CNS Drugs

, Volume 23, Issue 1, pp 35–58 | Cite as

Getting into the Brain

Approaches to Enhance Brain Drug Delivery
  • Mayur M. Patel
  • Bhoomika R. Goyal
  • Shraddha V. Bhadada
  • Jay S. Bhatt
  • Avani F. Amin
Review Article


Being the most delicate organ of the body, the brain is protected against potentially toxic substances by the blood-brain barrier (BBB), which restricts the entry of most pharmaceuticals into the brain. The developmental process for new drugs for the treatment of CNS disorders has not kept pace with progress in molecular neurosciences because most of the new drugs discovered are unable to cross the BBB. The clinical failure of CNS drug delivery may be attributed largely to a lack of appropriate drug delivery systems. Localized and controlled delivery of drugs at their desired site of action is preferred because it reduces toxicity and increases treatment efficiency. The present review provides an insight into some of the recent advances made in the field of brain drug delivery.

The various strategies that have been explored to increase drug delivery into the brain include (i) chemical delivery systems, such as lipid-mediated transport, the prodrug approach and the lock-in system; (ii) biological delivery systems, in which pharmaceuticals are re-engineered to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium; (iii) disruption of the BBB, for example by modification of tight junctions, which causes a controlled and transient increase in the permeability of brain capillaries; (iv) the use of molecular Trojan horses, such as peptidomimetic monoclonal antibodies totransport large molecules (e.g. antibodies, recombinant proteins, nonviral gene medicines or RNA interference drugs) across the BBB; and (v) particulate drug carrier systems. Receptor-mediated transport systems exist for certain endogenous peptides, such as insulin and transferrin, enabling these molecules to cross the BBB in vivo.

The use of polymers for local drug delivery has greatly expanded the spectrum of drugs available for the treatment of brain diseases, such as malignant tumours and Alzheimer’s disease. In addition, various drug delivery systems (e.g. liposomes, microspheres, nanoparticles, nanogels and bionanocapsules) have been used to enhance drug delivery to the brain. Recently, microchips and biodegradable polymers have become important in brain tumour therapy.

The intense search for alternative routes of drug delivery (e.g. intranasal drug delivery, convection-enhanced diffusion and intrathecal/intraventricular drug delivery systems) has been driven by the need to overcome the physiological barriers of the brain and to achieve high drug concentrations within the brain. For more than 30 years, considerable efforts have been made to enhance the delivery of therapeutic molecules across the vascular barriers of the CNS. The current challenge is to develop drug delivery strategies that will allow the passage of drug molecules through the BBB in a safe and effective manner.


Solid Lipid Nanoparticles Ommaya Reservoir Nipecotic Acid Prodrug Approach Large Neutral Amino Acid Transporter 
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 sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Brightman MW. Morphology of blood-brain interfaces. Exp Eye Res 1977; 25 Suppl.: 1–25PubMedCrossRefGoogle Scholar
  2. 2.
    Schlosshauer B. The blood-brain barrier: morphology, molecules, and neurothelin. Bioassays 1993 May; 15: 341–6CrossRefGoogle Scholar
  3. 3.
    Ricci M, Blasi P, Giovagnoli S, et al. Delivering drugs to the central nervous system: a medicinal chemistry or a pharmaceutical technology issue? Curr Med Chem 2006; 13: 1757–75PubMedCrossRefGoogle Scholar
  4. 4.
    Pardridge WM. Brain drug targeting: the future of brain drug development. Cambridge: Cambridge University Press, 2001CrossRefGoogle Scholar
  5. 5.
    Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledgebased approach in designing combinatorial or medicinal chemistry libraries for drug discovery: I. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1999 Jan; 1: 55–68Google Scholar
  6. 6.
    MDL® comprehensive medicinal chemistry [online]. Available from URL: [Accessed 2008 Nov 26]
  7. 7.
    Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 2000 Jul–Aug; 44: 235–49PubMedCrossRefGoogle Scholar
  8. 8.
    Regier DA, Boyd JH, Burke JD Jr, et al. One-month prevalence of mental disorders in the United States: based on five epidemiologic catchment area sites. Arch Gen Psychiatry 1988; 45: 977–86PubMedCrossRefGoogle Scholar
  9. 9.
