Novel and emerging strategies in drug delivery for overcoming the blood-brain barrier

Future Medicinal Chemistry

Volumn 1, Issue 9, 2009, Pages 1623-1641

  Stenehjem, David D ^a   Hartz, Anika M S ^b   Bauer, Bjrn ^a   Anderson, Grant W ^a  

^a UNIVERSITY OF MINNESOTA   (United States)

^b UNIVERSITY OF MINNESOTA DULUTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; ATORVASTATIN; BUSULFAN; CELL PENETRATING PEPTIDE; CENTRAL NERVOUS SYSTEM AGENTS; CHLORAMBUCIL; DAUNORUBICIN; DELTORPHIN; DIPHTHERIA TOXIN; DOXORUBICIN; ENKEPHALIN; FENAMIC ACID DERIVATIVE; GLIBENCLAMIDE; GLUCOSE TRANSPORTER 1; HYBRID PROTEIN; INSULIN RECEPTOR; KETOPROFEN; LEVODOPA; LIPOPROTEIN RECEPTOR; LOPERAMIDE; LOW DENSITY LIPOPROTEIN RECEPTOR; METHOTREXATE; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY OX26; ORGANIC ANION TRANSPORTER 2; PACLITAXEL; SAQUINAVIR; THYROXINE; TRANSFERRIN RECEPTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ACTIVE TRANSPORT; BLOOD BRAIN BARRIER; CEREBROVASCULAR ACCIDENT; DRUG DELIVERY SYSTEM; DRUG EFFECT; DRUG EFFICACY; DRUG TARGETING; ENDOTHELIUM CELL; GENE MUTATION; HUMAN; MICROVASCULARIZATION; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW;

BLOOD-BRAIN BARRIER; BRAIN; CELL-PENETRATING PEPTIDES; CENTRAL NERVOUS SYSTEM; DRUG DELIVERY SYSTEMS; HUMANS; MEMBRANE TRANSPORT PROTEINS; RECEPTORS, CELL SURFACE;

EID: 77953473441     PISSN: 17568919     EISSN: None     Source Type: Journal    
DOI: 10.4155/fmc.09.137     Document Type: Review

References (188)

1. Neuwelt E, Abbott NJ, Abrey L et al. Strategies to advance translational research into brain barriers. Lancet Neurol. 7, 84-96, (2008).
2. Brightman MW. Morphology of blood-brain interfaces. Exp. Eye Res. 25(Suppl. 1), 1-25, (1977).
3. Tamai I, Tsuji A. Transporter-mediated permeation of drugs across the blood-brain barrier. J. Pharm. Sci. 89, 1371-1388 (2000).
4. Enerson BE, Drewes LR. Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery. J. Pharm. Sci. 92, 1531-1544 (2003).
5. Banks WA, Kastin AJ. Peptide transport systems for opiates across the blood-brain barrier. Am. J. Physiol. 259, E1-10 (1990).
6. Girardin F. Membrane transporter proteins: a challenge for CNS drug development. Dialogues Clin. Neurosci. 8, 311-321 (2006).
7. Pardridge WM. Molecular Trojan horses for blood-brain barrier drug delivery. Curr. Opin. Pharmacol. 6, 494-500 (2006).
8. Clark DE. In silico prediction of blood-brain barrier permeation. Drug Discov. Today 8, 927-933 (2003).
9. Miller DS, Bauer B, Hartz AM. Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol. Rev. 60, 196-209 (2008).
10. de Boer AG, Gaillard PJ. Drug targeting to the brain. Annu. Rev. Pharmacol. Toxicol. 47, 323-355 (2007).
11. Rapoport SI. Advances in osmotic opening of the blood-brain barrier to enhance CNS chemotherapy. Expert Opin. Investig. Drugs 10, 1809-1818 (2001).
12. Erdlenbruch B, Alipour M, Fricker G et al. 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 (2003).
13. Borlongan CV, Emerich DF. Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist. Cereport. Brain Res. Bull. 60, 297-306 (2003).
14. Agarwal A, Lariya N, Saraogi G, Dubey N, Agrawal H, Agrawal GP. Nanoparticles as novel carrier for brain delivery: a review. Curr. Pharm. Des. 15, 917-925 (2009).
15. Begley DJ. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol. Ther. 104, 29-45 (2004).
16. Bennewitz MF, Saltzman WM. Nanotechnology for delivery of drugs to the brain for epilepsy. Neurotherapeutics 6, 323-336 (2009).
