Impacts of blood-brain barrier in drug delivery and targeting of brain tumors

BioImpacts

Volumn 2, Issue 1, 2012, Pages 5-22

  Omidi, Yadollah ^a,b   Barar, Jaleh ^a,b  

^a TABRIZ UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Blood brain barrier; Brain capillary endothelial cells; Brain tumor; Drug delivery; Drug targeting; Nanomedicines; Theranostics

Indexed keywords

ABC TRANSPORTER; ANTINEOPLASTIC AGENT; BETA CYCLODEXTRIN QUATERNARY AMMONIUM NANOPARTICLE; DAB 389IL 2; DENILEUKIN DIFTITOX; DOXORUBICIN; DTAT 13; GADOLINIUM PENTETATE; GREEN FLUORESCENT PROTEIN; IMMUNOTOXIN; INTERLEUKIN 4 PSEUDOMONAS EXOTOXIN CONJUGATE; LIPOSOME; MULTIDRUG RESISTANCE PROTEIN; NANOPARTICLE; NBI 3001; QUANTUM DOT; TP 38 PSEUDOMONAS EXOTOXIN CONJUGATE; ULTRASMALL SUPERPARAMAGNETIC IRON OXIDE; UNCLASSIFIED DRUG;

ARTICLE; ASTROCYTE; BLOOD BRAIN BARRIER; BRAIN CAPILLARY; BRAIN TUMOR; CELL FUNCTION; CELL INTERACTION; CELL MIGRATION; CELL SELECTION; CELL SPECIFICITY; CELL STRUCTURE; CUTANEOUS T CELL LYMPHOMA; DIAGNOSTIC ACCURACY; DIAGNOSTIC IMAGING; DRUG CYTOTOXICITY; DRUG DELIVERY SYSTEM; DRUG DOSAGE FORM COMPARISON; DRUG EFFECT; DRUG RESPONSE; DRUG TARGETING; ELECTRIC RESISTANCE; ENDOTHELIUM CELL; FLUORESCENCE ANALYSIS; GLIOBLASTOMA; HUMAN; MEMBRANE RESISTANCE; MOLECULAR DYNAMICS; NANOMEDICINE; NEAR INFRARED SPECTROSCOPY; NEUROIMAGING; NUCLEAR MAGNETIC RESONANCE IMAGING; PERICYTE; PROTEIN FUNCTION; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION; TIGHT JUNCTION; TUMOR MICROENVIRONMENT;

EID: 84876731279     PISSN: 22285652     EISSN: 22285660     Source Type: Journal    
DOI: 10.5681/bi.2012.002     Document Type: Article

References (101)

