIN; BRAIN NEOPLASMS; DRUG DELIVERY SYSTEM; DRUG EFFECTS; HUMAN; MENTAL DISORDERS; METABOLISM; NANOTECHNOLOGY; NEURODEGENERATIVE DISEASES; PATHOLOGY; ULTRASTRUCTURE; VASCULAR ENDOTHELIUM;

BLOOD-BRAIN BARRIER; BRAIN; BRAIN NEOPLASMS; DRUG DELIVERY SYSTEMS; ENDOTHELIUM, VASCULAR; HUMANS; LIPOSOMES; MENTAL DISORDERS; NANOTECHNOLOGY; NEURODEGENERATIVE DISEASES;

EID: 84904958288     PISSN: 09687688     EISSN: 14645203     Source Type: Journal    
DOI: 10.3109/09687688.2014.937468     Document Type: Review

References (184)

1. Abbott NJ. 2002. Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200:629-638.
2. Abbott NJ, Romero IA. 1996. Transporting therapeutics across the blood-brain barrier. Mol Med Today 2:106-113.
3. Abbott NJ, Ronnback L, Hansson E. 2006. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41-53.
4. Adams S, Brown H, Turner G. 2002. Breaking down the blood-brain barrier: Signaling a path to cerebral malaria? Trends Parasitol 18: 360-366.
5. Aono S, Nakagawa S, Reynolds AB, Takeichi M. 1999. p120(ctn) acts as an inhibitory regulator of cadherin function in colon carcinoma cells. J Cell Biol 145:551-562.
6. Avgoustakis K. 2004. Pegylated poly(lactide) and poly(lactideco- glycolide) nanoparticles: Preparation, properties and possible applications in drug delivery. Curr Drug Deliv 1:321-333.
7. Balda MS, Flores-Maldonado C, Cereijido M, Matter K. 2000. Multiple domains of occludin are involved in the regulation of paracellular permeability. J Cell Biochem 78:85-96.
8. Bartus RT, Snodgrass P, Marsh J, Agostino M, Perkins A, Emerich DF. 2000. Intravenous cereport (RMP-7) modifies topographic uptake profile of carboplatin within rat glioma and brain surrounding tumor, elevates platinum levels, and enhances survival. J Pharmacol Exp Ther 293:903-911.
9. Batycky RP, Hanes J, Langer R, Edwards DA. 1997. A theoretical model of erosion and macromolecular drug release from biodegrading microspheres. J Pharm Sci 86:1464-1477.
10. Bazile DV, Ropert C, Huve P, Verrecchia T, Marlard M, Frydman A, et al. 1992. Body distribution of fully biodegradable [14C]-poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats. Biomaterials 13:1093-1102.
11. Bazzoni G. 2006. Endothelial tight junctions: Permeable barriers of the vessel wall. Thromb Haemost 95:36-42.
12. Bazzoni G, Dejana E. 2004. Endothelial cell-To-cell junctions: Molecular organization and role in vascular homeostasis. Physiol Rev 84: 869-901.
13. Begley DJ. 2004. Delivery of therapeutic agents to the central nervous system: The problems and the possibilities. Pharmacol Ther 104:29-45.
14. Betz AL, Bowman PD, Goldstein GW. 1983. Hexose transport in microvascular endothelial cells cultured from bovine retina. Exp Eye Res 36:269-277.
15. Blasberg RG, Patlak C, Fenstermacher JD. 1975. Intrathecal chemotherapy: Brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 195:73-83.
16. Blasi P, Giovagnoli S, Schoubben A, Ricci M, Rossi C. 2007. Solid lipid nanoparticles for targeted brain drug delivery. Adv Drug Deliv Rev 59:454-477.
17. Booth R, Kim H. 2012. Characterization of a microfluidic in vitro model of the blood-brain barrier (muBBB). Lab Chip 12: 1784-1792.
18. Brasnjevic I, Steinbusch HW, Schmitz C, Martinez-Martinez P. 2009. Delivery of peptide and protein drugs over the blood-brain barrier. Prog Neurobiol 87:212-251.
19. Brigger I, Morizet J, Aubert G, Chacun H, Terrier-Lacombe MJ, Couvreur P, Vassal G. 2002. Poly(ethylene glycol)-coated hexadecylcyanoacrylate nanospheres display a combined effect for brain tumor targeting. J Pharmacol Exp Ther 303:928-936.