17. Denora N, Trapani A, Laquintana V, Lopedota A, Trapani G. Recent advances in medicinal chemistry and pharmaceutical technology - strategies for drug delivery to the brain. Curr. Top Med. Chem. 9, 182-196 (2009).
18. Smith QR. Drug delivery to brain and the role of carrier-mediated transport. Adv. Exp. Med. Biol. 331, 83-93 (1993).
19. Gaillard PJ, Brink A, de Boer AG. Diphtheria toxin receptor-targeted brain drug delivery. Int. Congress Ser. 1277, 185-198 (2005).
20. Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat. Rev. Drug Discov. 1, 131-139 (2002).
21. Duelli R, Enerson BE, Gerhart DZ, Drewes LR. Expression of large amino acid transporter LAT1 in rat brain endothelium. J. Cereb. Blood Flow Metab. 20, 1557-1562 (2000).
22. Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral amino acid transport across the blood-brain barrier. J. Neurochem. 49, 1651-1658 (1987).
23. van Bree JB, Audus KL, Borchardt RT. Carrier-mediated transport of baclofen across monolayers of bovine brain endothelial cells in primary culture. Pharm. Res. 5, 369-371 (1988).
24. Markovitz DC, Fernstrom JD. Diet and uptake of aldomet by the brain: competition with natural large neutral amino acids. Science 197, 1014-1015 (1977).
25. Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL. The 'on-off ' phenomenon in Parkinson's disease. Relation to levodopa absorption and transport. N. Engl. J. Med. 310, 483-488 (1984).
26. Killian DM, Hermeling S, Chikhale PJ. Targeting the cerebrovascular large neutral amino acid transporter (LAT1) isoform using a novel disulfide-based brain drug delivery system. Drug Deliv. 14, 25-31 (2007).
27. Gynther M, Laine K, Ropponen J et al. Large neutral amino acid transporter enables brain drug delivery via prodrugs. J. Med. Chem. 51, 932-936 (2008).
28. Uchino H, Kanai Y, Kim DK et al. Transport of amino acid-related compounds mediated by l-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. Mol. Pharmacol. 61, 729-737 (2002).
29. Kobayashi K, Ohnishi A, Promsuk J et al. Enhanced tumor growth elicited by l-type amino acid transporter 1 in human malignant glioma Cells. Neurosurgery 62, 493-503 (2008).
30. Farrell CL, Pardridge WM. Ultrastructural localization of blood-brain barrier-specific antibodies using immunogold-silver enhancement techniques. J. Neurosci. Methods 37, 103-110 (1991).
31. Guo X, Geng M, Du G. Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood-brain barrier. Biochem. Genet. 43, 175-187 (2005).
32. Halmos T, Santarromana M, Antonakis K, Scherman D. Synthesis of glucose- chlorambucil derivatives and their recognition by the human GLUT1 glucose transporter. Eur. J. Pharmacol. 318, 477-484 (1996).
33. Halmos T, Santarromana M, Antonakis K, Scherman D. 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, 15-21 (1997).
34. Polt R, Porreca F, Szabo LZ et al. Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier. Proc. Natl Acad. Sci. USA 91, 7114-7118 (1994).
35. Tomatis R, Marastoni M, Balboni G et al. Synthesis and pharmacological activity of deltorphin and dermorphin-related glycopeptides. J. Med. Chem. 40, 2948-2952 (1997).
36. Bilsky EJ, Egleton RD, Mitchell SA et al. Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability. J. Med. Chem. 43, 2586-2590 (2000).
37. Dhanasekaran M, Polt R. New prospects for glycopeptide based analgesia: glycosideinduced penetration of the blood-brain barrier. Curr. Drug Deliv. 2, 59-73 (2005).
38. Dhanasekaran M, Palian MM, Alves I et al. Glycopeptides related to b-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers. J. Am. Chem. Soc. 127, 5435-5448 (2005).
39. Westholm DE, Rumbley JN, Salo DR, Rich TP, Anderson GW. Organic aniontransporting polypeptides at the blood-brain and blood-cerebrospinal fluid barriers. Curr. Top Dev. Biol. 80, 135-170 (2008).
40. Westholm DE, Stenehjem DD, Rumbley JN, Drewes LR, Anderson GW. Competitive inhibition of organic anion transporting polypeptide 1c1-mediated thyroxine transport by the fenamate class of nonsteroidal antiinflammatory drugs. Endocrinology 150, 1025-1032 (2009).
