Clinical Pharmacokinetics

, Volume 46, Issue 7, pp 553–576 | Cite as

Strategies to Improve Drug Delivery Across the Blood-Brain Barrier

  • Albertus G. de Boer
  • Pieter J. Gaillard
Review Article


The blood-brain barrier (BBB), together with the blood-cerebrospinal-fluid barrier, protects and regulates the homeostasis of the brain. However, these barriers also limit the transport of small-molecule and, particularly, biopharmaceutical drugs such as proteins, genes and interference RNA to the brain, thereby limiting the treatment of many brain diseases. As a result, various drug delivery and targeting strategies are currently being developed to enhance the transport and distribution of drugs into the brain. In this review, we discuss briefly the biology and physiology of the BBB as the most important barrier for drug transport to the brain and, in more detail, the possibilities for delivering large-molecule drugs, particularly genes, by receptor-mediated nonviral drug delivery to the (human) brain. In addition, the systemic and intracellular pharmacokinetics of nonviral gene delivery, together with targeted brain imaging, are reviewed briefly.


Transferrin Insulin Receptor Diphtheria Toxin Receptor Associate Protein Homing Device 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No funding was provided to assist in the preparation of this review. Albertus G. de Boer is the Chairman of the scientific advisory board and Pieter J. Gaillard is the CEO of to-BBB technologies BV, Leiden, The Netherlands (which is developing CRM197). Both authors own stocks in to-BBB technologies BV, have received grants on the CRM197 technology and are co-inventors on patent applications covering the use of CRM197 technology.


  1. 1.
    Keep RG, Jones HC. A morphometric study on the development of the lateral ventricle choroids plexus, choroids plexus capillaries and ventricular ependyma in the rat. Brain Res Dev Brain Res 1990; 56: 47–53PubMedCrossRefGoogle Scholar
  2. 2.
    Ehrlich P. Das Sauerstoff-Bedurfnis des Organismus: eine farbenanalytische Studie. Berlin: Hirschwald, 1885Google Scholar
  3. 3.
    Goldman EE. Vitalfarbung am Zentralnervensystem. Abh Preuss Akad Wiss Phys Math 1913; K1: 1–60Google Scholar
  4. 4.
    Abbott NJ. Dynamics of CNS barriers: evolution, differentiation, and modulation. Cell Mol Neurobiol 2005; 25(1): 5–23PubMedCrossRefGoogle Scholar
  5. 5.
    Begley DJ, Brightman MW. Structural and functional aspects of the blood-brain barrier. Prog Drug Res 2003; 61: 39–78PubMedGoogle Scholar
  6. 6.
    Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 2005; 57(2): 173–85PubMedCrossRefGoogle Scholar
  7. 7.
    Abbott NJ. Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 2000; 20(2): 131–47PubMedCrossRefGoogle Scholar
  8. 8.
    Gaillard PJ, de Boer AG, Breimer DD. Pharmacological investigations on lipopolysaccharide-induced permeability changes in the blood-brain barrier in vitro. Microvasc Res 2003; 65(1): 24–31PubMedCrossRefGoogle Scholar
  9. 9.
    Pardridge WM. Molecular biology of the blood-brain barrier. Mol Biotechnol 2005; 30(1): 57–70PubMedCrossRefGoogle Scholar
  10. 10.
    de Vries HE, Kuiper J, de Boer AG, et al. The role of the blood-brain barrier in neuroinflammatory diseases. Pharmacol Rev 1997; 49(2): 143–55PubMedGoogle Scholar
  11. 11.
    Begley DJ. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther 2004; 104(1): 29–45PubMedCrossRefGoogle Scholar
  12. 12.
    Rubin LL, Staddon JM. The cell biology of the blood-brain barrier. Annu Rev Neurosci 1999; 22: 11–28PubMedCrossRefGoogle Scholar
  13. 13.
    Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987; 325(6101): 253–7PubMedCrossRefGoogle Scholar
  14. 14.
    Gaillard PJ, van der Sandt IC, Voorwinden LH, et al. Astrocytes increase the functional expression of P-glycoprotein in an in vitro model of the blood-brain barrier. Pharm Res 2000; 17(10): 1198–205PubMedCrossRefGoogle Scholar
  15. 15.
    Lai CH, Kuo KH. The critical component to establish in vitro BBB model: pericyte. Brain Res Dev Brain Res 2005; 50(2): 258–65Google Scholar
  16. 16.
    Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 1969; 40(3): 648–77PubMedCrossRefGoogle Scholar
  17. 17.
    Reese TS, Karnovsky MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 1967; 34(1): 207–17PubMedCrossRefGoogle Scholar
  18. 18.
    Ciechanover A. Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 2005; 61: 79–87CrossRefGoogle Scholar
  19. 19.
    el-Bacha RS, Minn A. Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell Mol Biol 1999; 45(1): 15–23PubMedGoogle Scholar
  20. 20.
    Wekerle H. Immune protection of the brain — efficient and delicate. J Infect Dis 2002; 186 Suppl. 2: S140–4PubMedCrossRefGoogle Scholar
  21. 21.
