Pharmaceutical Research

, Volume 24, Issue 9, pp 1733–1744 | Cite as

Drug Targeting to the Brain

Research Paper


The goal of brain drug targeting technology is the delivery of therapeutics across the blood–brain barrier (BBB), including the human BBB. This is accomplished by re-engineering pharmaceuticals to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium. Certain endogenous peptides, such as insulin or transferrin, undergo receptor-mediated transport (RMT) across the BBB in vivo. In addition, peptidomimetic monoclonal antibodies (MAb) may also cross the BBB via RMT on the endogenous transporters. The MAb may be used as a molecular Trojan horse to ferry across the BBB large molecule pharmaceuticals, including recombinant proteins, antibodies, RNA interference drugs, or non-viral gene medicines. Fusion proteins of the molecular Trojan horse and either neurotrophins or single chain Fv antibodies have been genetically engineered. The fusion proteins retain bi-functional properties, and both bind the BBB receptor, to trigger transport into brain, and bind the cognate receptor inside brain to induce the pharmacologic effect. Trojan horse liposome technology enables the brain targeting of non-viral plasmid DNA. Molecular Trojan horses may be formulated with fusion protein technology, avidin–biotin technology, or Trojan horse liposomes to target to brain virtually any large molecule pharmaceutical.

Key words

blood–brain barrier drug targeting genetic engineering non-viral gene transfer 


  1. 1.
    W. M. Pardridge. Biochemistry of the human blood–brain barrier. Blood–brain barrier: interface between internal medicine and the brain. Ann. Intern. Med. 105:82–95 (1986).PubMedGoogle Scholar
  2. 2.
    A. K. Ghose, V. N. Viswanadhan, and J. J. Wendoloski. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Com. Chem. 1:55–68 (1999).CrossRefGoogle Scholar
  3. 3.
    C. A. Lipinski. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods. 44:235–249 (2000).PubMedCrossRefGoogle Scholar
  4. 4.
    N. H. Greig, E. M. Daly, D. J. Sweeney, and S. I. Rapoport. Pharmacokinetics of chlorambucil–tertiary butyl ester, a lipophilic chlorambucil derivative that achieves and maintains high concentrations in brain. Cancer Chemother. Pharmacol. 25:320–325 (1990).PubMedCrossRefGoogle Scholar
  5. 5.
    W. M. Pardridge. Brain Drug Targeting: The Future of Brain Drug Development. Cambridge University Press, Cambridge, UK, 2001.Google Scholar
  6. 6.
    H. Fischer, R. Gottschlich, and A. Seelig. Blood–brain barrier permeation: molecular parameters governing passive diffusion. J. Membr. Biol. 165: 201–211 (1998).PubMedCrossRefGoogle Scholar
  7. 7.
    D. J. Hingson and J. M. Diamond. Comparison of nonelectrolyte permeability patterns in several epithelia. J. Membr. Biol. 10:93–135 (1972).PubMedCrossRefGoogle Scholar
  8. 8.
    B. E. Cohen and A. D. Bangham. Diffusion of small non-electrolytes across liposome membranes. Nature. 236:173–174 (1972).PubMedCrossRefGoogle Scholar
  9. 9.
    W. R. Lieb and W. D. Stein. Non-Stokesian nature of transverse diffusion within human red cell membranes. J. Membr. Biol. 92:111–119 (1986).Google Scholar
  10. 10.
    R. J. Boado, J. Y. Li, C. Chu, F. Ogoshi, P. Wise, and W. M. Pardridge. Site-directed mutagenesis of cysteine residues of large neutral amino acid transporter LAT1. Biochim. Biophys. Acta 1715:104–110 (2005).PubMedCrossRefGoogle Scholar
  11. 11.
    Y. Kanai, H. Segawa, K. Miyamoto, H. Uchino, E. Takeda, and H. Endou. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem. 273:23629–23632 (1998).PubMedCrossRefGoogle Scholar
  12. 12.