20. Brightman MW, Kadota Y. 1992. Nonpermeable and permeable vessels of the brain. NIDA Res Monogr 120:87-107.
21. Broadwell RD, Balin BJ, Salcman M. 1988. Transcytotic pathway for blood-borne protein through the blood-brain barrier. Proc Natl Acad Sci USA 85:632-636.
22. Brown D, Stow JL. 1996. Protein trafficking and polarity in kidney epithelium: From cell biology to physiology. Physiol Rev 76: 245-297.
23. Brown RC, Mark KS, Egleton RD, Davis TP. 2004. Protection against hypoxia-induced blood-brain barrier disruption: Changes in intracellular calcium. Am J Physiol Cell Physiol 286:C1045-C1052.
24. Brown RC, Morris AP, O'Neil RG. 2007. Tight junction protein expression and barrier properties of immortalized mouse brain microvessel endothelial cells. Brain Res 1130:17-30.
25. Burns AR, Bowden RA, MacDonell SD, Walker DC, Odebunmi TO, Donnachie EM, et al. 2000. Analysis of tight junctions during neutrophil transendothelial migration. J Cell Sci 113:45-57.
26. Burns AR, Walker DC, Brown ES, Thurmon LT, Bowden RA, Keese CR, et al. 1997. Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners. J Immunol 159:2893-2903.
27. Butt AM, Jones HC, Abbott NJ. 1990. Electrical resistance across the blood-brain barrier in anaesthetized rats: A developmental study. J Physiol 429:47-62.
28. Cancilla PA, eBault LE. 1983. Neutral amino acid transport properties of cerebral endothelial cells in vitro. J Neuropathol Exp Neurol 42: 191-199.
29. Chen H, Qin Y, Zhang Q, Jiang W, Tang L, Liu J, He Q. 2011. Lactoferrin modified doxorubicin-loaded procationic liposomes for the treatment of gliomas. Eur J Pharm Sci 44:164-173.
30. Cho CW, Liu Y, Cobb WN, Henthorn TK, Lillehei K, Christians U, Ng KY. 2002. Ultrasound-induced mild hyperthermia as a novel approach to increase drug uptake in brain microvessel endothelial cells. Pharm Res 19:1123-1129.
31. Citi S, Cordenonsi M. 1998. Tight junctions proteins. Biochim Biophys Acta 1448:1-11.
32. Cordenonsi M, D Atri F, Hammar E, Parry DA, Kendrick-Jones J, Shore D, Citi S. 1999. Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3 and myosin. J Cell Biol 147:1569-1582.
33. Couraud PO. 1998. Infiltration of inflammatory cells through brain endothelium. Pathol Biol (Paris) 46:176-180.
34. Craparo EF, Bondi ML, Pitarresi G, Cavallaro G. 2011. Nanoparticulate systems for drug delivery and targeting to the central nervous system. CNS Neurosci Ther 17:670-677.
35. Cucullo L, Hossain M, Rapp E, Manders T, Marchi N, Janigro D. 2007. Development of a humanized in vitro blood-brain barrier model to screen for brain penetration of antiepileptic drugs. Epilepsia 48: 505-516.
36. Dang W, Colvin OM, Brem H, Saltzman WM. 1994. Covalent coupling of methotrexate to dextran enhances the penetration of cytotoxicity into a tissue-like matrix. Cancer Res 54:1729-1735.
37. De Jong WH, Borm PJ. 2008. Drug delivery and nanoparticles: Applications and hazards. Int J Nanomed 3:133-149.
38. Dehouck MP, Meresse S, Delorme P, Fruchart JC, Cecchelli R. 1990. An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J Neurochem 54:1798-1801.
39. Denora N, Trapani A, Laquintana V, Lopedota A, Trapani G. 2009. Recent advances in medicinal chemistry and pharmaceutical technology-strategies for drug delivery to the brain. Curr Top Med Chem 9:182-196.
40. Doolittle ND, Petrillo A, Bell S, Cummings P, Eriksen S. 1998. Bloodbrain barrier disruption for the treatment of malignant brain tumors: The National Program. J Neurosci Nurs 30:81-90.
41. Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D. 1999. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51:691-743.
42. Duffy KR, Pardridge WM. 1987. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 420:32-38.
43. Emerich DF, Dean RL, Marsh J, Pink M, Lafreniere D, Snodgrass P, Bartus RT. 2000. Intravenous cereport (RMP-7) enhances delivery of hydrophilic chemotherapeutics and increases survival in rats with metastatic tumors in the brain. Pharm Res 17:1212-1219.