    Bechmann I, Galea I, Perry VH. What is the blood-brain barrier (not)? Trends Immunol 2007; 28(1): 5–11PubMedCrossRefGoogle Scholar
  22. 22.
    Biessels GJ, Bravenboer B, Gispen WH. Glucose, insulin and the brain: modulation of cognition and synaptic plasticityin health and disease: a preface. Eur J Pharmacol 2004; 490(1–3): 1–4PubMedCrossRefGoogle Scholar
  23. 23.
    Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 2001; 108(6): 779–84PubMedGoogle Scholar
  24. 24.
    Hendry SH, Jones EG, Beinfeld MC. Cholecystokinin-immu-noreactive neurons in rat and monkey cerebral cortex make symmetric synapses and have intimate associations with blood vessels. Proc Natl Acad Sci U S A 1983; 80(8): 2400–4PubMedCrossRefGoogle Scholar
  25. 25.
    Balabanov R, Dore-Duffy P. Role of the CNS microvascular pericyte in the blood-brain barrier. J Neurosci Res 1998; 53(6): 637–44PubMedCrossRefGoogle Scholar
  26. 26.
    Kim JA, Tran ND, Li Z, et al. Brain endothelial hemostasis regulation by pericytes. J Cereb Blood Flow Metab 2005; 26(2): 209–17CrossRefGoogle Scholar
  27. 27.
    Cordon-Cardo CJ, O’Brien JP, Casals D, et al. Multidrug-resistance gene P-glycoprotein is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A 1989; 86: 695–8PubMedCrossRefGoogle Scholar
  28. 28.
    Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdrla P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96(4): 1698–705PubMedCrossRefGoogle Scholar
  29. 29.
    Borst P, Evers R, Kool M, et al. The multidrug resistance protein family. Biochem Biophys Acta 1999; 1461: 347–57PubMedCrossRefGoogle Scholar
  30. 30.
    de Boer AG, van der Sandt IC, Gaillard PJ. The role of drug transporters at the blood-brain barrier. Annu Rev Pharmacol Toxicol 2003; 43: 629–56PubMedCrossRefGoogle Scholar
  31. 31.
    Lee G, Dallas S, Hong M, et al. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev 2001; 53(4): 569–96PubMedGoogle Scholar
  32. 32.
    Loscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 2005; 76(1): 22–76PubMedCrossRefGoogle Scholar
  33. 33.
    Ganapathy V, Miyauchi S. Transport systems for opioid peptides in mammalian tissues. AAPS J 2005; 7(4): E852–6PubMedCrossRefGoogle Scholar
  34. 34.
    Banks WA. Anorectic effects of circulating cytokines: role of the vascular blood-brain barrier. Nutrition 2001; 17(5): 434–7PubMedCrossRefGoogle Scholar
  35. 35.
    Ho RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 2005; 78(3): 260–77PubMedCrossRefGoogle Scholar
  36. 36.
    Abbott NJ. Physiology of the blood-brain barrier and its consequences for drug transport to the brain. In: de Boer A, editor. Esteve Foundation Symposium XI: drug transport(ers) and the diseased brain. International Congress Series 1277. Amsterdam: Elsevier, 2005: 3–18Google Scholar
  37. 37.
    van Vliet EA, da Costa Araujo S, Redeker S, et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 2007; 130 (Pt2): 521–34CrossRefGoogle Scholar
  38. 38.
    Marchi N, Angelov L, Masaryk T, et al. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia. Epub 2007 Feb 21Google Scholar
  39. 39.
    Jancso G, Domoki F, Santha P, et al. Beta-amyloid (1–42) peptide impairs blood-brain barrier function after intracarotid infusion in rats, Neurosci Lett 1998; 253(2): 139–41PubMedCrossRefGoogle Scholar
  40. 40.
    Lo EH, Singhai AB, Torchilin VP, et al. Drug delivery to damaged brain. Brain Res Brain Res Rev 2001; 38(1–2): 140–8PubMedCrossRefGoogle Scholar
  41. 41.
    Reichel A. The role of blood-brain barrier studies in the pharmaceutical industry. Curr Drug Metab 2006; 72: 183–203CrossRefGoogle Scholar
  42. 42.
    Liu X, Chen C. Strategies to optimize brain penetration in drug discovery. Curr Opin Drug Discov Devel 2005; 8(4): 505–12PubMedGoogle Scholar
  43. 43.
    Pardridge WM. Transport of small molecules through the blood-brain barrier: biology and methodology. Adv Drug Deliv Rev 1995; 15: 5–36CrossRefGoogle Scholar
  44. 44.
    Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46(1–3): 3–26PubMedCrossRefGoogle Scholar
  45. 45.
    Abraham MH, Chadha HS, Mitchell RC. Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain. J Pharm Sci 1994; 83(9): 1257–68PubMedCrossRefGoogle Scholar
  46. 46.
    Abbott NJ, Romero IA. Transporting therapeutics across the blood-brain barrier. Mol Med Today 1996; 2(3): 106–13PubMedCrossRefGoogle Scholar
  47. 47.
    Vorbrodt AW. Ultracytochemical characterization of anionic sites in the wall of brain capillaries. J Neurocytol 1989; 18(3): 359–68PubMedCrossRefGoogle Scholar
  48. 48.