41. Hagenbuch B, Gui C. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 38, 778-801 (2008).
42. Chang C, Pang KS, Swaan PW, Ekins S. Comparative pharmacophore modeling of organic anion transporting polypeptides: a meta-analysis of rat Oatp1a1 and human OATP1B1. J. Pharmacol. Exp. Ther. 314, 533-541 (2005).
43. Chang C, Swaan PW. Computational approaches to modeling drug transporters. Eur. J. Pharm. Sci. 27, 411-424 (2006).
44. Gui C, Wahlgren B, Lushington GH, Hagenbuch B. Identification, Ki determination and CoMFA analysis of nuclear receptor ligands as competitive inhibitors of OATP1B1-mediated estradiol- 17beta-glucuronide transport. Pharmacol. Res. 60, 50-56 (2009).
45. Yarim M, Moro S, Huber R et al. Application of QSAR analysis to organic anion transporting polypeptide 1a5 (Oatp1a5) substrates. Bioorg. Med. Chem. 13, 463-471 (2005).
46. Westholm DE, Salo DR, Viken KJ, Rumbley JN, Anderson GW. The blood-brain barrier thyroxine transporter Oatp1c1 displays atypical transport kinetics. Endocrinology 150(11), 5153-5162 (2009).
47. Bronger H, Konig J, Kopplow K et al. ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res. 65, 11419-11428 (2005).
48. Gao B, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, Meier PJ. Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J. Pharmacol. Exp. Ther. 294, 73-79 (2000).
49. Roberts LM, Woodford K, Zhou M et al. Expression of the thyroid hormone transporters MCT8 (SLC16A2) and OATP14 (SLCO1C1) at the blood-brain barrier. Endocrinology 149(12), 6251-6261 (2008).
50. Sugiyama D, Kusuhara H, Taniguchi H et al. Functional characterization of rat brainspecific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine. J. Biol. Chem. 278, 43489-43495 (2003).
51. Gao B, Huber RD, Wenzel A et al. Localization of organic anion transporting polypeptides in the rat and human ciliary body epithelium. Exp. Eye Res. 80, 61-72 (2005).
52. Gao B, Stieger B, Noe B, Fritschy JM, Meier PJ. Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. J. Histochem. Cytochem. 47, 1255-1264 (1999).
53. Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol. Neurobiol. 20, 77-95 (2000).
54. Huwyler J, Pardridge WM. Examination of blood-brain barrier transferrin receptor by confocal fluorescent microscopy of unfixed isolated rat brain capillaries. J. Neurochem. 70, 883-886 (1998).
55. Jefferies WA, Brandon MR, Hunt SV, Williams AF, Gatter KC, Mason DY. Transferrin receptor on endothelium of brain capillaries. Nature 312, 162-163 (1984).
56. Moos T, Rosengren-Nielsen T, Skjorringe T, Morgan EH. Iron trafficking inside the brain. J. Neurochem. 103, 1730-1740 (2007).
57. Qian ZM, Li H, Sun H, Ho K. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol. Rev. 54, 561-587 (2002).
58. Lee HJ, Engelhardt B, Lesley J, Bickel U, Pardridge WM. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse. J. Pharmacol. Exp. Ther. 292, 1048-1052 (2000).
59. Lesley J, Schulte R, Woods J. Modulation of transferrin receptor expression and function by anti-transferrin receptor antibodies and antibody fragments. Exp. Cell Res. 182, 215-233 (1989).
60. Kissel K, Hamm S, Schulz M, Vecchi A, Garlanda C, Engelhardt B. Immunohistochemical localization of the murine transferrin receptor (TfR) on blood-tissue barriers using a novel anti-TfR monoclonal antibody. Histochem. Cell Biol. 110, 63-72 (1998).
61. Boado RJ, Zhang Y, Wang Y, Pardridge WM. Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood-brain barrier delivery in the mouse. Biotechnol. Bioeng. 102(4), 1251-1258 (2008).
62. Pardridge WM. Drug and gene targeting to the brain via blood-brain barrier receptormediated transport systems. International Congress Series 1277, 11 (2005).
63. Jones AR, Shusta EV. Blood-brain barrier transport of therapeutics via receptormediation. Pharm. Res. 24, 1759-1771 (2007).
64. Zhang Y, Pardridge WM. Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion. Brain Res. 1111, 227-229 (2006).
65. Zhang Y, Pardridge WM. Conjugation of brain-derived neurotrophic factor to a blood-brain barrier drug targeting system enables neuroprotection in regional brain ischemia following intravenous injection of the neurotrophin. Brain Res. 889, 49-56 (2001).