    Pardridge WM. Blood-brain barrier delivery. Drug Discov Today 2007 Jan; 12: 54–61PubMedCrossRefGoogle Scholar
  10. 10.
    Pardridge WM. Why is the global CNS pharmaceutical market so underpenetrated? Drug Discov Today 2002 Jan; 7: 5–7PubMedCrossRefGoogle Scholar
  11. 11.
    Misra A, Ganesh S, Aliasgar S, et al. Drug delivery to the central nervous system: a review. J Pharm Pharmaceut Sci 2003 May–Aug; 6: 252–73Google Scholar
  12. 12.
    Pardridge WM. Recent advances in blood brain-barrier transport. Annu Rev Pharmacol Toxicol 1988 Apr; 28: 25–39PubMedCrossRefGoogle Scholar
  13. 13.
    Jamal T, Scherrmann JM, Rees AR, et al. Brain drug delivery technologies: novel approaches for transporting therapeutics. Pharm Sci Technol Today 2000 May; 3: 155–62CrossRefGoogle Scholar
  14. 14.
    Greig NH. Drug delivery to the brain by blood-barrier: circumvention and drug modification. In: Neuwelt EA, editor. Implications of the blood-brain barrier and its manipulation. New York: Plenum Press, 1989: 311–67CrossRefGoogle Scholar
  15. 15.
    Sawynok J. The therapeutic use of heroin: a review of the pharmacological literature. Can J Physiol Pharmacol 1986 Jan; 64: 1–6PubMedCrossRefGoogle Scholar
  16. 16.
    Pardridge WM, Mietus LJ. Transport of steroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone. J Clin Invest 1979 Jul; 64: 145–54PubMedCrossRefGoogle Scholar
  17. 17.
    Lesniak MS. Novel advances in drug delivery to brain cancer. Technol Cancer Res Treat 2005 Aug; 4: 417–28PubMedGoogle Scholar
  18. 18.
    Albrecht KW, de Witt PC, Leenstra S, et al. High concentration of daunorubicin and daunorubicinol in human malignant astrocytomas after systemic administration of liposomal daunorubicin. J Neurooncol 2001 Jul; 53: 267–71PubMedCrossRefGoogle Scholar
  19. 19.
    Koukourakis MI, Koukouraki S, Fezoulidis I, et al. High intratumoural accumulation of stealth liposomal doxorubicin (caelyx) in glioblastomas and in metastatic brain tumours. Br J Cancer 2000 Nov; 83: 1281–6PubMedCrossRefGoogle Scholar
  20. 20.
    Fabel K, Dietrich J, Hau P, et al. Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin. Cancer 2001 Oct; 92: 1936–42PubMedCrossRefGoogle Scholar
  21. 21.
    Lippens RJ. Liposomal daunorubicin (Daunoxome) in children with recurrent or progressive brain tumors. Pediatr Hematol Oncol 1999 Mar–Apr; 16: 131–9PubMedCrossRefGoogle Scholar
  22. 22.
    Greig NH, Daly EM, Sweeney DJ, et al. Pharmacokinetics of chlorambucil-tertiary butyl ester, a lipophilic chlorambucil derivative that achieves and maintains high concentrations in brain. Cancer Chemother Pharmacol 1990; 25: 320–5PubMedCrossRefGoogle Scholar
  23. 23.
    Pardridge WM. Drug targeting to the brain. Pharm Res 2007 Sep; 24: 1733–44PubMedCrossRefGoogle Scholar
  24. 24.
    Fischer H, Gottschlich R, Seelig A. Blood-brain barrier permeation: molecular parameters governing passive diffusion. J Membrane Biol 1998 Oct; 165: 201–11CrossRefGoogle Scholar
  25. 25.
    Pardridge WM. Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv 2003 Mar; 3: 90–105PubMedCrossRefGoogle Scholar
  26. 26.
    Bodor N, Kaminski JJ. Prodrugs and site-specific chemical delivery systems. Annu Rep Med Chem 1987; 22: 303–13CrossRefGoogle Scholar
  27. 27.
    Lambert DM. Rationale and applications of lipids as prodrug carriers. Eur J Pharm Sci 2000; 11Suppl. 2: S15–27PubMedCrossRefGoogle Scholar
  28. 28.