    Lockman PR, Koziara JM, Mumper RJ, et al. Nanoparticle surface charges alter blood-brain barrier integrity and permeability. J Drug Target 2004; 12(9–10): 635–41PubMedCrossRefGoogle Scholar
  49. 49.
    Abbott NJ, Romero IA. Transporting therapeutics across the blood-brain barrier. Mol Med Today 1996; 2(3): 106–13PubMedCrossRefGoogle Scholar
  50. 50.
    Tamai I, Tsuji A. Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci 2000; 89(11): 1371–88PubMedCrossRefGoogle Scholar
  51. 51.
    Smith QR. Drug delivery to brain and the role of carrier mediated transport. Adv Exp Med Biol 1993; 331: 83–93PubMedCrossRefGoogle Scholar
  52. 52.
    Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 1987; 420(1): 32–8PubMedCrossRefGoogle Scholar
  53. 53.
    Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol 2000; 20(1): 77–95PubMedCrossRefGoogle Scholar
  54. 54.
    Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier transferrin receptor. Metabolism 1987; 36(9): 892–5PubMedCrossRefGoogle Scholar
  55. 55.
    Dehouck B, Fenart L, Dehouck MP, et al. A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier. J Cell Biol 1997; 138(4): 877–89PubMedCrossRefGoogle Scholar
  56. 56.
    Bjorbaek C, Elmquist JK, Michl P, et al. Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 1998; 139(8): 3485–91PubMedCrossRefGoogle Scholar
  57. 57.
    Duffy KR, Pardridge WM, Rosenfeld RG. Human blood-brain barrier insulin-like growth factor receptor. Metabolism 1988; 37(2): 136–40PubMedCrossRefGoogle Scholar
  58. 58.
    Loscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 2005; 6(8): 591–602PubMedCrossRefGoogle Scholar
  59. 59.
    van der Sandt IC, de Boer AG, Breimer DD. Implications of Pgp for the transport and distribution of drugs into the brain. In: Sharma HS, Wesman J, editors. Blood-spinal cord and brain barriers in health and disease. San Diego (CA): Academic Press, 2003: 63–72Google Scholar
  60. 60.
    Zhang Y, Han H, Elmquist WF, et al. Expression of various multidrug resistance-associated protein MRP: homologues in brain microvessel endothelial cells. Brain Res 2000; 876(1–2): 148–53PubMedCrossRefGoogle Scholar
  61. 61.
    Yokoyama M. Drug targeting with nano-sized carrier systems. J Artif Organs 2005; 8(2): 77–84PubMedCrossRefGoogle Scholar
  62. 62.
    Kreuter J. Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain. J Nanosci Nanotechnol 2004; 4(5): 484–8PubMedCrossRefGoogle Scholar
  63. 63.
    Marcucci F, Lefoulon F. Active targeting with particulate drug carriers in tumor therapy: fundamentals. Drug Discov Today 2004; 9(5): 219–28PubMedCrossRefGoogle Scholar
  64. 64.
    Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986; 46 (Pt12): 6387–92Google Scholar
  65. 65.
    Vogler C, Levy B, Grubb JH, et al. Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII. Proc Natl Acad Sci USA 2005; 102(41): 14777–82PubMedCrossRefGoogle Scholar
  66. 66.
    Banks WA. Are the extracellular pathways a conduit for the delivery of therapeutics to the brain? Curr Pharm Des 2004; 10(12): 1365–70PubMedCrossRefGoogle Scholar
  67. 67.
    Egleton RD, Davis TP. Development of neuropeptide drugs that cross the blood-brain barrier. NeuroRx 2005; 21: 44–53CrossRefGoogle Scholar
  68. 68.
    Miller G. Drug targeting: breaking down barriers. Science 2002; 297(5584): 1116–8PubMedCrossRefGoogle Scholar
  69. 69.
    Kroll RA, Neuwelt EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neu-rosurgery 1998; 42: 1083–100Google Scholar
  70. 70.
    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 2003; 140: 1201–10PubMedCrossRefGoogle Scholar
  71. 71.
    Matsukado K, Inamura T, Nakano S, et al. Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7. Neurosur-gery 1996; 39: 125–33CrossRefGoogle Scholar
  72. 72.
    Prados MD, Schold Jr SC, Fine HA, et al. A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro-Oncology 2003; 5(2): 96–103PubMedGoogle Scholar
  73. 73.
    Dietz GP, Bahr M. Delivery of bioactive molecules into the cell: the Trojan horse approach. Mol Cell Neurosci 2004; 27(2): 85–131PubMedCrossRefGoogle Scholar
  74. 74.
    Lindgren M, Hallbrink M, Prochiantz A, et al. Cell-penetrating peptides. Trends Pharmacol Sci 2000; 21(3): 99–103PubMedCrossRefGoogle Scholar
  75. 75.
    Jeang KT, Xiao H, Rich EA. Multifaceted activities of the HIV-1 transactivator of transcription. Tat J Biol Chem 1999; 274(41): 28837–40CrossRefGoogle Scholar
  76. 76.