    R. Pfeiffer, B. Spindler, J. Loffing, P. J. Skelly, C. B. Shoemaker, and F. Verrey. Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond. FEBS Lett. 439:157–162 (1998).PubMedCrossRefGoogle Scholar
  13. 13.
    R. J. Boado, J. Y. Li, and W. M. Pardridge. Site-directed mutagenesis of rabbit LAT1 at amino acids 219 and 234. J. Neurochem. 84:1322–1331 (2003).PubMedCrossRefGoogle Scholar
  14. 14.
    R. G. Blasberg, C. Patlak, and J. D. Fenstermacher. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J. Pharmacol. Exp. Ther. 195:73–83 (1975).PubMedGoogle Scholar
  15. 15.
    N. P. Christy and R. A. Fishman. Studies of the blood–cerebrospinal fluid barrier to cortisol in the dog. J. Clin. Invest. 40:1997–2006 (1961).PubMedGoogle Scholar
  16. 16.
    R. B. Aird. A study of intrathecal, cerebrospinal fluid-to-brain exchange. Exp. Neurol. 86:342–358 (1984).PubMedCrossRefGoogle Scholar
  17. 17.
    L. K. Fung, M. Shin, B. Tyler, H. Brem, and W. M. Saltzman. Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharm. Res. 13:671–682 (1996).PubMedCrossRefGoogle Scholar
  18. 18.
    C. E. Krewson, M. L. Klarman, and W. M. Saltzman. Distribution of nerve growth factor following direct delivery to brain interstitium. Brain. Res. 680:196–206 (1995).PubMedCrossRefGoogle Scholar
  19. 19.
    M. L. Rennels, T. F. Gregory, O. R. Blaumanis, K. Fujimoto, and P. A. Grady. Evidence for a ‘paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res. 326:47–63 (1985).PubMedCrossRefGoogle Scholar
  20. 20.
    M. T. Krauze, R. Saito, C. Noble, J. Bringas, J. Forsayeth, T. R. McKnight, J. Park, and K. S. Bankiewicz. Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen. Exp. Neurol. 196:104–111 (2005).PubMedCrossRefGoogle Scholar
  21. 21.
    I. Szentistvanyi, C. S. Patlak, R. A. Ellis, and H. F. Cserr. Drainage of interstitial fluid from different regions of rat brain. Am. J. Physiol. 246:F835–844 (1984).PubMedGoogle Scholar
  22. 22.
    H. Davson, K. Welch, and M.B. Segal. Secretion of cerebrospinal fluid. In The Physiology and Pathophysiology of the Cerebrospinal Fluid. Churchill Livingstone, London, 1987, p. 201.Google Scholar
  23. 23.
    Y. Ai, W. Markesbery, Z. Zhang, R. Grondin, D. Elseberry, G. A. Gerhardt, and D. M. Gash. Intraputamenal infusion of GDNF in aged rhesus monkeys: distribution and dopaminergic effects. J. Comp. Neurol. 461:250–261 (2003).PubMedCrossRefGoogle Scholar
  24. 24.
    T. C. Anand Kumar, G. F. David, A. Sankaranarayanan, V. Puri, and K. R. Sundram. Pharmacokinetics of progesterone after its administration to ovariectomized rhesus monkeys by injection, infusion, or nasal spraying. Proc. Natl. Acad. Sci. U. S. A. 79:4185–4189 (1982).PubMedCrossRefGoogle Scholar
  25. 25.
    T. Sakane, M. Akizuki, S. Yamashita, T. Nadai, M. Hashida, and H. Sezaki. The transport of a drug to the cerebrospinal fluid directly from the nasal cavity: the relation to the lipophilicity of the drug. Chem. Pharm. Bull. (Tokyo). 39:2456–2458 (1991).Google Scholar
  26. 26.
    H. Yamazumi. Infiltration of India ink from subarachnoid space to nasal mucosa along olfactory nerves in rabbits. Nippon Jibi Inkoka Gakkai Kaiho. 92:608–616 (1989).Google Scholar
  27. 27.