66. Wu D, Pardridge WM. Central nervous system pharmacologic effect in conscious rats after intravenous injection of a biotinylated vasoactive intestinal peptide analog coupled to a blood-brain barrier drug delivery system. J. Pharmacol. Exp. Ther. 279, 77-83 (1996).
67. Song BW, Vinters HV, Wu D, Pardridge WM. Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. J. Pharmacol. Exp. Ther. 301, 605-610 (2002).
68. Kordower JH, Charles V, Bayer R et al. Intravenous administration of a transferrin receptor antibody-nerve growth factor conjugate prevents the degeneration of cholinergic striatal neurons in a model of Huntington disease. Proc. Natl Acad. Sci. USA 91, 9077-9080 (1994).
69. Shi N, Boado RJ, Pardridge WM. Receptormediated gene targeting to tissues in vivo following intravenous administration of pegylated immunoliposomes. Pharm. Res. 18, 1091-1095 (2001).
70. Zhang Y, Calon F, Zhu C, Boado RJ, Pardridge WM. Intravenous nonviral gene therapy causes normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism. Hum. Gene Ther. 14, 1-12 (2003).
71. Zhang Y, Boado RJ, Pardridge WM. In vivo knockdown of gene expression in brain cancer with intravenous RNAi in adult rats. J. Gene Med. 5, 1039-1045 (2003).
72. Xia CF, Boado RJ, Zhang Y, Chu C, Pardridge WM. Intravenous glial-derived neurotrophic factor gene therapy of experimental Parkinson's disease with Trojan horse liposomes and a tyrosine hydroxylase promoter. J. Gene Med. 10, 306-315 (2008).
73. Ulbrich K, Hekmatara T, Herbert E, Kreuter J. Transferrin- and transferrinreceptor- antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB). Eur. J. Pharm. Biopharm. 71(2), 251-256 (2008).
74. Schnyder A, Krahenbuhl S, Drewe J, Huwyler J. Targeting of daunomycin using biotinylated immunoliposomes: pharmacokinetics, tissue distribution and in vitro pharmacological effects. J. Drug Target 13, 325-335 (2005).
75. Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res. 420, 32-38 (1987).
76. Bickel U, Yoshikawa T, Pardridge WM. Delivery of peptides and proteins through the blood-brain barrier. Adv. Drug Deliv. Rev. 46, 247-279 (2001).
77. Pardridge WM, Kang YS, Buciak JL, Yang J. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate. Pharm. Res. 12, 807-816 (1995).
78. Coloma MJ, Lee HJ, Kurihara A et al. Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor. Pharm. Res. 17, 266-274 (2000).
79. Boado RJ, Zhang Y, Pardridge WM. Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier. Biotechnol. Bioeng. 96, 381-391 (2007).
80. Boado RJ, Zhang Y, Wang Y, Pardridge WM. GDNF fusion protein for targeted-drug delivery across the human blood-brain barrier. Biotechnol. Bioeng. 100, 387-396 (2008).
81. Boado RJ, Zhang Y, Pardridge WM. Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood-brain barrier. Biotechnol. Bioeng. 97, 1376-1386 (2007).
82. Boado RJ, Zhang Y, Xia CF, Wang Y, Pardridge WM. Genetic engineering of a lysosomal enzyme fusion protein for targeted delivery across the human blood-brain barrier. Biotechnol. Bioeng. 99, 475-484 (2008).
83. Boado RJ, Zhang Y, Wang Y, Pardridge WM. IgG-paraoxonase-1 fusion protein for targeted drug delivery across the human blood-brain barrier. Mol. Pharm. 5(6), 1037-1043 (2008).
84. Boado RJ, Zhang Y, Xia CF, Pardridge WM. Fusion antibody for Alzheimer's disease with bidirectional transport across the blood-brain barrier and a b-fibril disaggregation. Bioconjug. Chem. 18, 447-455 (2007).
85. Hussain MM, Strickland DK, Bakillah A. The mammalian low-density lipoprotein receptor family. Annu. Rev. Nutr. 19, 141-172 (1999).
86. Stefansson S, Chappell DA, Argraves KM, Strickland DK, Argraves WS. Glycoprotein 330/low density lipoprotein receptor-related protein-2 mediates endocytosis of low density lipoproteins via interaction with apolipoprotein B100. J. Biol. Chem. 270, 19417-19421 (1995).