    Perez F, Joliot A, Bloch-Gallego E, et al. Antennapedia homeobox as a signal for the cellular internalization and nuclear addressing of a small exogenous peptide. J Cell Sci 1992; 102 (Pt4): 717–22Google Scholar
  77. 77.
    Rousselle C, Clair P, Lefauconnier JM, et al. New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy. Mol Pharmacol 2000; 57(4): 679–86PubMedGoogle Scholar
  78. 78.
    Langedijk JP, Olijhoek T, Schut D, et al. New transport peptides broaden the horizon of applications for peptidic pharmaceuti-cals. Mol Divers 2004; 8(2): 101–11PubMedCrossRefGoogle Scholar
  79. 79.
    Wender PA, Mitchell DJ, Pattabiraman K, et al. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci U S A 2000; 97(24): 13003–8PubMedCrossRefGoogle Scholar
  80. 80.
    Saar K, Lindgren M, Hansen M, et al. Cell-penetrating peptides: a comparative membrane toxicity study. Anal Biochem 2005; 345(1): 55–65PubMedCrossRefGoogle Scholar
  81. 81.
    Scherrmann J-M. Pharmacogenomics of the blood-brain barrier. In: Licinio J, Wong M-L, editors. Pharmacogenomics: the search for individualized therapies. Wernheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2002: 311–35Google Scholar
  82. 82.
    Yamada T, Fialho AM, Punj V, et al. Internalization of bacterial redox protein azurin in mammalian cells: entry domain and specificity. Cell Microbiol 2005; 7(10): 1418–31PubMedCrossRefGoogle Scholar
  83. 83.
    Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 2004; 432(7014): 173–8PubMedCrossRefGoogle Scholar
  84. 84.
    Batrakova EV, Vinogradov SV, Robinson SM, et al. Polypeptide point modifications with fatty acid and amphiphilic block co-polymers for enhanced brain delivery. Bioconjug Chem 2005; 16(5): 793–802PubMedCrossRefGoogle Scholar
  85. 85.
    Bartsch M, Weeke-Klimp AH, Meijer DK, et al. Cell-specific targeting of lipid-based carriers for ODN and DNA. J Liposome Res 2005; 15(1–2): 59–92PubMedGoogle Scholar
  86. 86.
    Wagner E, Culmsee C, Boeckle S. Targeting of polyplexes: toward synthetic virus vector systems. Adv Genet 2005; 53: 333–54PubMedCrossRefGoogle Scholar
  87. 87.
    Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 2002; 1(2): 131–9PubMedCrossRefGoogle Scholar
  88. 88.
    Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature 2003; 422(6927): 37–44PubMedCrossRefGoogle Scholar
  89. 89.
    Gumbleton M, Abulrob AG, Campbell L. Caveolae: an alternative membrane transport compartment. Pharm Res 2000; 17(9): 1035–48PubMedCrossRefGoogle Scholar
  90. 90.
    Cuervo AM. Autophagy: many paths to the same end. Mol Cell Biochem 2004; 263(1–2): 55–72PubMedCrossRefGoogle Scholar
  91. 91.
    Shir A, Ogris M, Wagner E, et al. EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice. PLoS Med 2005; 3(1): e6PubMedCrossRefGoogle Scholar
  92. 92.
    Raab G, Klagsbrun M. Heparin-binding EGF-like growth factor. Biochim Biophys Acta 1999; 1333(3): F179–99Google Scholar
  93. 93.
    Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol 2000; 20(1): 77–95PubMedCrossRefGoogle Scholar
  94. 94.
    Ponka P, Lok CN. The transferrin receptor: role in health and disease. Int J Biochem Cell Biol 1999; 31(10): 1111–37PubMedCrossRefGoogle Scholar
  95. 95.
    Visser CC, Stevanovic S, Voorwinden LH, et al. Targeting liposomes with protein drugs to the blood-brain barrier in vitro. Eur J Pharm Sci 2005; 25(2–3): 299–305PubMedCrossRefGoogle Scholar
  96. 96.
    Moos T, Morgan EH. The significance of the mutated divalent metal transporter DMT1 on iron transport into the Belgrade rat brain. J. Neurochem 2004; 88(1): 233–45CrossRefGoogle Scholar
  97. 97.
    Zhang Y, Pardridge WM. Rapid transferrin efflux from brain to blood across the blood-brain barrier. J Neurochem 2001; 76(5): 1597–600PubMedCrossRefGoogle Scholar
  98. 98.
    Deane R, Zheng W, Zlokovic BV. Brain capillary endothelium and choroid plexus epithelium regulate transport of transferrin-bound and free iron into the rat brain. J Neurochem 2004; 88(4): 813–20PubMedCrossRefGoogle Scholar
  99. 99.
    Broadwell RD, Baker-Cairns BJ, Friden PM, et al. Transcytosis of protein through the mammalian cerebral epithelium and endothelium. III. Receptor-mediated transcytosis through the blood-brain barrier of blood-borne transferrin and antibody against the transferrin receptor. Exp Neurol 1996; 142(1): 47–65PubMedCrossRefGoogle Scholar
  100. 100.