44. Engelhardt B, Sorokin L. 2009. The blood-brain and the bloodcerebrospinal fluid barriers: Function and dysfunction. Semin Immunopathol 31:497-511.
45. Erdlenbruch B, Alipour M, Fricker G, Miller DS, Kugler W, Eibl H, Lakomek M. 2003. Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries. Br J Pharmacol 140:1201-1210.
46. Ettmayer P, Amidon GL, Clement B, Testa B. 2004. Lessons learned from marketed and investigational prodrugs. J Med Chem 47:2393-2404.
47. Farrell CL, Pardridge WM. 1991. Blood-brain barrier glucose transporter is asymmetrically distributed on brain capillary endothelial lumenal and ablumenal membranes: An electron microscopic immunogold study. Proc Natl Acad Sci USA 88:5779-5783.
48. Frank MM. 1993. The reticuloendothelial system and bloodstream clearance. J Lab Clin Med 122:487-488.
49. Fricker G, Miller DS. 2004. Modulation of drug transporters at the blood-brain barrier. Pharmacology 70:169-176.
50. Furuse M, Sasaki H, Tsukita S. 1999. Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147:891-903.
51. Gaillard PJ. 2011. Case study: To-BBB's G-Technology, getting the best from drug-delivery research with industry-Academia partnerships. Ther Deliv 2:1391-1394.
52. Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst RD, et al. 2005. In vitro models for the blood-brain barrier. Toxicol In Vitro 19: 299-334.
53. Geldenhuys WJ, Allen DD, Bloomquist JR. 2012. Novel models for assessing blood-brain barrier drug permeation. Expert Opin Drug Metab Toxicol 8:647-653.
54. Goeckeler ZM, Wysolmerski RB. 1995. Myosin light chain kinaseregulated endothelial cell contraction: The relationship between isometric tension, actin polymerization, and myosin phosphorylation. J Cell Biol 130:613-627.
55. Gonzalez-Mariscal L, Betanzos A, Avila-Flores A. 2000. MAGUK proteins: Structure and role in the tight junction. Semin Cell Dev Biol 11:315-324.
56. Grammatopoulos TN, Jones SM, Yoshimura M, Hoover BR, Das M, Snyder EY, et al. 2010. Neurotrasplantation of stem cells genetically modified to express human dopamine transporter reduces alcohol consumption. Stem Cell Res Ther 1:36-49.
57. Grau GE, Piguet PF, Vassalli P, Lambert PH. 1989. Tumor-necrosis factor and other cytokines in cerebral malaria: Experimental and clinical data. Immunolog Rev 112:49-70.
58. Greenwood J, Luthert PJ, Pratt OE, Lantos PL. 1988. Hyperosmolar opening of the blood-brain barrier in the energy-depleted rat brain. Part 1. Permeability studies. J Cereb Blood Flow Metab 8:9-15.
59. Gumbiner B. 1987. Structure, biochemistry, and assembly of epithelial tight junctions. Am J Physiol 253:C749-C758.
60. Haseloff RF, Blasig IE, Bauer HC, Bauer H. 2005. In search of the astrocytic factor(s) modulating blood-brain barrier functions in brain capillary endothelial cells in vitro. Cell Mol Neurobiol 25:25-39.
61. Hatzfeld M. 2005. The p120 family of cell adhesion molecules. Eur J Cell Biol 84:205-214.
62. Hawkins BT, Davis TP. 2005. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173-185.
63. Hayashi Y, Nomura M, Yamagishi S, Harada S, Yamashita J, Yamamoto H. 1997. Induction of various blood-brain barrier properties in non-neural endothelial cells by close apposition to co-cultured astrocytes. Glia 19:13-26.
64. Heiskala M, Peterson PA, Yang Y. 2001. The roles of claudin superfamily proteins in paracellular transport. Traffic 2:93-98.
65. Hellstrom M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, Betsholtz C. 2001. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153:543-553.
66. Hirase T, Staddon JM, Saitou M, Ando-Akatsuka Y, Itoh M, Furuse M, et al. 1997. Occludin as a possible determinant of tight junction permeability in endothelial cells. J Cell Sci 110:1603-1613.