87. Demeule M, Currie JC, Bertrand Y et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector Angiopep-2. J. Neurochem. 106, 1534-1544 (2008).
88. Fillebeen C, Descamps L, Dehouck MP et al. Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J. Biol. Chem. 274, 7011-7017 (1999).
89. Demeule M, Poirier J, Jodoin J et al. High transcytosis of melanotransferrin (P97) across the blood-brain barrier. J. Neurochem. 83, 924-933 (2002).
90. Kennard ML, Feldman H, Yamada T, Jefferies WA. Serum levels of the iron binding protein p97 are elevated in Alzheimer's disease. Nat. Med. 2, 1230-1235 (1996).
91. Wolff JE, Trilling T, Molenkamp G, Egeler RM, Jurgens H. Chemosensitivity of glioma cells in vitro: a meta analysis. J. Cancer Res. Clin. Oncol. 125, 481-486 (1999).
92. Tsuji A. P-glycoprotein-mediated efflux transport of anticancer drugs at the blood- brain barrier. Ther. Drug Monit. 20, 588-590 (1998).
93. Takamiya Y, Abe Y, Tanaka Y et al. Murine P-glycoprotein on stromal vessels mediates multidrug resistance in intracerebral human glioma xenografts. Br. J. Cancer 76, 445-450 (1997).
94. Karkan D, Pfeifer C, Vitalis TZ et al. A unique carrier for delivery of therapeutic compounds beyond the blood-brain barrier. PLoS ONE 3, e2469 (2008).
95. Demeule M, Regina A, Che C et al. Identification and design of peptides as a new drug delivery system for the brain. J. Pharmacol. Exp. Ther. 324, 1064-1072 (2008).
96. Kounnas MZ, Moir RD, Rebeck GW et al. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell 82, 331-340 (1995).
97. Tseng SH, Bobola MS, Berger MS, Silber JR. Characterization of paclitaxel (Taxol) sensitivity in human glioma- and medulloblastoma-derived cell lines. Neuro. Oncol. 1, 101-108 (1999).
98. Fellner S, Bauer B, Miller DS et al. Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo. J. Clin. Invest. 110, 1309-1318 (2002).
99. Breedveld P, Beijnen JH, Schellens JH. Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol. Sci. 27, 17-24 (2006).
100. Gallo JM, Li S, Guo P, Reed K, Ma J. The effect of P-glycoprotein on paclitaxel brain and brain tumor distribution in mice. Cancer Res. 63, 5114-5117 (2003).
101. Cahan MA, Walter KA, Colvin OM, Brem H. Cytotoxicity of taxol in vitro against human and rat malignant brain tumors. Cancer Chemother. Pharmacol. 33, 441-444 (1994).
102. Regina A, Demeule M, Che C et al. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br. J. Pharmacol. 155(2), 185-197 (2008).
103. Spencer BJ, Verma IM. Targeted delivery of proteins across the blood-brain barrier. Proc. Natl Acad. Sci. USA 104, 7594-7599 (2007).
104. Raab G, Klagsbrun M. Heparin-binding EGF-like growth factor. Biochim. Biophys. Acta 1333, F179-199 (1997).
105. Mishima K, Higashiyama S, Nagashima Y et al. Regional distribution of heparin-binding epidermal growth factor-like growth factor mRNA and protein in adult rat forebrain. Neurosci. Lett. 213, 153-156 (1996).
106. Gaillard PJ, Visser CC, de Boer AG. Targeted delivery across the blood-brain barrier. Expert Opin. Drug Deliv. 2, 299-309 (2005).
107. Mishima K, Higashiyama S, Asai A et al. Heparin-binding epidermal growth factor-like growth factor stimulates mitogenic signaling and is highly expressed in human malignant gliomas. Acta Neuropathol. 96, 322-328 (1998).
108. Opanashuk LA, Mark RJ, Porter J, Damm D, Mattson MP, Seroogy KB. Heparin-binding epidermal growth factor-like growth factor in hippocampus: modulation of expression by seizures and anti-excitotoxic action. J. Neurosci. 19, 133-146 (1999).
109. Tanaka N, Sasahara M, Ohno M, Higashiyama S, Hayase Y, Shimada M. Heparin-binding epidermal growth factor-like growth factor mRNA expression in neonatal rat brain with hypoxic/ischemic injury. Brain Res. 827, 130-138 (1999).