1. Abbott NJ. 2005. Dynamics of CNS barriers: evolution, differentiation, and modulation. Cell Mol Neurobiol, 25(1), 5-23.
2. Abbott NJ, Hughes CC, Revest PA and Greenwood J. 1992. Development and characterisation of a rat brain capillary endothelial culture: towards an in vitro blood-brain barrier. J Cell Sci, 103(Pt 1) 23-37.
3. Abbott NJ, Ronnback L and Hansson E. 2006. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci, 7(1), 41-53.
4. Afonso PV, Ozden S, Prevost MC, Schmitt C, Seilhean D, Weksler B, et al. 2007. Human blood-brain barrier disruption by retroviral-infected lymphocytes: role of myosin light chain kinase in endothelial tight-junction disorganization. J Immunol, 179(4), 2576-83.
5. Agarwal S, Hartz AM, Elmquist WF and Bauer B. 2011. Breast cancer resistance protein and P-glycoprotein in brain cancer: two gatekeepers team up. Curr Pharm Des, 17(26), 2793-802.
6. Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, et al. 2010. Pericytes regulate the blood-brain barrier. Nature, 468(7323), 557-61.
7. Balabanov R and Dore-Duffy P. 1998. Role of the CNS microvascular pericyte in the blood-brain barrier. J Neurosci Res, 53(6), 637-44.
8. Balbuena P, Li W and Ehrich M. 2011. Assessments of tight junction proteins occludin, claudin 5 and scaffold proteins ZO1 and ZO2 in endothelial cells of the rat blood-brain barrier: cellular responses to neurotoxicants malathion and lead acetate. Neurotoxicology, 32(1), 58-67.
9. Banks WA. 2010. Blood-brain barrier as a regulatory interface. Forum Nutr, 63 102-10.
10. Barar J and Omidi Y. 2008. Bioelectrical and permeability properties of brain microvasculature endothelial cells: Effects of tight junction modulators. J Biol Sci, 8(3), 556-562.
11. Begley DJ. 2004. ABC transporters and the blood-brain barrier. Curr Pharm Des, 10(12), 1295-312.
12. Bellavance MA, Poirier MB and Fortin D. 2010. Uptake and intracellular release kinetics of liposome formulations in glioma cells. Int J Pharm, 395(1-2), 251-9.
13. Betz AL, Firth JA and Goldstein GW. 1980. Polarity of the blood-brain barrier: distribution of enzymes between the luminal and antiluminal membranes of brain capillary endothelial cells. Brain Res, 192(1), 17-28.
14. Burgess A, Ayala-Grosso CA, Ganguly M, Jordao JF, Aubert I and Hynynen K. 2011. Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier. PLoS One, 6(11), e27877.
15. Caram-Salas N, Boileau E, Farrington GK, Garber E, Brunette E, Abulrob A, et al. 2011. In vitro and in vivo methods for assessing FcRn-mediated reverse transcytosis across the blood-brain barrier. Methods Mol Biol, 763 383-401.
16. Cascorbi I and Haenisch S. 2010. Pharmacogenetics of ATP-binding cassette transporters and clinical implications. Methods Mol Biol, 596 95-121.
17. Chang J, Jallouli Y, Kroubi M, Yuan XB, Feng W, Kang CS, et al. 2009. Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood-brain barrier. Int J Pharm, 379(2), 285-92.
18. Chekhonin VP, Baklaushev VP, Yusubalieva GM, Belorusova AE, Gulyaev MV, Tsitrin EB, et al. 2012. Targeted delivery of liposomal nanocontainers to the peritumoral zone of glioma by means of monoclonal antibodies against GFAP and the extracellular loop of Cx43. Nanomedicine, 8(1), 63-70.
19. Chen H, Tang L, Qin Y, Yin Y, Tang J, Tang W, et al. 2010a. Lactoferrin-modified procationic liposomes as a novel drug carrier for brain delivery. Eur J Pharm Sci, 40(2), 94-102.
20. Chen PY, Liu HL, Hua MY, Yang HW, Huang CY, Chu PC, et al. 2010b. Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment. Neuro Oncol, 12(10), 1050-60.
21. Chertok B, David AE and Yang VC. 2010. Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration. Biomaterials, 31(24), 6317-24.
22. Cohen-Kashi Malina K, Cooper I and Teichberg VI. 2009. Closing the gap between the in-vivo and in-vitro blood-brain barrier tightness. Brain Res, 1284 12-21.
23. Correale J and Villa A. 2009. Cellular elements of the blood-brain barrier. Neurochem Res, 34(12), 2067-77.
24. Elwi AN, Damaraju VL, Kuzma ML, Baldwin SA, Young JD, Sawyer MB, et al. 2009. Human concentrative nucleoside transporter 3 is a determinant of fludarabine transportability and cytotoxicity in human renal proximal tubule cell cultures. Cancer Chemother Pharmacol, 63(2), 289-301.