67. Holly J, Perks C. 2006. The role of insulin-like growth factor binding proteins. Neuroendocrinology 83:154-160.
68. Huang FY, Chen WJ, Lee WY, Lo ST, Lee TW, Lo JM. 2013. In vitro and in vivo evaluation of lactoferrin-conjugated liposomes as a novel carrier to improve the brain delivery. Int J Mol Sci 14: 2862-2874.
69. Hwang SR, Kim K. 2014. Nano-enabled delivery systems across the blood-brain barrier. Arch Pharm Res 37:24-30.
70. Igarashi Y, Utsumi H, Chiba H, Yamada-Sasamori Y, Tobioka H, Kamimura Y, et al. 1999. Glial cell line-derived neurotrophic factor induces barrier function of endothelial cells forming the blood-brain barrier. Biochem Biophys Res Commun 261:108-112.
71. Illum L. 2000. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 11:1-18.
72. Isobe I, Watanabe T, Yotsuyanagi T, Hazemoto N, Yamagata K, Ueki T, et al. 1996. Astrocytic contributions to blood-brain barrier (BBB) formation by endothelial cells: A possible use of aortic endothelial cell for in vitro BBB model. Neurochem Int 28:523-533.
73. Jain KK. 2007. Use of nanoparticles for drug delivery in glioblastoma multiforme. Expert Rev Neurother 7:363-372.
74. Janzer RC, Raff MC. 1987. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325:253-257.
75. Juillerat-Jeanneret L. 2008. The targeted delivery of cancer drugs across the blood-brain barrier: Chemical modifications of drugs or drugnanoparticles? Drug Discov Today 13:1099-1106.
76. Kacem K, Lacombe P, Seylaz J, Bonvento G. 1998. Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: A confocal microscopy study. Glia 23:1-10.
77. Kang YS, Pardridge WM. 1994. Brain delivery of biotin bound to a conjugate of neutral avidin and cationized human albumin. Pharm Res 11:1257-1264.
78. Kern DS, Maclean KN, Jiang H, Synder EY, Sladek Jr. JR, Bjugstad KB. 2011. Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn Down syndrome mice. Cell Transplant 20: 371-379.
79. Kim GY, Tyler BM, Tupper MM, Karp JM, Langer RS, Brem H, Cima MJ. 2007. Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model. J Control Release 123: 172-178.
80. Kreuter J. 1994. Drug targeting with nanoparticles. Eur J Drug Metab Pharmacokinet 19:253-256.
81. Kreuter J, Shamenkov D, Petrov V, Ramge P, Cychutek K, Koch-Brandt C, Alyautdin R. 2002. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target 10: 317-325.
82. Kroll RA, Neuwelt EA. 1998. Outwitting the blood-brain barrier for therapeutic purposes: Osmotic opening and other means. Neurosurgery 42:1083-1099; discussion 1099-1100.
83. Kutcher ME, Herman IM. 2009. The pericyte: Cellular regulator of microvascular blood flow. Microvasc Res 77:235-246.
84. Kwiatkowski D. 1990. Tumour necrosis factor, fever and fatality in falciparum malaria. Immunol Lett 25:213-216.
85. Lai CH, Kuo KH. 2005. The critical component to establish in vitro BBB model: Pericyte. Brain Res Rev 50:258-265.
86. Lai F, Fadda AM, Sinico C. 2013. Liposomes for brain delivery. Expert Opin Drug Deliv 10:1003-1022.
87. Lalatsa A, Schatzlein AG, Ucheqbu IF. 2014. Strategies to deliver peptide drugs to the brain. Mol Pharm 11:1081-1093.
88. Lampugnani MG, Corada M, Andriopoulou P, Esser S, Risau W, Dejana E. 1997. Cell confluence regulates tyrosine phosphorylation of adherens junction components in endothelial cells. J Cell Sci 110: 2065-2077.
89. Lampugnani MG, Corada M, Caveda L, Breviario F, Ayalon O, Geiger B, Dejana E. 1995. The molecular organization of endothelial cell to cell junctions: Differential association of plakoglobin, beta-catenin, and alpha-catenin with vascular endothelial cadherin (VE-cadherin). J Cell Biol 129:203-217.
90. Lasic DD. 1998. Novel applications of liposomes. Trends Biotechnol 16: 307-321.
91. Lee G, Dallas S, Hong M, Bendayan R. 2001. Drug transporters in the central nervous system: Brain barriers and brain parenchyma considerations. Pharmacol Rev 53:569-596.