110. Shinefield HR, Black S, Ray P et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatr. Infect. Dis. J. 18, 757-763 (1999).
111. Anderson P, Pichichero ME, Insel RA. Immunogens consisting of oligosaccharides from the capsule of Haemophilus influenzae type b coupled to diphtheria toxoid or the toxin protein CRM197. J. Clin. Invest. 76, 52-59 (1985).
112. Gaillard PJ, de Boer AG. 2B-trans technology: targeted drug delivery across the blood-brain barrier. Methods Mol. Biol. 437, 161-175 (2008).
113. Seelig A, Landwojtowicz E. Structure- activity relationship of P-glycoprotein substrates and modifiers. Eur. J. Pharm. Sci. 12, 31-40 (2000).
114. Gatlik-Landwojtowicz E, Aanismaa P, Seelig A. Quantification and characterization of P-glycoprotein-substrate interactions. Biochemistry 45, 3020-3032 (2006).
115. Turunen BJ, Ge H, Oyetunji J et al. Paclitaxel succinate analogs: anionic and amide introduction as a strategy to impart blood-brain barrier permeability. Bioorg. Med. Chem. Lett. 18, 5971-5974 (2008).
116. Raub TJ. P-glycoprotein recognition of substrates and circumvention through rational drug design. Mol. Pharm. 3, 3-25 (2006).
117. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res. 41, 1967-1972 (1981).
118. Ford JM, Yang JM, Hait WN. P-glycoprotein-mediated multidrug resistance: experimental and clinical strategies for its reversal. Cancer Treat. Res. 87, 3-38 (1996).
119. Leonard GD, Polgar O, Bates SE. ABC transporters and inhibitors: new targets, new agents. Curr. Opin. Investig. Drugs 3, 1652-1659 (2002).
120. Twentyman PR. Cyclosporins as drug resistance modifiers. Biochem. Pharmacol. 43, 109-117 (1992).
121. Kemper EM, Cleypool C, Boogerd W, Beijnen JH, van Tellingen O. The influence of the P-glycoprotein inhibitor zosuquidar trihydrochloride (LY335979) on the brain penetration of paclitaxel in mice. Cancer Chemother. Pharmacol. 53, 173-178 (2004).
122. Kemper EM, van Zandbergen AE, Cleypool C et al. Increased penetration of paclitaxel into the brain by inhibition of P-glycoprotein. Clin. Cancer Res. 9, 2849-2855 (2003).
123. Walker J, Martin C, Callaghan R. Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy. Eur. J. Cancer 40, 594-605 (2004).
124. Kemper EM, Boogerd W, Thuis I, Beijnen JH, van Tellingen O. Modulation of the blood- brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours? Cancer Treat Rev. 30, 415-423 (2004).
125. Mayer U, Wagenaar E, Dorobek B, Beijnen JH, Borst P, Schinkel AH. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J. Clin. Invest. 100, 2430-2436 (1997).
126. Hubensack M, Muller C, Hocherl P et al. Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. J. Cancer Res. Clin. Oncol. 134, 597-607 (2008).
127. Bankstahl JP, Kuntner C, Abrahim A et al. Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with R-11C-verapamil and PET. J. Nucl. Med. 49, 1328-1335 (2008).
128. Kurnik D, Sofowora GG, Donahue JP et al. Tariquidar, a selective P-glycoprotein inhibitor, does not potentiate loperamide's opioid brain effects in humans despite full inhibition of lymphocyte P-glycoprotein. Anesthesiology 109, 1092-1099 (2008).
129. Eisenblatter T, Galla HJ. A new multidrug resistance protein at the blood-brain barrier. Biochem. Biophys. Res. Commun. 293, 1273-1278 (2002).
130. Cooray HC, Blackmore CG, Maskell L, Barrand MA. Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuroreport 13, 2059-2063 (2002).
131. Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB. The expression and functional characterization of ABCG2 in brain endothelial cells and vessels. FASEB J. 17, 2085-2087 (2003).
132. Dean M. ABC transporters, drug resistance, and cancer stem cells. J. Mammary Gland Biol. Neoplasia 14, 3-9 (2009).
133. Chen Y, Agarwal S, Shaik NM, Chen C, Yang Z, Elmquist WF. P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib. J. Pharmacol. Exp. Ther. 330(3), 956-963 (2009).
134. de Vries NA, Zhao J, Kroon E, Buckle T, Beijnen JH, van Tellingen O. P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clin. Cancer Res. 13, 6440-6449 (2007).