25. Fattori S, Becherini F, Cianfriglia M, Parenti G, Romanini A and Castagna M. 2007. Human brain tumors: multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells. Virchows Arch, 451(1), 81-7.
26. Fletcher JI, Haber M, Henderson MJ and Norris MD. 2010. ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer, 10(2), 147-56.
27. Frankel AE, Powell BL and Lilly MB. 2002. Diphtheria toxin conjugate therapy of cancer. Cancer Chemother Biol Response Modif, 20 301-13.
28. Georgieva JV, Kalicharan D, Couraud PO, Romero IA, Weksler B, Hoekstra D, et al. 2011. Surface characteristics of nanoparticles determine their intracellular fate in and processing by human blood-brain barrier endothelial cells in vitro. Mol Ther, 19(2), 318-25.
29. Gil ES, Li J, Xiao H and Lowe TL. 2009. Quaternary ammonium beta-cyclodextrin nanoparticles for enhancing doxorubicin permeability across the in vitro blood-brain barrier. Biomacromolecules, 10(3), 505-16.
30. Gumbleton M and Audus KL. 2001. Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier. J Pharm Sci, 90(11), 1681-98.
31. Hawkins BT and Davis TP. 2005. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev, 57(2), 173-85.
32. He H, Li Y, Jia XR, Du J, Ying X, Lu WL, et al. 2011. PEGylated Poly(amidoamine) dendrimer-based dual-targeting carrier for treating brain tumors. Biomaterials, 32(2), 478-87.
33. Herve F, Ghinea N and Scherrmann JM. 2008. CNS delivery via adsorptive transcytosis. The AAPS journal, 10(3), 455-72.
34. Hu J, Yuan X, Ko MK, Yin D, Sacapano MR, Wang X, et al. 2007. Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model. Mol Cancer, 6 22.
35. Hubeek I, Stam RW, Peters GJ, Broekhuizen R, Meijerink JP, Van Wering ER, et al. 2005. The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia. Br J Cancer, 93(12), 1388-94.
36. Jallouli Y, Paillard A, Chang J, Sevin E and Betbeder D. 2007. Influence of surface charge and inner composition of porous nanoparticles to cross blood-brain barrier in vitro. Int J Pharm, 344(1-2), 103-9.
37. Jensen RL. 2009. Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol, 92(3), 317-35.
38. Jinga VV, Gafencu A, Antohe F, Constantinescu E, Heltianu C, Raicu M, et al. 2000. Establishment of a pure vascular endothelial cell line from human placenta. Placenta, 21(4), 325-36.
39. Kafil V and Omidi Y. 2011. Cytotoxic Impacts of Linear and Branched Polyethylenimine Nanostructures in A431 Cells. BioImpacts, 1(1), 23-30.
40. Kantelhardt SR, Caarls W, De Vries AH, Hagen GM, Jovin TM, Schulz-Schaeffer W, et al. 2010. Specific visualization of glioma cells in living low-grade tumor tissue. PLoS One, 5(6), e11323.
41. Kievit FM, Veiseh O, Fang C, Bhattarai N, Lee D, Ellenbogen RG, et al. 2010. Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma. ACS Nano, 4(8), 4587-94.
42. Kim HR, Gil S, Andrieux K, Nicolas V, Appel M, Chacun H, et al. 2007. Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells. Cell Mol Life Sci, 64(3), 356-64.
43. Kniesel U and Wolburg H. 2000. Tight junctions of the blood-brain barrier. Cell Mol Neurobiol, 20(1), 57-76.
44. Krause D, Kunz J and Dermietzel R. 1993. Cerebral pericytes--a second line of defense in controlling blood-brain barrier peptide metabolism. Adv Exp Med Biol, 331 149-52.
45. Krizbai IA and Deli MA. 2003. Signalling pathways regulating the tight junction permeability in the blood-brain barrier. Cell Mol Biol (Noisy-le-grand), 49(1), 23-31.
46. Kuo YC and Chung CY. 2012. Transcytosis of CRM197-grafted polybutylcyanoacrylate nanoparticles for delivering zidovudine across human brain-microvascular endothelial cells. Colloids Surf B Biointerfaces, 91 242-9.
47. Laske DW, Youle RJ and Oldfield EH. 1997. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med, 3(12), 1362-8.
48. Leslie EM, Deeley RG and Cole SP. 2005. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol, 204(3), 216-37.
49. Li YM and Hall WA. 2010. Targeted toxins in brain tumor therapy. Toxins, 2(11), 2645-62.
50. Liebner S, Czupalla CJ and Wolburg H. 2011. Current concepts of blood-brain barrier development. Int J Dev Biol, 55(4-5), 467-76.
51. Liu HL, Hua MY, Yang HW, Huang CY, Chu PC, Wu JS, et al. 2010. Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc Natl Acad Sci U S A, 107(34), 15205-10.
52. Liu HL, Yang HW, Hua MY and Wei KC. 2012. Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status. Neurosurg Focus, 32(1), E4.