    P. Merkus, H. J. Guchelaar, D. A. Bosch, and F. W. Merkus. Direct access of drugs to the human brain after intranasal drug administration? Neurology. 60:1669–1671 (2003).PubMedGoogle Scholar
  28. 28.
    W. M. Pardridge. Blood–brain barrier delivery. Drug Discov Today. 12:54–61 (2007).PubMedCrossRefGoogle Scholar
  29. 29.
    M. P. van den Berg, P. Merkus, S. G. Romeijn, J. C. Verhoef, and F. W. Merkus. Uptake of melatonin into the cerebrospinal fluid after nasal and intravenous delivery: studies in rats and comparison with a human study. Pharm. Res. 21:799–802 (2004).PubMedCrossRefGoogle Scholar
  30. 30.
    W. H. Oldendorf. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am. J. Physiol. 221:1629–1639 (1971).PubMedGoogle Scholar
  31. 31.
    W. M. Pardridge. Brain metabolism: a perspective from the blood–brain barrier. Physiol. Rev. 63:1481–1535 (1983).PubMedGoogle Scholar
  32. 32.
    W. M. Pardridge, R. J. Boado, and C. R. Farrell. Brain-type glucose transporter (GLUT-1) is selectively localized to the blood–brain barrier. Studies with quantitative western blotting and in situ hybridization. J. Biol. Chem. 265:18035–18040 (1990).PubMedGoogle Scholar
  33. 33.
    J. Y. Li, R. J. Boado, and W. M. Pardridge. Cloned blood–brain barrier adenosine transporter is identical to the rat concentrative Na+ nucleoside cotransporter CNT2. J. Cereb. Blood Flow Metab. 21:929–936 (2001).PubMedCrossRefGoogle Scholar
  34. 34.
    W. M. Pardridge, T. Yoshikawa, Y. S. Kang, and L. P. Miller. Blood–brain barrier transport and brain metabolism of adenosine and adenosine analogs. J. Pharmacol. Exp. Ther. 268:14–18 (1994).PubMedGoogle Scholar
  35. 35.
    A. Tsuji and I. I. Tamai. Carrier-mediated or specialized transport of drugs across the blood–brain barrier. Adv. Drug. Deliv. Rev. 36:277–290 (1999).PubMedCrossRefGoogle Scholar
  36. 36.
    T. Terasaki and K. Hosoya. The blood–brain barrier efflux transporters as a detoxifying system for the brain. Adv. Drug Deliv. Rev. 36:195–209 (1999).PubMedCrossRefGoogle Scholar
  37. 37.
    H. Kusuhara and Y. Sugiyama. Efflux transport systems for drugs at the blood–brain barrier and blood–cerebrospinal fluid barrier (Part 1). Drug Discov. Today. 6:150–156 (2001).PubMedCrossRefGoogle Scholar
  38. 38.
    T. Terasaki. Development of Brain Efflux Index (BEI) method and its application to the blood–brain barrier efflux transport study. In Introduction to the Blood–Brain Barrier; Methodology, Biology and Pathology, Cambridge University Press, Cambridge, 1998, pp. 24–31.Google Scholar
  39. 39.
    E. M. Cornford, S. Hyman, M. E. Cornford, and M. J. Caron. Glut1 glucose transporter activity in human brain injury. J. Neurotrauma. 13:523–536 (1996).PubMedCrossRefGoogle Scholar
  40. 40.
    K. R. Duffy and W. M. Pardridge. Blood–brain barrier transcytosis of insulin in developing rabbits. Brain Res. 420:32–38 (1987).PubMedCrossRefGoogle Scholar
  41. 41.
    J. Holly and C. Perks. The role of insulin-like growth factor binding proteins. Neuroendocrinology. 83:154–160 (2006).PubMedCrossRefGoogle Scholar
  42. 42.
    W. M. Pardridge, J. L. Buciak, and P. M. Friden. Selective transport of an anti-transferrin receptor antibody through the blood–brain barrier in vivo. J. Pharmacol. Exp. Ther. 259:66–70 (1991).PubMedGoogle Scholar
  43. 43.