92. Lee KR, Kawai N, Kim S, Sagher O, Hoff JT. 1997. Mechanisms of edema formation after intracerebral hemorrhage: Effects of thrombin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model. J Neurosurg 86:272-278.
93. Lee SW, Kim WJ, Choi YK, Song HS, Son MJ, Gelman IH, et al. 2003. SSeCKS regulates angiogenesis and tight junction formation in bloodbrain barrier. Nat Med 9:900-906.
94. Leigh K, Elisevich K, Rogers KA. 1994. Vascularization and microvascular permeability in solid versus cell-suspension embryonic neural grafts. J Neurosurg 81:272-283.
95. Leong KW, Brott BC, Langer R. 1985. Bioerodible polyanhydrides as drug-carrier matrices. I: Characterization, degradation, and release characteristics. J Biomed Mater Res 19:941-955.
96. Liang Y, Agren L, Lyczek A, Walczak P, Bulte JW. 2013. Neural progenitor cell survival in mouse brain can be improved by cotransplantation of helper cells expressing bFGF under doxycycline control. Exp Neurol 247:73-79.
97. Liu L, Venkatraman SS, Yang YY, Guo K, Lu J, He B, Moochhala S, Kan L. 2008. Polymeric micelles anchores with TAT for delivery of antibiotics across the blood-brain barrier. Biopolymers 90: 617-623.
98. Lockman PR, Mumper RJ, Khan MA, Allen DD. 2002. Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm 28:1-13.
99. Loch-Neckel G, Koepp J. 2010. The blood-brain barrier and drug delivery in the central nervous system. Rev Neurol 51:165-174.
100. Loscher W, Potschka H. 2005. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 76:22-76.
101. Mackic JB, Weiss MH, Miao W, Kirkman E, Ghiso J, Calero M, et al.1998. Cerebrovascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer's amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathy. J Neurochem 70: 210-215.
102. Madrid Y, Langer LF, Brem H, Langer R. 1991. New directions in the delivery of drugs and other substances to the central nervous system. Adv Pharmacol 22:299-324.
103. Madsen SJ, Hirschberg H. 2010. Site-specific opening of the blood-brain barrier. J Biophotonics 3:356-367.
104. Maher PA, Pasquale EB. 1988. Tyrosine phosphorylated proteins in different tissues during chick embryo development. J Cell Biol 106: 1747-1755.
105. Mann GE, Yudilevich DL, Sobrevia L. 2003. Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev 83:183-252.
106. Masi BC, Tyler BM, Bow H, Wicks RT, Xue Y, Brem H, et al. 2012. Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model. Biomaterials 33:5768-5775.
107. Matsukado K, Inamura T, Nakano S, Fukui M, Bartus RT, Black KL. 1996. Enhanced tumor uptake of carboplatin and survival in gliomabearing rats by intracarotid infusion of bradykinin analog, RMP-7. Neurosurgery 39:125-133; discussion 133-134.
108. McAllister MS, Krizanac-Bengez L, Macchia F, Naftalin RJ, Pedley KC, Mayberg MR, et al. 2001. Mechanisms of glucose transport at the blood-brain barrier: An in vitro study. Brain Res 904:20-30.
109. McCrea PD, Gumbiner BM. 1991. Purification of a 92-kDa cytoplasmic protein tightly associated with the cell-cell adhesion molecule E-cadherin (uvomorulin). Characterization and extractability of the protein complex from the cell cytostructure. J Biol Chem 266: 4514-4520.
110. Mi H, Haeberle H, Barres BA. 2001. Induction of astrocyte differentiation by endothelial cells. J Neurosci 21:1538-1547.
111. Miller G. 2002. Drug targeting. Breaking down barriers. Science 297: 1116-1118.
112. Mishra V, Mahor S, Rawat A, Gupta PN, Dubey P, Khatri K, Vyas SP. 2006. Targeted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles. J Drug Target 14:45-53.
113. Mizuguchi H, Utoguchi N, Mayumi T. 1997. Preparation of glial extracellular matrix: A novel method to analyze glial-endothelial cell interaction. Brain Res Brain Res Protoc 1:339-343.
114. Montenegro L, Trapani A, Latrofa A, Puglisi G. 2012. In vitro evaluation on a model of blood brain barrier of idebenone-loaded solid lipid nanoparticles. J Nanosci Nanotechnol 12:330-337.