53. Lu W, Melancon MP, Xiong C, Huang Q, Elliott A, Song S, et al. 2011. Effects of photoacoustic imaging and photothermal ablation therapy mediated by targeted hollow gold nanospheres in an orthotopic mouse xenograft model of glioma. Cancer Res, 71(19), 6116-21.
54. Marce S, Molina-Arcas M, Villamor N, Casado FJ, Campo E, Pastor-Anglada M, et al. 2006. Expression of human equilibrative nucleoside transporter 1 (hENT1) and its correlation with gemcitabine uptake and cytotoxicity in mantle cell lymphoma. Haematologica, 91(7), 895-902.
55. Mata JF, Garcia-Manteiga JM, Lostao MP, Fernandez-Veledo S, Guillen-Gomez E, Larrayoz IM, et al. 2001. Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol Pharmacol, 59(6), 1542-8.
56. Micheli MR, Bova R, Magini A, Polidoro M and Emiliani C. 2012. Lipid-Based Nanocarriers for CNS-Targeted Drug Delivery. Recent Pat CNS Drug Discov, 7(1), 71-86.
57. Molina-Arcas M, Marce S, Villamor N, Huber-Ruano I, Casado FJ, Bellosillo B, et al. 2005. Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells. Leukemia, 19(1), 64-8.
58. Nakhlband A and Omidi Y. 2011. Barrier Functionality of Porcine and Bovine Brain Capillary Endothelial Cells. BioImpacts, 1(3), 153-159.
59. Nico B and Ribatti D. 2012. Morphofunctional aspects of the blood-brain barrier. Curr Drug Metab.
60. Ningaraj NS, Rao M, Hashizume K, Asotra K and Black KL. 2002. Regulation of blood-brain tumor barrier permeability by calcium-activated potassium channels. J Pharmacol Exp Ther, 301(3), 838-51.
61. Ningaraj NS, Salimath BP, Sankpal UT, Perera R and Vats T. 2007. Targeted brain tumor treatment-current perspectives. Drug Target Insights, 2 197-207.
62. Ohtsuki S and Terasaki T. 2007. Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res, 24(9), 1745-58.
63. Omidi Y, Barar J, Ahmadian S, Heidari HR and Gumbleton M. 2008. Characterization and astrocytic modulation of system L transporters in brain microvasculature endothelial cells. Cell Biochem Funct, 26(3), 381-91.
64. Omidi Y, Campbell L, Barar J, Connell D, Akhtar S and Gumbleton M. 2003. Evaluation of the immortalised mouse brain capillary endothelial cell line, b.End3, as an in vitro blood-brain barrier model for drug uptake and transport studies. Brain Res, 990(1-2), 95-112.
65. Omidi Y and Gumbleton M. 2005. Biological Membranes and Barriers, In: Biomaterials for delivery and targeting of proteins and nucleic acids. Mahato R (Ed.) New York, CRC Press, 220-263.
66. Orlowski M, Sessa G and Green JP. 1974. Gamma-glutamyl transpeptidase in brain capillaries: possible site of a blood-brain barrier for amino acids. Science, 184(4132), 66-8.
67. Orringer DA, Koo YE, Chen T, Kopelman R, Sagher O and Philbert MA. 2009. Small solutions for big problems: the application of nanoparticles to brain tumor diagnosis and therapy. Clin Pharmacol Ther, 85(5), 531-4.
68. Orthmann A, Zeisig R, Koklic T, Sentjurc M, Wiesner B, Lemm M, et al. 2010. Impact of membrane properties on uptake and transcytosis of colloidal nanocarriers across an epithelial cell barrier model. J Pharm Sci, 99(5), 2423-33.
69. Pang Z, Gao H, Yu Y, Chen J, Guo L, Ren J, et al. 2011. Brain delivery and cellular internalization mechanisms for transferrin conjugated biodegradable polymersomes. Int J Pharm, 415(1-2), 284-92.
70. Powell DW. 1981. Barrier function of epithelia. Am J Physiol, 241(4), G275-88.
71. Provenzale JM, Mukundan S and Dewhirst M. 2005. The role of blood-brain barrier permeability in brain tumor imaging and therapeutics. AJR Am J Roentgenol, 185(3), 763-7.
72. Ramsauer M, Kunz J, Krause D and Dermietzel R. 1998. Regulation of a blood-brain barrier-specific enzyme expressed by cerebral pericytes (pericytic aminopeptidase N/pAPN) under cell culture conditions. J Cereb Blood Flow Metab, 18(11), 1270-81.
73. Reese TS and Karnovsky MJ. 1967. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol, 34(1), 207-17.
74. Robert AM and Robert L. 1998. Extracellular matrix and blood-brain barrier function. Pathol Biol (Paris), 46(7), 535-42.
75. Robey RW, Massey PR, Amiri-Kordestani L and Bates SE. 2010. ABC transporters: unvalidated therapeutic targets in cancer and the CNS. Anticancer Agents Med Chem, 10(8), 625-33.
76. Roger M, Clavreul A, Venier-Julienne MC, Passirani C, Montero-Menei C and Menei P. 2011. The potential of combinations of drug-loaded nanoparticle systems and adult stem cells for glioma therapy. Biomaterials, 32(8), 2106-16.