    Moos T, Morgan EH. Restricted transport of antitransferrin receptor antibody OX26 through the blood-brain barrier in the rat. J Neurochem 2001; 79(1): 119–29PubMedCrossRefGoogle Scholar
  101. 101.
    Visser CC, Voorwinden LH, Crommelin DJ, et al. Characterization and modulation of the transferrin receptor on brain capillary endothelial cells. Pharm Res 2004; 21(5): 761–9PubMedCrossRefGoogle Scholar
  102. 102.
    Pardridge WM. Drug and gene targeting to the brain via blood-brain barrier receptor-mediated transport systems. Int Congr Series 2005; 1277: 49–59CrossRefGoogle Scholar
  103. 103.
    Xu L, Tang WH, Huang CC, et al. Systemic p53 gene therapy of cancer with immunolipoplexes targeted by antitransferrin receptor scFv. Mol Med 2001; 7(10): 723–34PubMedGoogle Scholar
  104. 104.
    Lee JH, Engler JA, Collawn JF, et al. Receptor mediated uptake of peptides that bind the human transferrin receptor. Eur J Biochem 2001; 268(7): 2004–12PubMedCrossRefGoogle Scholar
  105. 105.
    Bottaro DP, Bonner-Weir S, King GL. Insulin receptor recycling in vascular endothelial cells: regulation by insulin and phorbol ester. J Biol Chem 1989; 264(10): 5916–23PubMedGoogle Scholar
  106. 106.
    Wu D, Yang J, Pardridge WM. Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor. J Clin Invest 1997; 100(7): 1804–12PubMedCrossRefGoogle Scholar
  107. 107.
    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 2000; 17(3): 266–74PubMedCrossRefGoogle Scholar
  108. 108.
    Boucher P, Gotthardt M, Li WP, et al. LRP: role in vascular wall integrity and protection from atherosclerosis. Science 2003; 300(5617): 329–32PubMedCrossRefGoogle Scholar
  109. 109.
    Yepes M, Sandkvist M, Moore EG, et al. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest 2003; 112(10): 1533–40PubMedGoogle Scholar
  110. 110.
    Demeule M, Poirier J, Jodoin J, et al. High transcytosis of melanotransferrin P97 across the blood-brain barrier. J Neurochem 2002; 83(4): 924–33PubMedCrossRefGoogle Scholar
  111. 111.
    Deane R, Wu Z, Zlokovic BV. RAGE yin versus LRP yang balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke 2004; 3511 Suppl. 1: 2628–31CrossRefGoogle Scholar
  112. 112.
    Chun JT, Wang L, Pasinetti GM, et al. Glycoprotein 330/megalin LRP-2 has low prevalence as mRNA and protein in brain microvessels and choroid plexus. Exp Neurol 1999; 157(1): 194–201PubMedCrossRefGoogle Scholar
  113. 113.
    Richardson DR, Morgan EH. The transferrin homologue, melanotransferrin p97, is rapidly catabolized by the liver of the rat and does not effectively donate iron to the brain. Biochim Biophys Acta 2004; 1690(2): 124–33PubMedCrossRefGoogle Scholar
  114. 114.
    Gabathuler R, Arthur G, Kennard M, et al. Development of a potential vector NeuroTrans to deliver drugs across the blood-brain barrier. Int Congr Series 2005; 1277: 171–84CrossRefGoogle Scholar
  115. 115.
    Pan W, Kastin AJ, Zankel TC, et al. Efficient transfer of receptor-associated protein RAP across the blood-brain barrier. J. Cell Sci 2004; 117 (Pt21): 5071–8CrossRefGoogle Scholar
  116. 116.
    Béliveau R, Demeule M. A method for transporting a compound across the blood-brain barrier. Canadian patent application WO2004060403. 2004 Jul 22Google Scholar
  117. 117.
    Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004; 128(3): 442–8PubMedCrossRefGoogle Scholar
  118. 118.
    Jefferies WA, Food MR, Gabathuler R, et al. Reactive microglia specifically associated with amyloid plaques in Alzheimer’s disease brain tissue express melanotransferrin. Br Res 1996; 712(1): 122–6CrossRefGoogle Scholar
  119. 119.
    Demeule M, Bertrand Y, Michaud-Levesque J, et al. Regulation of plasminogen activation: a role for melanotransferrin p97 in cell migration. Blood 2003; 102(5): 1723–31PubMedCrossRefGoogle Scholar
  120. 120.
    Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007; 297(5): 471–9PubMedCrossRefGoogle Scholar
  121. 121.
    Gaillard PJ, Brink A, de Boer AG. Diphtheria toxin receptor-targeted brain drug delivery. Int Congr Series 2005; 1277: 185–95CrossRefGoogle Scholar
  122. 122.
    Anderson P. Antibody responses to Haemophilus influenzae type b and diphtheria toxin induced by conjugates of oligosaccharides of the type b capsule with the nontoxic protein CRM197. Infect Immun 1983; 39(1): 233–8PubMedGoogle Scholar
  123. 123.
    Buzzi S, Rubboli D, Buzzi G, et al. CRM197 nontoxic diphtheria toxin: effects on advanced cancer patients. Cancer Immunol Immunother 2004; 53(11): 1041–8PubMedCrossRefGoogle Scholar
  124. 124.