115. Nagafuchi A, Takeichi M. 1989. Transmembrane control of cadherinmediated cell adhesion: A 94 kDa protein functionally associated with a specific region of the cytoplasmic domain of E-cadherin. Cell Regul 1:37-44.
116. Neuwelt EA. 2004. Mechanisms of disease: The blood-brain barrier. Neurosurgery 54:131-140; discussion 141-142.
117. Newton HB. 2006. Advances in strategies to improve drug delivery to brain tumors. Expert Rev Neurother 6:1495-1509.
118. Nusrat A, Brown GT, Tom J, Drake A, Bui TT, Quan C, Mrsny RJ. 2005. Multiple protein interactions involving proposed extracellular loop domains of the tight junction protein occludin. Mol Biol Cell 16:1725-1734.
119. Olivier JC. 2005. Drug transport to brain with targeted nanoparticles. NeuroRx 2:108-119.
120. Orthmann A, Fichtner I, Zeisig R. 2011. Improving the transport of chemotherapeutic drugs across the blood-brain barrier. Expert Rev Clin Pharmacol 4:477-490.
121. Palmeri D, van Zante A, Huang CC, Hemmerich S, Rosen SD. 2000. Vascular endothelial junction-Associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells. J Biol Chem 275:19139-19145.
122. Pardridge WM. 1992. Recent developments in peptide drug delivery to the brain. Pharmacol Toxicol 71:3-10.
123. Pardridge WM. 1994. New approaches to drug delivery through the blood-brain barrier. Trends Biotechnol 12:239-245.
124. Pardridge WM, Oldendorf WH. 1975. Kinetic analysis of blood-brain barrier transport of amino acids. Biochim Biophys Acta 401:128-136.
125. Pardridge WM, Triguero D, Buciak J, Yang J. 1990. Evaluation of cationized rat albumin as a potential blood-brain barrier drug transport vector. J Pharmacol Exp Ther 255:893-899.
126. Patel MM, Goyal BR, Bhadada SV, Bhatt JS, Amin AF. 2009. Getting into the brain: Approaches to enhance brain drug delivery. CNS Drugs 23:35-58.
127. Perry VH, Anthony DC, Bolton SJ, Brown HC. 1997. The blood-brain barrier and the inflammatory response. Mol Med Today 3:335-341.
128. Petty MA, Lo EH. 2002. Junctional complexes of the blood-brain barrier: Permeability changes in neuroinflammation. Prog Neurobiol 68: 311-323.
129. Polli EE. 2000. Transplanting bone-marrow stem cells in the central nervous system. Haematologica 85:1009-1010.
130. Ponting CP, Phillips C, Davies KE, Blake DJ. 1997. PDZ domains: Targeting signalling molecules to sub-membranous sites. Bioessays 19:469-479.
131. Prieto P, Blaauboer BJ, de Boer AG, Boveri M, Cecchelli R, Clemedson C, et al. 2004. Blood-brain barrier in vitro models and their application in toxicology. The report and recommendations of ECVAM Workshop 49. Altern Lab Anim 32:37-50.
132. Qin Y, Chen H, Yuan W, Kuai R, Zhang Q, Xie F, et al. 2011. Liposome formulated with TAT-modified cholesterol for enhancing the brain delivery. Int J Pharm 419:85-95.
133. Qu B, Li X, Guan M, Li X, Hai L, Wu Y. 2014. Design, synthesis and biological evaluation of multivalent glucosides with high affinity as ligands for brain targeting liposomes. Eur J Med Chem 72:110-118.
134. Rao KS, Reddy MK, Horning JL, Labhasetwar V. 2008. TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs. Biomaterials 29:4429-4438.
135. Ratcliffe MJ, Rubin LL, Staddon JM. 1997. Dephosphorylation of the cadherin-Associated p100/p120 proteins in response to activation of protein kinase C in epithelial cells. J Biol Chem 272: 31894-31901.
136. Rautio J, Laine K, Gynther M, Savolainen J. 2008. Prodrug approaches for CNS delivery. Aaps J 10:92-102.
137. Reinhardt CA, Gloor S.M. 1997. Co-culture blood-brain barrier models and their use for pharmatoxicological screening. Toxicol In Vitro 11 513-518.
138. Rempe R, Cramer S, Huwel S, Galla HJ. 2011. Transport of Poly (n-butylcyano-Acrylate) nanoparticles across the blood-brain barrier in vitro and their influence on barrier integrity. Biochem Biophys Res Commun 406:64-69.