135. Robey RW, Shukla S, Finley EM et al. Inhibition of P-glycoprotein (ABCB1)- and multidrug resistance-associated protein 1 (ABCC1)-mediated transport by the orally administered inhibitor, CBT-1((R)). Biochem. Pharmacol. 75, 1302-1312 (2008).
136. Shukla S, Robey RW, Bates SE, Ambudkar SV. Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab. Dispos. 37, 359-365 (2009).
137. Tiwari AK, Sodani K, Wang SR et al. Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem. Pharmacol. 78, 153-161 (2009).
138. Boumendjel A, McLeer Florin A, Champelovier P et al. A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models. BMC Cancer 9, 242 (2009).
139. Wu CP, Shukla S, Calcagno AM, Hall MD, Gottesman MM, Ambudkar SV. Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance linked ABCG2 transporter. Mol. Cancer Ther. 6, 3287-3296 (2007).
140. Dogrukol-Ak D, Kumar VB, Ryerse JS et al. Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer and stroke models. J. Cereb. Blood Flow Metab. 29, 411-422 (2009).
141. Hartz AM, Bauer B, Fricker G, Miller DS. Rapid regulation of P-glycoprotein at the blood-brain barrier by endothelin-1. Mol. Pharmacol. 66, 387-394 (2004).
142. Hartz AM, Bauer B, Fricker G, Miller DS. Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-a and lipopolysaccharide. Mol. Pharmacol. 69, 462-470 (2006).
143. Guerrini R. Epilepsy in children. Lancet 367, 499-524 (2006).
144. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N. Engl. J. Med. 342, 314-319 (2000).
145. Kwan P, Brodie MJ. Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy. Neurology 60, S2-S12 (2003).
146. Loscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat. Rev. Neurosci. 6, 591-602 (2005).
147. Dombrowski SM, Desai SY, Marroni M et al. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 42, 1501-1506 (2001).
148. Lazarowski A, Sevlever G, Taratuto A, Massaro M, Rabinowicz A. Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy. Pediatr. Neurol. 21, 731-734 (1999).
149. Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain 125, 22-31 (2002).
150. Tishler DM, Weinberg KI, Hinton DR, Barbaro N, Annett GM, Raffel C. MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 36, 1-6 (1995).
151. Brandt C, Bethmann K, Gastens AM, Loscher W. The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol. Dis. 24, 202-211 (2006).
152. Marchi N, Guiso G, Rizzi M et al. A pilot study on brain-to-plasma partition of 10,11-dyhydro-10-hydroxy-5H-dibenzo(b,f) azepine-5-carboxamide and MDR1 brain expression in epilepsy patients not responding to oxcarbazepine. Epilepsia 46, 1613-1619 (2005).
153. Potschka H, Loscher W. In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain barrier of rats. Epilepsia 42, 1231-1240 (2001).
154. van Vliet EA, van Schaik R, Edelbroek PM et al
155. Desjardins P, Sauvageau A, Bouthillier A et al. Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis. Neurochem. Int. 42, 299-303 (2003).
156. Lee B, Dziema H, Lee KH, Choi YS, Obrietan K. CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticus. Neurobiol. Dis. 25, 80-91 (2007).
157. Marchi N, Fan Q, Ghosh C et al. Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol. Dis. 33, 171-181 (2009).
158. Bauer B, Hartz AM, Pekcec A, Toellner K, Miller DS, Potschka H. Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. Mol. Pharmacol. 73, 1444-1453 (2008).
159. Zibell G, Unkruer B, Pekcec A et al. Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. Neuropharmacology 56, 849-855 (2009).
160. Bellavance MA, Blanchette M, Fortin D. Recent advances in blood-brain barrier disruption as a CNS delivery strategy. AAPS J. 10, 166-177 (2008).
161. Kroll RA, Neuwelt EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 42, 1083-1100 (1998).
162. Marchi N, Angelov L, Masaryk T et al. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 48, 732-742 (2007).
163. Jahnke K, Kraemer DF, Knight KR et al. Intraarterial chemotherapy and osmotic blood-brain barrier disruption for patients with embryonal and germ cell tumors of the central nervous system. Cancer 112, 581-588 (2008).
164. Erdlenbruch B, Kugler W, Schinkhof C, Neurath H, Eibl H, Lakomek M. Blood-brain barrier opening with alkylglycerols: biodistribution of 1-O-pentylglycerol after intravenous and intracarotid administration in rats. J. Drug Target 13, 143-150 (2005).