    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 1996; 213(3): 153–6PubMedGoogle Scholar
  125. 125.
    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 1998; 96(4): 322–8PubMedCrossRefGoogle Scholar
  126. 126.
    Tanaka N, Sasahara M, Ohno M, et al. Heparin-binding epidermal growth factor-like growth factor mRNA expression in neonatal rat brain with hypoxic/ischemic injury. Brain Res 1999; 827(1–2): 130–8PubMedCrossRefGoogle Scholar
  127. 127.
    de Boer AG, Gaillard PJ. Drug targeting to the brain. Annu Rev Pharmacol Toxicol 2007; 47: 323–55PubMedCrossRefGoogle Scholar
  128. 128.
    Montagner C, Perier A, Pichard S, et al. Behavior of the N-terminal helices of the diphtheria toxin T domain during the successive steps of membrane interaction. Biochemistry 2007; 46(7): 1878–87PubMedCrossRefGoogle Scholar
  129. 129.
    Cha JH, Chang MY, Richardson JA, et al. Transgenic mice expressing the diphtheria toxin receptor are sensitive to the toxin. Mol Microbiol 2003; 49(1): 235–40PubMedCrossRefGoogle Scholar
  130. 130.
    Opanashuk LA, Mark RJ, Porter J, et al. Heparin-binding epidermal growth factor-like growth factor in hippocampus: modulation of expression by seizures and antiexcitotoxic action. J Neurosci 1999; 19(1): 133–46PubMedGoogle Scholar
  131. 131.
    Luciani A, Olivier JC, Clement O, et al. Glucose-receptor MR imaging of tumors: study in mice with PEGylated paramagnetic niosomes. Radiology 2004; 231(1): 135–42PubMedCrossRefGoogle Scholar
  132. 132.
    Pollard H, Remy JS, Loussouarn G, et al. Polyethylenimine but not cationic lipids promotes transgene delivery to the nucleus in mammalian cells. J Biol Chem 1998; 273(13): 7507–11PubMedCrossRefGoogle Scholar
  133. 133.
    Rolland A. Gene medicines: the end of the beginning? Adv Drug Deliv Rev 2005; 57(5): 669–73PubMedCrossRefGoogle Scholar
  134. 134.
    Yu P, Wang X, Fu YX. Enhanced local delivery with reduced systemic toxicity: delivery, delivery, and delivery. Gene Ther 2006; 13(15): 1131–2PubMedCrossRefGoogle Scholar
  135. 135.
    Yew NS. Controlling the kinetics of transgene expression by plasmid design. Adv Drug Deliv Rev 2005; 57(5): 769–80PubMedCrossRefGoogle Scholar
  136. 136.
    de Wolf HK, Snel CJ, Verbaan FJ, et al. Effect of cationic carriers on the pharmacokinetics and tumor localization of nucleic acids after intravenous administration. Int J Pharm 2007; 331(2): 167–75PubMedCrossRefGoogle Scholar
  137. 137.
    Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408(6813): 740–5PubMedCrossRefGoogle Scholar
  138. 138.
    Schiedner G, Bloch W, Hertel S, et al. A hemodynamic response to intravenous adenovirus vector particles is caused by systemic Kupffer cell-mediated activation of endothelial cells. Hum Gene Ther 2003; 14(17): 1631–41PubMedCrossRefGoogle Scholar
  139. 139.
    Wang X, Kong L, Zhang GR, et al. Targeted gene transfer to nigrostriatal neurons in the rat brain by helper virus-free HSV-1 vector particles that contain either a chimeric HSV-1 glyco-protein C-GDNF or a gC-BDNF protein. Brain Res Mol Brain Res 2005; 139(1): 88–102PubMedCrossRefGoogle Scholar
  140. 140.
    Kootstra NA, Verma IM. Gene therapy with viral vectors. Annu Rev Pharmacol Toxicol 2003; 43: 413–39PubMedCrossRefGoogle Scholar
  141. 141.
    Lungwitz U, Breunig M, Blunk T, et al. Polyethylenimine-based non-viral gene delivery systems. Eur J Pharm Biopharm 2005; 60(2): 247–66PubMedCrossRefGoogle Scholar
  142. 142.
    Ogris M, Wagner E. Tumor-targeted gene transfer with DNA polyplexes. Somat Cell Mol Genet 2002; 27(1–6): 85–95PubMedCrossRefGoogle Scholar
  143. 143.
    Kircheis R, Blessing T, Brunner S, et al. Tumor targeting with surface-shielded ligand -polycation DNA complexes. J Control Release 2001; 72(1–3): 165–70PubMedCrossRefGoogle Scholar
  144. 144.
    Godbey WT, Wu KK, Mikos AG. Poly (ethylenimine) and its role in gene delivery. J Control Release 1999; 60(2–3): 149–60PubMedCrossRefGoogle Scholar
  145. 145.
    Clamme JP, Krishnamoorthy G, Mely Y. Intracellular dynamics of the gene delivery vehicle polyethylenimine during transfection: investigation by two-photon fluorescence correlation spectroscopy. Biochim Biophys Acta 2003; 1617(1–2): 52–61PubMedGoogle Scholar
  146. 146.