139. Ricci M, Blasi P, Giovagnoli S, Rossi C. 2006. Delivering drugs to the central nervous system: A medicinal chemistry or a pharmaceutical technology issue? Curr Med Chem 13:1757-1775.
140. Ridet JL, Malhotra SK, Privat A, Gage FH. 1997. Reactive astrocytes: Cellular and molecular cues to biological function. Trends Neurosci 20:570-577.
141. Risau W, Wolburg H. 1990. Development of the blood-brain barrier. Trends Neurosci 13:174-178.
142. Rubin LL, Hall DE, Porter S, Barbu K, Cannon C, Horner HC, et al.1991. A cell culture model of the blood-brain barrier. J Cell Biol 115: 1725-1735.
143. Rubin LL, Staddon JM. 1999. The cell biology of the blood-brain barrier. Annu Rev Neurosci 22:11-28.
144. Salahuddin TS, Kalimo H, Johansson BB, Olsson Y. 1988. Observations on exsudation of fibronectin, fibrinogen and albumin in the brain after carotid infusion of hyperosmolar solutions. An immunohistochemical study in the rat indicating longlasting changes in the brain microenvironment and multifocal nerve cell injuries. Acta Neuropathol 76:1-10.
145. Santini Jr. JT, Cima MJ, Langer R. 1999. A controlled-release microchip. Nature 397:335-338.
146. Sarna GS, Bradbury MW, Cremer JE, Lai JC, Teal HM. 1979. Brain metabolism and specific transport at the blood-brain barrier after portocaval anastomosis in the rat. Brain Res 160:69-83.
147. Satoh H, Zhong Y, Isomura H, Saitoh M, Enomoto K, Sawada N, Mori M. 1996. Localization of 7H6 tight junctions-Associated antigen along the cell border of vascular endothelial cells correlates with paracellular barrier function against ions, large molecules, and cancer cells. Exp Cell Res 222:269-274.
148. Scheld WM. 1989. Drug delivery to the central nervous system: General principles and relevance to therapy for infections of the central nervous system. Rev Infect Dis 11:S1669-S1690.
149. Scherrmann JM. 2002. Drug delivery to brain via the blood-brain barrier. Vascul Pharmacol 38:349-354.
150. Schinkel AH. 1999. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 36:179-194.
151. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. 1994. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491-502.
152. Schinkel AH, Wagenaar E, Mol CA, Van Deemter L. 1996. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97:2517-2524.
153. Schlageter KE, Molnar P, Lapin GD, Groothuis DR. 1999. Microvessel organization and structure in experimental brain tumors: Microvessel populations with distinctive structural and functional properties. Microvasc Res 58:312-328.
154. Schroeter ML, Mertsch K, Giese H, Muller S, Sporbert A, Hickel B, Blasig IE. 1999. Astrocytes enhance radical defence in capillary endothelial cells constituting the blood-brain barrier. FEBS Lett 449: 241-244.
155. Schulze C, Firth JA. 1993. Immunohistochemical localization of adherens junction components in blood-brain barrier microvessels of the rat. J Cell Sci 104:773-782.
156. Sharma G, Modgil A, Zhong T, Sun C, Singh J. 2014. Influence of shortchain cell-penetrating peptides on transport of doxorubicin encapsulating receptor-Targeted liposomes across brain endothelial barrier. Pharm Res 31:1194-1209.
157. Sobue K, Yamamoto N, Yoneda K, Hodgson ME, Yamashiro K, Tsuruoka N, et al. 1999. Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci Res 35:155-164.
158. Soni V, Kohli DV, Jain SK. 2005. Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil. J Drug Target 13: 245-250.
159. Staddon JM, Rubin LL. 1996. Cell adhesion, cell junctions and the blood-brain barrier. Curr Opin Neurobiol 6:622-627.
160. Stamatovic SM, Keep RF, Andjelkovic AV. 2008. Brain endothelial cell-cell junctions: How to 'open' the blood brain barrier. Curr Neuropharmacol 6:179-192.
161. Stanness KA, Westrum LE, Fornaciari E, Mascagni P, Nelson JA, Stenglein SG, et al. 1997. Morphological and functional characterization of an in vitro blood-brain barrier model. Brain Res 771: 329-342.
162. Stewart PA, Wiley MJ. 1981. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: A study using quail-chick transplantation chimeras. Dev Biol 84:183-192.