    Y. Zhang and W. M. Pardridge. Mediated efflux of IgG molecules from brain to blood across the blood–brain barrier. J. Neuroimmunol. 114:168–172 (2001).PubMedCrossRefGoogle Scholar
  44. 44.
    H. F. Cserr, D. N. Cooper, P. K. Suri, and C. S. Patlak. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am. J. Physiol. 240:F319–F328 (1981).PubMedGoogle Scholar
  45. 45.
    F. Schlachetzki, C. Zhu, and W. M. Pardridge. Expression of the neonatal Fc receptor (FcRn) at the blood–brain barrier. J. Neurochem. 81:203–206 (2002).PubMedCrossRefGoogle Scholar
  46. 46.
    D. Triguero, J. Buciak, and W. M. Pardridge. Capillary depletion method for quantification of blood–brain barrier transport of circulating peptides and plasma proteins. J. Neurochem. 54:1882–1888 (1990).PubMedCrossRefGoogle Scholar
  47. 47.
    H. J. Lee, B. Engelhardt, J. Lesley, U. Bickel, and W. M. Pardridge. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood–brain barrier in mouse. J. Pharmacol. Exp. Ther. 292:1048–1052 (2000).PubMedGoogle Scholar
  48. 48.
    W. M. Pardridge, Y. S. Kang, J. L. Buciak, and J. Yang. 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).PubMedCrossRefGoogle Scholar
  49. 49.
    D. Wu, J. Yang, and W. M. Pardridge. 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. 100:1804–1812 (1997).PubMedCrossRefGoogle Scholar
  50. 50.
    T. S. Salahuddin, B. B. Johansson, H. Kalimo, and Y. Olsson. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions. An electron microscopic study. Acta Neuropathol. (Berlin). 77:5–13 (1988).CrossRefGoogle Scholar
  51. 51.
    A. S. Lossinsky, A. W. Vorbrodt, and H. M. Wisniewski. Scanning and transmission electron microscopic studies of microvascular pathology in the osmotically impaired blood–brain barrier. J. Neurocytol. 24:795–806 (1995).PubMedCrossRefGoogle Scholar
  52. 52.
    E. A. Neuwelt and S. I. Rapoport. Modification of the blood–brain barrier in the chemotherapy of malignant brain tumors. Fed. Proc. 43:214–219 (1984).PubMedGoogle Scholar
  53. 53.
    L. I. Larsson, J. Fahrenkrug, O. Schaffalitzky De Muckadell, F. Sundler, R. Hakanson, and J. R. Rehfeld. Localization of vasoactive intestinal polypeptide (VIP) to central and peripheral neurons. Proc. Natl. Acad. Sci. U. S. A. 73:3197–3200 (1976).PubMedCrossRefGoogle Scholar
  54. 54.
    J. McCulloch and L. Edvinsson. Cerebral circulatory and metabolic effects of vasoactive intestinal polypeptide. Am. J. Physiol. 238:H449–H456 (1980).PubMedGoogle Scholar
  55. 55.
    D. Wu and W. M. Pardridge. 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).PubMedGoogle Scholar
  56. 56.
    D. Wu and W. M. Pardridge. Neuroprotection with noninvasive neurotrophin delivery to the brain. Proc. Natl. Acad. Sci. U. S. A. 96:254–259 (1999).PubMedCrossRefGoogle Scholar
  57. 57.
    T. Sakane and W. M. Pardridge. Carboxyl-directed pegylation of brain-derived neurotrophic factor markedly reduces systemic clearance with minimal loss of biologic activity. Pharm. Res. 14:1085–1091 (1997).PubMedCrossRefGoogle Scholar
  58. 58.
    Y. Zhang and W. M. Pardridge. 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).PubMedCrossRefGoogle Scholar
  59. 59.
    Y. Zhang and W. M. Pardridge. Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood–brain barrier drug targeting system. Stroke. 32:1378–1384 (2001).PubMedGoogle Scholar
  60. 60.