165. Preston E, Slinn J, Vinokourov I, Stanimirovic D. Graded reversible opening of the rat blood-brain barrier by intracarotid infusion of sodium caprate. J. Neurosci. Methods 168, 443-449 (2008).
166. Hynynen K. Ultrasound for drug and gene delivery to the brain. Adv. Drug Deliv. Rev. 60, 1209-1217 (2008).
167. Hynynen K, McDannold N, Sheikov NA, Jolesz FA, Vykhodtseva N. Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage 24, 12-20 (2005).
168. Meairs S, Alonso A. Ultrasound, microbubbles and the blood-brain barrier. Prog. Biophys. Mol. Biol. 93, 354-362 (2007).
169. Meairs S, Alonso A, Fatar M, Kern R, Hennerici M. Microbubbles traversing the blood-brain barrier for imaging and therapy. Med. Biol. Eng. Comput. 47(8), 839-849 (2009).
170. Liu LB, Xue YX, Liu YH, Wang YB. Bradykinin increases blood-tumor barrier permeability by down-regulating the expression levels of ZO-1, occludin, and claudin-5 and rearranging actin cytoskeleton. J. Neurosci. Res. 86, 1153-1168 (2008).
171. Rodi D, Couture R, Ongali B, Simonato M. Targeting kinin receptors for the treatment of neurological diseases. Curr. Pharm. Des. 11, 1313-1326 (2005).
172. Emerich DF, Dean RL, Osborn C, Bartus RT. The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation. Clin. Pharmacokinet. 40, 105-123 (2001).
173. Belanger S, Bovenzi V, Cote J et al. Structure-activity relationships of novel peptide agonists of the human bradykinin B2 receptor. Peptides 30, 777-787 (2009).
174. Packer RJ, Krailo M, Mehta M et al. A Phase I study of concurrent RMP-7 and carboplatin with radiation therapy for children with newly diagnosed brainstem gliomas. Cancer 104, 1968-1974 (2005).
175. Prados MD, Schold SJS, Fine HA et al. A randomized, double-blind, placebocontrolled, Phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro. Oncol. 5, 96-103 (2003).
176. Warren K, Jakacki R, Widemann B et al. Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group. Cancer Chemother. Pharmacol. 58, 343-347 (2006).
177. Warren KE, Patel MC, Aikin AA et al. Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors. Cancer Chemother. Pharmacol. 48, 275-282 (2001).
178. Gregor A, Lind M, Newman H et al. Phase II studies of RMP-7 and carboplatin in the treatment of recurrent high grade glioma. RMP-7 European Study Group. J. Neurooncol. 44, 137-145 (1999).
179. Black KL, Yin D, Ong JM et al. PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res. 1230, 290-302 (2008).
180. Tetrault S, Chever O, Sik A, Amzica F. Opening of the blood-brain barrier during isoflurane anaesthesia. Eur. J. Neurosci. 28, 1330-1341 (2008).
181. Wagstaff KM, Jans DA. Protein transduction: cell penetrating peptides and their therapeutic applications. Curr. Med. Chem. 13, 1371-1387 (2006).
182. Foerg C, Merkle HP. On the biomedical promise of cell penetrating peptides: limits versus prospects. J. Pharm. Sci. 97, 144-162 (2008).
183. Herve F, Ghinea N, Scherrmann JM. CNS delivery via adsorptive transcytosis. AAPS J. 10, 455-472 (2008).
184. Rousselle C, Smirnova M, Clair P et al. Enhanced delivery of doxorubicin into the brain via a peptide-vector-mediated strategy: saturation kinetics and specificity. J. Pharmacol. Exp. Ther. 296, 124-131 (2001).
185. Rousselle C, Clair P, Temsamani J, Scherrmann JM. Improved brain delivery of benzylpenicillin with a peptide-vectormediated strategy. J. Drug Target 10, 309-315 (2002).
186. Rousselle C, Clair P, Smirnova M et al. Improved brain uptake and pharmacological activity of dalargin using a peptide-vectormediated strategy. J. Pharmacol. Exp. Ther. 306, 371-376 (2003).
187. Del Amo EM, Urtti A, Yliperttula M. Pharmacokinetic role of l-type amino acid transporters LAT1 and LAT2. Eur. J. Pharm. Sci. 35(3), 161-174 (2008).
188. Cockrell AS, Kafri T. Gene delivery by lentivirus vectors. Mol. Biotechnol. 36, 184-204 (2007).