    Zou SM, Erbacher P, Remy JS, et al. Systemic linear polyethylenimine (L-PEI)-mediated gene delivery in the mouse. J Gene Med 2000; 2(2): 128–34PubMedCrossRefGoogle Scholar
  147. 147.
    Kloeckner J, Wagner E, Ogris M. Degradable gene carriers based on oligomerized polyamines. Eur J Pharm Sci 2006; 29(5): 414–25PubMedCrossRefGoogle Scholar
  148. 148.
    Ogris M, Walker G, Blessing T, et al. Tumor-targeted gene therapy: strategies for the preparation of ligand-polyethylene glycol-polyethylenimine/DNA complexes. J Control Release 2003; 91(1–2): 173–81PubMedCrossRefGoogle Scholar
  149. 149.
    Kursa M, Walker GF, Roessler V, et al. Novel shielded transferrin-polyethylene glycol-polyethylenimine/DNA complexes for systemic tumor-targeted gene transfer. Bioconjug Chem 2003; 14(1): 222–31PubMedCrossRefGoogle Scholar
  150. 150.
    Plank C, Mechtler K, Szoka Jr FC, et al. Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery. Hum Gene Ther 1996; 7(12): 1437–46PubMedCrossRefGoogle Scholar
  151. 151.
    Kircheis R, Schuller S, Brunner S, et al. Polycation-based DNA complexes for tumor-targeted gene delivery in vivo. J Gene Med 1999; 1(2): 111–20PubMedCrossRefGoogle Scholar
  152. 152.
    Boeckle S, Fahrmeir J, Roedl W, et al. Melittin analogs with high lytic activity at endosomal pH enhance transfection with purified targeted PEI polyplexes. J Control Release 2006; 112(2): 240–8PubMedCrossRefGoogle Scholar
  153. 153.
    Shir A, Ogris M, Wagner E, et al. EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice. PLoS Med 2006; 3(1): e6PubMedCrossRefGoogle Scholar
  154. 154.
    Wu GY, Wu CH. Receptor-mediated gene delivery and expression in vivo. J Biol Chem 1988; 263(29): 14621–4PubMedGoogle Scholar
  155. 155.
    Zhang JS, Liu F, Huang L. Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity. Adv Drug Deliv Rev 2005; 57(5): 689–98PubMedCrossRefGoogle Scholar
  156. 156.
    Zhang JS, Liu F, Conwell CC, et al. Mechanistic studies of sequential injection of cationic liposome and plasmid DNA. Mol Ther 2006; 13(2): 429–37PubMedCrossRefGoogle Scholar
  157. 157.
    Dow SW, Fradkin LG, Liggitt DH, et al. Lipid-DNA complexes induce potent activation of innate immune responses and antitumor activity when administered intravenously. J Immunol 1999; 163(3): 1552–61PubMedGoogle Scholar
  158. 158.
    Yew NS, Cheng SH. Reducing the immunostimulatory activity of CpG-containing plasmid DNA vectors for non-viral gene therapy. Expert Opin Drug Deliv 2004; 1(1): 115–25PubMedCrossRefGoogle Scholar
  159. 159.
    Dauty E, Remy JS, Blessing T, et al. Dimerizable cationic detergents with a low cmc condense plasmid DNA into nanometric particles and transfect cells in culture. J Am Chem Soc 2001; 123(38): 9227–34PubMedCrossRefGoogle Scholar
  160. 160.
    da Cruz MT, Cardoso AL, de Almeida LP, et al. Tf-lipoplex-mediated NGF gene transfer to the CNS: neuronal protection and recovery in an excitotoxic model of brain injury. Gene Ther 2005; 12(16): 1242–52PubMedCrossRefGoogle Scholar
  161. 161.
    Zhang Y, Schlachetzki F, Zhang YF, et al. Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter. Hum Gene Ther 2004; 15(4): 339–50PubMedCrossRefGoogle Scholar
  162. 162.
    Zhang Y, Zhang YF, Bryant J, et al. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin Cancer Res 2004; 10(11): 3667–77PubMedCrossRefGoogle Scholar
  163. 163.
    Tan Y, Liu F, Li Z, et al. Sequential injection of cationic liposome and plasmid DNA effectively transferts the lung with minimal inflammatory toxicity. Mol Ther 2001; 3 (5 Pt1): 673–82CrossRefGoogle Scholar
  164. 164.
    Nishikawa M, Takakura Y, Hashida M. Theoretical considerations involving the pharmacokinetics of plasmid DNA. Adv Drug Deliv Rev 2005; 57(5): 675–88PubMedCrossRefGoogle Scholar
  165. 165.
    Torchilin VP. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu Rev Biomed Eng 2006; 8: 343–75PubMedCrossRefGoogle Scholar
  166. 166.
    Lechardeur D, Verkman AS, Lukacs GL. Intracellular routing of plasmid DNA during non-viral gene transfer. Adv Drug Deliv Rev 2005; 57(5): 755–67PubMedCrossRefGoogle Scholar
  167. 167.
    von Gersdorff K, Sanders NN, Vandenbroucke R, et al. The internalization route resulting in successful gene expression depends on both cell line and polyethylenimine polyplex type. Mol Ther 2006; 14(5): 745–53CrossRefGoogle Scholar
  168. 168.