    B. W. Song, H. V. Vinters, D. Wu, and W. M. Pardridge. 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).PubMedCrossRefGoogle Scholar
  61. 61.
    L. Belayev, R. Busto, W. Zhao, and M. D. Ginsberg. Quantitative evaluation of blood–brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res. 739:88–96 (1996).PubMedCrossRefGoogle Scholar
  62. 62.
    A. Kurihara and W. M. Pardridge. Imaging brain tumors by targeting peptide radiopharmaceuticals through the blood–brain barrier. Cancer Res. 59:6159–6163 (1999).PubMedGoogle Scholar
  63. 63.
    A. Kurihara, Y. Deguchi, and W. M. Pardridge. Epidermal growth factor radiopharmaceuticals: 111In chelation, conjugation to a blood–brain barrier delivery vector via a biotin-polyethylene linker, pharmacokinetics, and in vivo imaging of experimental brain tumors. Bioconjug. Chem. 10:502–511 (1999).PubMedCrossRefGoogle Scholar
  64. 64.
    H. J. Lee, Y. Zhang, C. Zhu, K. Duff, and W. M. Pardridge. Imaging brain amyloid of Alzheimer disease in vivo in transgenic mice with an Abeta peptide radiopharmaceutical. J. Cereb. Blood Flow Metab. 22:223–231 (2002).PubMedCrossRefGoogle Scholar
  65. 65.
    Y. Saito, J. Buciak, J. Yang, and W. M. Pardridge. Vector-mediated delivery of 125I-labeled beta-amyloid peptide A beta 1–40 through the blood–brain barrier and binding to Alzheimer disease amyloid of the A beta 1–40/vector complex. Proc. Natl. Acad. Sci. U. S. A. 92:10227–10231 (1995).CrossRefGoogle Scholar
  66. 66.
    T. Suzuki, D. Wu, F. Schlachetzki, J. Y. Li, R. J. Boado, and W. M. Pardridge. Imaging endogenous gene expression in brain cancer in vivo with 111In-peptide nucleic acid antisense radiopharmaceuticals and brain drug-targeting technology. J. Nucl. Med. 45:1766–1775 (2004).PubMedGoogle Scholar
  67. 67.
    T. Suzuki, Y. Zhang, Y. F. Zhang, F. Schlachetzki, and W. M. Pardridge. Imaging gene expression in regional brain ischemia in vivo with a targeted [111in]-antisense radiopharmaceutical. Mol. Imaging 3:356–363 (2004).PubMedCrossRefGoogle Scholar
  68. 68.
    W. M. Pardridge, R. J. Boado, and Y. S. Kang. Vector-mediated delivery of a polyamide (“peptide”) nucleic acid analogue through the blood–brain barrier in vivo. Proc. Natl. Acad. Sci. U. S. A. 92:5592–5596 (1995).PubMedCrossRefGoogle Scholar
  69. 69.
    Y. Zhang and W. M. Pardridge. Delivery of beta-galactosidase to mouse brain via the blood–brain barrier transferrin receptor. J. Pharmacol. Exp. Ther. 313:1075–1081 (2005).PubMedCrossRefGoogle Scholar
  70. 70.
    M. J. Coloma, H. J. Lee, A. Kurihara, E. M. Landaw, R. J. Boado, S. L. Morrison, and W. M. Pardridge. 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).PubMedCrossRefGoogle Scholar
  71. 71.
    R. J. Boado, Y. Zhang, and W. M. Pardridge. Humanization of anti-human insulin receptor antibody for drug targeting across the human blood–brain barrier. Biotechnol. Bioeng. 96:381–391 (2007).PubMedCrossRefGoogle Scholar
  72. 72.
    R. J. Boado, Y. Zhang, and W. M. Pardridge. 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. in press (2007).Google Scholar
  73. 73.
    R. J. Boado, Y. Zhang, C. F. Xia, and W. M. Pardridge. Fusion antibody for Alzheimer’s disease with bidirectional transport across the blood–brain barrier and abeta fibril disaggregation. Bioconjug Chem. 18:447–455 (2007).Google Scholar
  74. 74.