77. Rubin LL and Staddon JM. 1999. The cell biology of the blood-brain barrier. Annu Rev Neurosci, 22 11-28.
78. Rustamzadeh E, Vallera DA, Todhunter DA, Low WC, Panoskaltsis-Mortari A and Hall WA. 2006. Immunotoxin pharmacokinetics: a comparison of the anti-glioblastoma bi-specific fusion protein (DTAT13) to DTAT and DTIL13. J Neurooncol, 77(3), 257-66.
79. Sampson JH, Akabani G, Archer GE, Bigner DD, Berger MS, Friedman AH, et al. 2003. Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol, 65(1), 27-35.
80. Schinkel AH, Mol CA, Wagenaar E, Van Deemter L, Smit JJ and Borst P. 1995a. Multidrug resistance and the role of P-glycoprotein knockout mice. Eur J Cancer, 31A(7-8), 1295-8.
81. Schinkel AH, Wagenaar E, Van Deemter L, Mol CA and Borst P. 1995b. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest, 96(4), 1698-705.
82. Shi F and Audus KL. 1994. Biochemical characteristics of primary and passaged cultures of primate brain microvessel endothelial cells. Neurochem Res, 19(4), 427-33.
83. Shimamura T, Husain SR and Puri RK. 2006. The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapy. Neurosurg Focus, 20(4), E11.
84. Smith M, Omidi Y and Gumbleton M. 2007. Primary porcine brain microvascular endothelial cells: biochemical and functional characterisation as a model for drug transport and targeting. J Drug Target, 15(4), 253-68.
85. Smith MW and Gumbleton M. 2006. Endocytosis at the blood-brain barrier: from basic understanding to drug delivery strategies. J Drug Target, 14(4), 191-214.
86. Stamatovic SM, Keep RF, Wang MM, Jankovic I and Andjelkovic AV. 2009. Caveolae-mediated internalization of occludin and claudin-5 during CCL2-induced tight junction remodeling in brain endothelial cells. J Biol Chem, 284(28), 19053-66.
87. Tatsuta T, Naito M, Oh-Hara T, Sugawara I and Tsuruo T. 1992. Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem, 267(28), 20383-91.
88. Terasaki T, Ohtsuki S, Hori S, Takanaga H, Nakashima E and Hosoya K. 2003. New approaches to in vitro models of blood-brain barrier drug transport. Drug Discov Today, 8(20), 944-54.
89. Tilling T, Korte D, Hoheisel D and Galla HJ. 1998. Basement membrane proteins influence brain capillary endothelial barrier function in vitro. J Neurochem, 71(3), 1151-7.
90. Tomanek B, Iqbal U, Blasiak B, Abulrob A, Albaghdadi H, Matyas JR, et al. 2012. Evaluation of brain tumor vessels specific contrast agents for glioblastoma imaging. Neuro Oncol, 14(1), 53-63.
91. Trehin R, Figueiredo JL, Pittet MJ, Weissleder R, Josephson L and Mahmood U. 2006. Fluorescent nanoparticle uptake for brain tumor visualization. Neoplasia, 8(4), 302-11.
92. Vallera DA, Li C, Jin N, Panoskaltsis-Mortari A and Hall WA. 2002. Targeting urokinase-type plasminogen activator receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT. J Natl Cancer Inst, 94(8), 597-606.
93. Veiseh O, Gunn JW and Zhang M. 2010. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliv Rev, 62(3), 284-304.
94. Veiseh O, Sun C, Fang C, Bhattarai N, Gunn J, Kievit F, et al. 2009. Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain barrier. Cancer Res, 69(15), 6200-7.
95. Veiseh O, Sun C, Gunn J, Kohler N, Gabikian P, Lee D, et al. 2005. Optical and MRI multifunctional nanoprobe for targeting gliomas. Nano Lett, 5(6), 1003-8.
96. Wakui S, Furusato M, Hasumura M, Hori M, Takahashi H, Kano Y, et al. 1989. Two- and three-dimensional ultrastructure of endothelium and pericyte interdigitations in capillary of human granulation tissue. J Electron Microsc (Tokyo), 38(2), 136-42.
97. Wang P, Xue Y, Shang X and Liu Y. 2010. Diphtheria toxin mutant CRM197-mediated transcytosis across blood-brain barrier in vitro. Cell Mol Neurobiol, 30(5), 717-25.
98. Weber F, Asher A, Bucholz R, Berger M, Prados M, Chang S, et al. 2003. Safety, tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neurooncol, 64(1-2), 125-37.
99. Wolburg H. 2006. The Endothelial Frontier, In: Boold Brain Barriers. Dermietzel R, Spray DC and Nedergaard M (Ed.), Weinheim, WILEY-VCH Verlag GmbH & Co. KGaA.
100. Wong HL, Wu XY and Bendayan R. 2011. Nanotechnological advances for the delivery of CNS therapeutics. Adv Drug Deliv Rev, (in press).
101. Zhang Y, Han H, Elmquist WF and Miller DW. 2000. Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res, 876(1-2), 148-53.