    Han HK, Amidon GL. Targeted prodrug design to optimize drug delivery. AAPS PharmSci 2000; 2: E6PubMedGoogle Scholar
  29. 29.
    Bodor N. Drug targeting and retrometabolic drug design approaches. Adv Drug Deliv Rev 1994 Jun–Jul; 14: 157–66CrossRefGoogle Scholar
  30. 30.
    Bodor N, Buchwald P. Drug targeting via retrometabolic approaches. Pharmacol Ther 1997 Oct–Dec; 76: 1–27PubMedCrossRefGoogle Scholar
  31. 31.
    Somogyi G, Nishitani S, Nomi D, et al. Targeted drug delivery to the brain via phosphonate derivatives: I. Design, synthesis, and evaluation of an anionic chemical delivery system for testosterone. Int J Pharm 1998 May; 166: 15–26Google Scholar
  32. 32.
    Somogyi G, Buchwald P, Nomi D, et al. Targeted drug delivery to the brain via phosphonate derivatives: II. Anionic chemical delivery system for zidovudine (AZT). Int J Pharm 1998; 166: 27–35Google Scholar
  33. 33.
    Terasaki T, Tsuji A. Drug delivery to the brain utilizing bloodbrain barrier transport systems. J Control Release 1994 Feb; 29: 163–9CrossRefGoogle Scholar
  34. 34.
    Pardridge WM. New approaches to drug delivery through the blood-brain barrier. Trends Biotechnol 1994 Jun; 12: 239–45PubMedCrossRefGoogle Scholar
  35. 35.
    Kang YS, Pardridge WM. Brain delivery of biotin bound to a conjugate of neutral avidin and cationized human albumin. Pharm Res 1994 Sep; 11: 1257–64PubMedCrossRefGoogle Scholar
  36. 36.
    Pardridge WM, Triguero D, Buciak JL, et al. Beta-endorphin chimeric peptides: transport through the blood-brain barrier in vivo and cleavage of disulfide linkage by brain. Endocrinology 1990 Feb; 126: 977–84PubMedCrossRefGoogle Scholar
  37. 37.
    Oldendorf WH. Brain uptake of radiolabeled amino acids, amines and hexoses after arterial injection. Am J Physiol 1971 Dec; 221: 1629–39PubMedGoogle Scholar
  38. 38.
    Mena I, Cotzias GC. Protein intake and treatment of Parkinson’s disease with levodopa. N Engl J Med 1975 Jan; 292: 181–4PubMedCrossRefGoogle Scholar
  39. 39.
    Cornford EM, Young D, Paxton JW, et al. Melphalan penetration of the blood-brain barrier via the neurtral amino acid transporter in tumor-bearing brain. Cancer Res 1992 Jan; 52: 138–43PubMedGoogle Scholar
  40. 40.
    Markovitz DC, Fernstrom JD. Diet and uptake of aldomet by the brain: competition with natural large neutral amino acids. Science 1977 Sep; 197: 1014–5PubMedCrossRefGoogle Scholar
  41. 41.
    Uchino H, Kanai Y, Kim DK, et al. Transport of amino acidrelated compounds mediated by L-type amino acid transporterl (LAT1): insights into the mechanisms of substrate recognition. Mol Pharmacol 2002 Apr; 61: 729–37PubMedCrossRefGoogle Scholar
  42. 42.
    Dalpiaz A, Pavan B, Vertuani S, et al. Ascorbic and 6-Brascorbic acid conjugates as a tool to increase the therapeutic effects of potentially central active drugs. Eur J Pharm Sci 2005 Mar; 24: 259–69PubMedCrossRefGoogle Scholar
  43. 43.
    Cornford EM, Oldendorf WH. Independent blood-brain barrier transport systems for nucleic acid precursors. Biochim Biophys Acta 1975 Jun; 394: 211–9PubMedCrossRefGoogle Scholar
  44. 44.
    Cornford EM, Braun LD, Oldendorf WH. Carrier mediated blood-brain barrier transport of choline and certain choline analogs. J Neurochem 1978 Feb; 30: 299–308PubMedCrossRefGoogle Scholar
  45. 45.
    Pardridge WM, Boado RJ, Farrell CR. 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 1990 Oct; 265: 18035–40PubMedGoogle Scholar
  46. 46.