    J. Norman, W. Denham, D. Denham, J. Yang, G. Carter, A. Abouhamze, C. L. Tannahill, S. L. MacKay, and L. L. Moldawer. Liposome-mediated, nonviral gene transfer induces a systemic inflammatory response which can exacerbate pre-existing inflammation. Gene Ther. 7:1425–1430 (2000).PubMedCrossRefGoogle Scholar
  75. 75.
    D. Simberg, S. Weisman, Y. Talmon, A. Faerman, T. Shoshani, and Y. Barenholz. The role of organ vascularization and lipoplex-serum initial contact in intravenous murine lipofection. J. Biol. Chem. 278:39858–39865 (2003).PubMedCrossRefGoogle Scholar
  76. 76.
    N. Shi and W. M. Pardridge. Noninvasive gene targeting to the brain. Proc. Natl. Acad. Sci. U. S. A. 97:7567–7572 (2000).PubMedCrossRefGoogle Scholar
  77. 77.
    Y. Zhang, F. Schlachetzki, and W. M. Pardridge. Global non-viral gene transfer to the primate brain following intravenous administration. Mol. Ther. 7:11–18 (2003).PubMedCrossRefGoogle Scholar
  78. 78.
    N. Shi, Y. Zhang, C. Zhu, R. J. Boado, and W. M. Pardridge. Brain-specific expression of an exogenous gene after i.v. administration. Proc. Natl. Acad. Sci. U. S. A. 98:12754–12759 (2001).PubMedCrossRefGoogle Scholar
  79. 79.
    N. Shi, R. J. Boado, and W. M. Pardridge. Receptor-mediated gene targeting to tissues in vivo following intravenous administration of pegylated immunoliposomes. Pharm. Res. 18:1091–1095 (2001).PubMedCrossRefGoogle Scholar
  80. 80.
    Y. Zhang, F. Schlachetzki, J. Y. Li, R. J. Boado, and W. M. Pardridge. Organ-specific gene expression in the rhesus monkey eye following intravenous non-viral gene transfer. Mol. Vis. 9:465–472 (2003).PubMedGoogle Scholar
  81. 81.
    D. J. Zack, J. Bennett, Y. Wang, C. Davenport, B. Klaunberg, J. Gearhart, and J. Nathans. Unusual topography of bovine rhodopsin promoter-lacZ fusion gene expression in transgenic mouse retinas. Neuron. 6:187–199 (1991).PubMedCrossRefGoogle Scholar
  82. 82.
    C. Zhu, Y. Zhang, Y. F. Zhang, J. Yi Li, R. J. Boado, and W. M. Pardridge. Organ-specific expression of the lacZ gene controlled by the opsin promoter after intravenous gene administration in adult mice. J. Gene Med. 6:906–912 (2004).PubMedCrossRefGoogle Scholar
  83. 83.
    Y. Zhang, F. Schlachetzki, Y. F. Zhang, R. J. Boado, and W. M. Pardridge. 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. 15:339–350 (2004).PubMedCrossRefGoogle Scholar
  84. 84.
    Y. Zhang, C. Zhu, and W. M. Pardridge. Antisense gene therapy of brain cancer with an artificial virus gene delivery system. Mol. Ther. 6:67–72 (2002).PubMedCrossRefGoogle Scholar
  85. 85.
    Y. Zhang, Y. F. Zhang, J. Bryant, A. Charles, R. J. Boado, and W. M. Pardridge. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin. Cancer Res. 10:3667–3677 (2004).PubMedCrossRefGoogle Scholar
  86. 86.
    W. M. Pardridge. Recent advances in blood–brain barrier transport. Annu. Rev. Pharmacol. Toxicol. 28:25–39 (1988).PubMedCrossRefGoogle Scholar
  87. 87.
    Y. F. Zhang, R. J. Boado, and W. M. Pardridge. Absence of toxicity of chronic weekly intravenous gene therapy with pegylated immunoliposomes. Pharm. Res. 20:1779–1785 (2003).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of MedicineUCLALos AngelesUSA

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