    Sonawane ND, Szoka Jr FC, Verkman AS. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem 2003; 278(45): 44826–31PubMedCrossRefGoogle Scholar
  169. 169.
    Uherek C, Fominaya J, Wels W. A modular DNA carrier protein based on the structure of diphtheria toxin mediates target cell-specific gene delivery. J Biol Chem 1998; 273(15): 8835–41PubMedCrossRefGoogle Scholar
  170. 170.
    Kloeckner J, Boeckle S, Persson D, et al. DNA polyplexes based on degradable oligoethylenimine-derivatives: combination with EGF receptor targeting and endosomal release functions. J Control Release 2006; 116(2): 115–22PubMedCrossRefGoogle Scholar
  171. 171.
    Pollard H, Toumaniantz G, Amos JL, et al. Ca2+-sensitive cytosolic nucleases prevent efficient delivery to the nucleus of injected plasmids. J Gene Med 2001; 3(2): 153–64PubMedCrossRefGoogle Scholar
  172. 172.
    Harel A, Forbes DJ. Welcome to the nucleus: CAN I take your coat? Nat Cell Biol 2001; 3(12): E267–9PubMedCrossRefGoogle Scholar
  173. 173.
    Brisson M, Huang L. Liposomes: conquering the nuclear barrier. Curr Opin Mol Ther 1999; 1(2): 140–6PubMedGoogle Scholar
  174. 174.
    Zanta MA, Belguise-Valladier P, Behr JP. Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus. Proc Natl Acad Sci U S A 1999; 96(1): 91–6PubMedCrossRefGoogle Scholar
  175. 175.
    Branden LJ, Mohamed AJ, Smith CI. A peptide nucleic acid-nuclear localization signal fusion that mediates nuclear transport of DNA. Nat Biotechnol 1999; 17(8): 784–7PubMedCrossRefGoogle Scholar
  176. 176.
    Jacobs AH, Winkler A, Castro MG, et al. Human gene therapy and imaging in neurological diseases. Eur J Nucl Med Mol Imaging 2005; 32 Suppl. 2: S358–83PubMedCrossRefGoogle Scholar
  177. 177.
    Provenzale JM, Mukundan S, Barboriak DP. Diffusion-weighted and perfusion MR imaging for brain tumor characterization and assessment of treatment response. Radiology 2006; 239(3): 632–49PubMedCrossRefGoogle Scholar
  178. 178.
    Richardson JC, Bowtell RW, Mader K, et al. Pharmaceutical applications of magnetic resonance imaging (MRI). Adv Drug Deliv Rev 2005; 57(8): 1191–209PubMedCrossRefGoogle Scholar
  179. 179.
    Morawski AM, Lanza GA, Wickline SA. Targeted contrast agents for magnetic resonance imaging and ultrasound. Curr Opin Biotechnol 2005; 16(1): 89–92PubMedCrossRefGoogle Scholar
  180. 180.
    Koo YE, Reddy GR, Bhojani M, et al. Brain cancer diagnosis and therapy with nanoplatforms. Adv Drug Deliv Rev 2006; 58(14): 1556–77PubMedCrossRefGoogle Scholar
  181. 181.
    Hamilton AJ, Huang SL, Warnick D, et al. Intravascular ultrasound molecular imaging of atheroma components in vivo. J Am Coll Cardiol 2004 Feb 4; 43(3): 453–60PubMedCrossRefGoogle Scholar
  182. 182.
    Ellegala DB, Leong-Poi H, Carpenter JE, et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha (v)beta3. Circulation 2003; 108(3): 336–41PubMedCrossRefGoogle Scholar
  183. 183.
    Kinoshita M, McDannold N, Jolesz FA, et al. Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem Biophys Res Commun 2006; 340(4): 1085–90PubMedCrossRefGoogle Scholar
  184. 184.
    Paliwal S, Mitragotri S. Ultrasound-induced cavitation: applications in drug and gene delivery. Expert Opin Drug Deliv 2006; 3(6): 713–26PubMedCrossRefGoogle Scholar
  185. 185.
    Abulrob A, Sprong H, Van Bergenen Henegouwen P, et al. The blood-brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells. J Neurochem 2005; 95(4): 1201–14PubMedCrossRefGoogle Scholar
  186. 186.
    Demeule M, Bertrand Y, Michaud-Levesque J, et al. Regulation of plasminogen activation: a role for melanotransferrin p97 in cell migration. Blood 2003; 102(5): 1723–31PubMedCrossRefGoogle Scholar
  187. 187.
    Zlokovic BB, Martel CL, Matsubara E, et al. Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cere-brospinal fluid barriers. Proc Natl Acad Sci U S A 1996; 93(9): 4229–34PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Blood-Brain-Barrier Research Group, Division of Pharmacology, Leiden-Amsterdam Center for Drug ResearchUniversity of LeidenLeidenThe Netherlands
  2. technologies BVLeidenThe Netherlands

Personalised recommendations