    Bonina FP, Arenare L, Palagiano F, et al. Synthesis, stability, and pharmacological evaluation of nipecotic acid prodrugs. J Pharm Sci 1999 May; 88: 561–7PubMedCrossRefGoogle Scholar
  47. 47.
    Bonina FP, Arenare L, Ippolito R, et al. Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. Int J Pharm 2000 Jul; 202: 79–88PubMedCrossRefGoogle Scholar
  48. 48.
    Li JY, Boado RJ, Pardridge WM. Cloned blood-brain barrier adenosine transporter is identical to the rat concentrative Na+ nucleoside cotransporter CNT2. J Cereb Blood Flow Metab 2001 Aug; 21: 929–36PubMedCrossRefGoogle Scholar
  49. 49.
    Pardridge WM, Yoshikawa T, Kang YS, et al. Blood-brain barrier transport and brain metabolism of adenosine and adenosine analogs. J Pharmacol Exp Ther 1994 Jan; 268: 14–8PubMedGoogle Scholar
  50. 50.
    Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 1987 Sep; 420: 32–8PubMedCrossRefGoogle Scholar
  51. 51.
    Holly J, Perks C. The role of insulin-like growth factor binding proteins. Neuroendocrinology 2006; 83: 154–60PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang Y, Pardridge WM. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. J Neuroimmunol 2001 Mar; 114: 168–72PubMedCrossRefGoogle Scholar
  53. 53.
    Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem 2002 Apr; 81: 203–6PubMedCrossRefGoogle Scholar
  54. 54.
    Triguero D, Buciak J, Pardridge WM. Capillary depletion method for quantification of blood—brain barrier transport of circulating peptides and plasma proteins. J Neurochem 1990 Jun; 54: 1882–8PubMedCrossRefGoogle Scholar
  55. 55.
    Shin SU, Friden P, Moran M, et al. Transferrin-antibody fusion proteins are effective in brain targeting. Proc Natl Acad Sci 1995 Mar; 92: 2820–4PubMedCrossRefGoogle Scholar
  56. 56.
    Danielyan K, Ding BS, Gottstein C, et al. Delivery of antiplatelet-endothelial cell adhesion molecule single-chain variable fragment-urokinase fusion protein to the cerebral vasculature lyses arterial clots and attenuates postischemic brain edema. J Pharmacol Exp Ther 2007 Jun; 321: 947–52PubMedCrossRefGoogle Scholar
  57. 57.
    Kreuter J, et al. Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles). Brain Res 1995 Mar; 674: 171–4PubMedCrossRefGoogle Scholar
  58. 58.
    Schroeder U, Sommerfeld P, Ulrich S, et al. Nanoparticle technology for delivery of drugs across the blood-brain barrier. J Pharm Sci 1998 Nov; 87: 1305–7PubMedCrossRefGoogle Scholar
  59. 59.
    Alyautdin RN, Petrov VE, Langer K, et al. Delivery of loperamide across the bloodbrain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm Res 1997 Mar; 14: 325–8PubMedCrossRefGoogle Scholar
  60. 60.
    Alyautdin RN, Tezikov EB, Ramge P, et al. Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study. J Microencapsul 1998 Jan–Feb; 15: 67–74PubMedCrossRefGoogle Scholar
  61. 61.
    Friese A, Seiller E, Quack G, et al. Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system. Eur J Pharm Biopharm 2000 Mar; 49: 103–9PubMedCrossRefGoogle Scholar
  62. 62.
    Gulyaev AE, Gelperina SE, Skidan IN, et al. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles. Pharm Res 1999 Oct; 16: 1564–9PubMedCrossRefGoogle Scholar
  63. 63.
    Kreuter J. Nanoparticlate systems for brain delivery of drugs. Adv Drug Deliv Rev 2001 Mar; 47: 65–81PubMedCrossRefGoogle Scholar
  64. 64.
    Kim HR, Andrieux K, Delomenie C, et al. Analysis of plasma protein adsorption onto PEGylated nanoparticles by complementary methods: 2-DE, CE and Protein Lab-on-chip® system. Electrophoresis 2007 Jul; 28: 2252–61PubMedCrossRefGoogle Scholar
  65. 65.