163. Sumbria RK, Boado RJ, Pardridge WM. 2013. Combination stroke therapy in the mouse with bloo-brain barrier penetrating IgG-GDNF and IgG-TNF decoy receptor fusion proteins. Brain Res 1507:91-96.
164. Sun H, Dai H, Shaik N, Elmquist WF. 2003. Drug efflux transporters in the CNS. Adv Drug Deliv Rev 55:83-105.
165. Taki H, Kanazawa T, Akiyama F, Takashima Y, Okada H. 2012. Intranasal delivery of camptothecin-loaded tat-modified nanomicells for treatment of intracranial brain tumors. Pharmaceuticals (Basel) 5: 1092-1102.
166. Tamai I, Tsuji A. 2000. Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci 89:1371-1388.
167. Thomas WE. 1999. Brain macrophages: On the role of pericytes and perivascular cells. Brain Res Rev 31:42-57.
168. Thorne RG, Emory CR, Ala TA, Frey 2nd WH. 1995. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res 692:278-282.
169. Thorne RG, Frey 2nd WH. 2001. Delivery of neurotrophic factors to the central nervous system: Pharmacokinetic considerations. Clin Pharmacokinet 40:907-946.
170. Tiwari SB, Amiji MM. 2006. A review of nanocarrier-based CNS delivery systems. Curr Drug Deliv 3:219-232.
171. Treeratanapiboon L, Psathaki K, Wegener J, Looareesuwan S, Galla HJ, Udomsangpetch R. 2005. In vitro study of malaria parasite induced disruption of blood-brain barrier. Biochem Biophys Res Communic 335:810-818.
172. Verkman AS. 2002. Aquaporin water channels and endothelial cell function. J Anat 200:617-627.
173. Vlieghe P, Khrestchatisky M. 2013. Medicinal chemistry based approaches and nanotechnology-based systems to improve CNS drug targeting and delivery. Med Res Rev 33:457-516.
174. Vykhodtseva N, McDannold N, Hynynen K. 2008. Progress and problems in the application of focused ultrasound for blood-brain barrier disruption. Ultrasonics 48:279-296.
175. Williams LA, Martin-Padura I, Dejana E, Hogg N, Simmons DL. 1999. Identification and characterisation of human Junctional Adhesion Molecule (JAM). Mol Immunol 36:1175-1188.
176. Witt KA, Gillespie TJ, Huber JD, Egleton RD, Davis TP. 2001. Peptide drug modifications to enhance bioavailability and blood-brain barrier permeability. Peptides 22:2329-2343.
177. Wolburg H, Lippoldt A. 2002. Tight junctions of the blood-brain barrier: Development, composition and regulation. Vascul Pharmacol 38: 323-337.
178. Wu G, Barth RF, Yang W, Kawabata S, Zhang L, Green-Church K. 2006. Targeted delivery of methotrexate to epidermal growth factor receptor-positive brain tumors by means of cetuximab (IMC-C225) dendrimer bioconjugates. Mol Cancer Ther 5:52-59.
179. Yamanaka T, Horikoshi Y, Suzuki A, Sugiyama Y, Kitamura K, Maniwa R, et al. 2001. PAR-6 regulates a PKC activity in a novel way and mediates cellcell contact-induced formation of the epithelial junctional complex. Genes Cells 6:721-731.
180. Ying X, Wen H, Lu WL, Du J, Guo J, Tian W, et al. 2010. Dual-Targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals. J Control Release 141:183-192.
181. Zhang C, Su Z, Zhao B, Qu Q, Tan Y, Cai L, Li X. 2010. Tat-modified leptin is more accessible to hypothalamus through brain-blood barrier with a significant inhibition of body-weight gain in high-fat-diet fed mice. Exp Clin Endocrinol Diabetes 118:31-37.
182. Zhang Y, Zhang YF, Bryant J, Charles A, Boado RJ, Pardridge WM. 2004. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin Cancer Res 10:3667-3677.
183. Zhang Y, Zhu C, Pardridge WM. 2002. Antisense gene therapy of brain cancer with an artificial virus gene delivery system. Mol Ther 6:67-72.
184. Zhu Y, Bu Q, Liu X, Hu W, Wang Y. 2014. Neuroprotective effect of TAT-14-3-3" fusion protein against cerebral ischemia/reperfusion injury in rats. PLoS One 26:e93334..