    Kim HR, Andrieux K, Gil S, et al. Translocation of poly(ethylene glycol-co-hexadecyl)cyanoacrylate nanoparticles into rat brain endothelial cells: role of apolipoproteins in receptormediated endocytosis. Biomacromolecules 2007 Mar; 8: 793–9PubMedCrossRefGoogle Scholar
  66. 66.
    Kim HR, Gill S, Andrieux K, et al. Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells. Cell Mol Life Sci 2007 Feb; 64: 356–64PubMedCrossRefGoogle Scholar
  67. 67.
    Kaur IP, Bhandari R, Bhandari S, et al. Potential of solid lipid nanoparticles in brain targeting. J Control Release 2008 Apr; 127: 97–109PubMedCrossRefGoogle Scholar
  68. 68.
    Oyewumi MO, Yokel RA, Jay M, et al. Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J Control Release 2004 Mar; 95: 613–26PubMedCrossRefGoogle Scholar
  69. 69.
    Weitman SD, Lark RH, Coney LR, et al. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res 1992 Jun; 52: 3396–401PubMedGoogle Scholar
  70. 70.
    Lee RJ, Low PS. Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. Biochim Biophys Acta 1995 Feb; 1233: 134–44PubMedCrossRefGoogle Scholar
  71. 71.
    Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2003 Mar; 2: 214–21PubMedCrossRefGoogle Scholar
  72. 72.
    Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005 Jan; 2: 3–14PubMedCrossRefGoogle Scholar
  73. 73.
    Cornford EM, Hyman S, Swartz BE. The human brain GLUT1 glucose transporter: ultrastructural localization to the bloodbrain barrier endothelia. J Cereb Blood Flow Metab 1994 Jan; 14: 106–12PubMedCrossRefGoogle Scholar
  74. 74.
    Derossi D, Chassaing G, Prochiantz A. Trojan peptides: the penetratin system for intracellular delivery. Trends Cell Biol 1998 Feb; 8: 84–7PubMedGoogle Scholar
  75. 75.
    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 April; 57: 679–86PubMedGoogle Scholar
  76. 76.
    Schwarze SR, Ho A, Vocero-Akbani A, et al. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 1999 Sep; 285: 1569–72PubMedCrossRefGoogle Scholar
  77. 77.
    Salahuddin TS, Johansson BB, Kalimo H, et al. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions: an electron microscopic study. Acta Neuropathol 1988; 77: 5–13PubMedCrossRefGoogle Scholar
  78. 78.
    Lossinsky AS, Vorbrodt AW, Wisniewski HM. Scanning and transmission electron microscopic studies of microvascular pathology in the osmotically impaired blood-brain barrier. J Neurocytol 1995 Oct; 24: 795–806PubMedCrossRefGoogle Scholar
  79. 79.
    Kroll RA, Neuwelt EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 1998 May; 42: 1083–100PubMedCrossRefGoogle Scholar
  80. 80.
    Greenwood J, Luthert PJ, Pratt OE, et al. Hyperosmolar opening of the blood-brain barrier in the energy-depleted rat brain: part 1. Permeability studies. J Cereb Blood Flow Metab 1988 Feb; 8: 9–15CrossRefGoogle Scholar
  81. 81.
    Doolittle ND, Petrillo A, Bell S, et al. Blood-brain barrier disruption for the treatment of malignant brain tumors: the National Program. J Neurosci Nurs 1998 Apr; 30: 81–90PubMedCrossRefGoogle Scholar
  82. 82.
    Salahuddin TS, Johansson BB, Kalimo H, et al. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions: a light microscopic and immunohistochemical study. Neuropathol Appl Neurobiol Neuropeptides 1988 Nov–Dec; 14: 467–82CrossRefGoogle Scholar
  83. 83.
    Miller G. Drug targeting: breaking down barriers. Science 2002 Aug; 297: 1116–8PubMedCrossRefGoogle Scholar
  84. 84.
    Matsukado K, Inamura T, Nakano S, et al. Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of the bradykinin analog, RMP-7. Neurosurgery 1996 Jul; 39: 125–33PubMedCrossRefGoogle Scholar
  85. 85.
    Abbott NJ, Romero IA. Transporting therapeutics across the blood-brain barrier. Mol Med Today 1996 Mar; 2: 106–13PubMedCrossRefGoogle Scholar
  86. 86.
    Emerich DF, Dean RL, Osborn C, et al. 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 2001; 40: 105–23PubMedCrossRefGoogle Scholar
  87. 87.
    Saija A, Princi P, Trombetta D, et al. Changes in the permeability of the blood-brain barrier following sodium dodecyl sulphate administration in the rat. Exp Brain Res 1997; 115: 546–51PubMedCrossRefGoogle Scholar
  88. 88.
    Hanig JP, Morrison JM Jr, Krop S, et al. Ethanol enhancement of blood-brain barrier permeability to catecholamines in chicks. Eur J Pharmacol 1972 Apr; 18: 79–82PubMedCrossRefGoogle Scholar
  89. 89.
    Kobiler D, Lustig S, Gozes Y, et al. Sodium dodecylsulphate induces a breach in the blood-brain barrier and enables a West Nile virus variant to penetrate into mouse brain. Brain Res 1989 Sep; 496: 314–6PubMedCrossRefGoogle Scholar
  90. 90.
    Azmin MN, Stuart JF, Florence AT, et al. The distribution and elimination of methotrexate in mouse blood and brain after concurrent administration of polysorbate 80. Cancer Chemother Pharmacol 1985; 14: 238–42PubMedCrossRefGoogle Scholar
  91. 91.
    Zhang Y, Miller DW. Pathways for drug delivery to the central nervous system. In: Wang B, Siahaan T, Soltero RA, editors. Drug delivery: principles and applications. New Jersey (NJ): Wiley Interscience, 2005: 29–56CrossRefGoogle Scholar
  92. 92.
    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 Pharm 2003 Dec; 140: 1201–10CrossRefGoogle Scholar
  93. 93.
    Erdlenbruch B, Jendrossek V, Eibl H, et al. Transient and controllable opening of the blood-brain barrier to cytostatic and antibiotic agents by alkylglycerols in rats. Exp Brain Res 2000 Dec; 135: 417–22PubMedCrossRefGoogle Scholar
  94. 94.
    Erdlenbruch B, Jendrossek V, Kugler W, et al. Increased delivery of erucylphosphocholine to C6 gliomas by chemical opening of the blood-brain barrier using intracarotid pentylglycerol in rats. Cancer Chemother Pharmacol 2002 Oct; 50: 299–304PubMedCrossRefGoogle Scholar
  95. 95.
    Erdlenbruch B, Schinkhof C, Kugler W, et al. Intracarotid administration of short-chain alkylglycerols for increased delivery of methotrexate to the rat brain. Br J Pharm 2003 Jun; 139: 685–94CrossRefGoogle Scholar
  96. 96.
    Pardridge WM, Kang YS, Buciak JL, et al. 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 1995 Jun; 12: 807–16PubMedCrossRefGoogle Scholar
  97. 97.
    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 Oct; 100: 1804–12PubMedCrossRefGoogle Scholar
  98. 98.
    Boado RJ, Zhang Y, Zhang Y, et al. 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 2007 Aug; 97: 1376–86PubMedCrossRefGoogle Scholar
  99. 99.
    Lee HJ, Engelhardt B, Lesley J, et al. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse. J Pharmacol Exp Ther 2000 Mar; 292: 1048–52PubMedGoogle Scholar
  100. 100.
    Pardridge WM, Buciak JL, Friden PM. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J Pharmacol Exp Ther 1991 Oct; 259: 66–70PubMedGoogle Scholar
  101. 101.
    Neuwelt EA, Rapoport SI. Modification of the blood-brain barrier in the chemotherapy of malignant brain tumors. Fed Proc 1984 Feb; 43: 214–9PubMedGoogle Scholar
  102. 102.
    Suzuki T, Zhang Y, Zhang YF, et al. Imaging gene expression in regional brain ischemia in vivo with a targeted [111in]-antisense radiopharmaceutical. Mol Imaging 2004 Oct; 3: 356–63PubMedCrossRefGoogle Scholar
  103. 103.
    Suzuki T, Wu D, Schlachetzki F, et al. Imaging endogenous gene expression in brain cancer in vivo with 111In-peptide nucleic acid antisense radiopharmaceuticals and brain drug-targeting technology. J Nucl Med 2004 Oct; 45: 1766–75PubMedGoogle Scholar
  104. 104.
    Zhang Y, Pardridge WM. Delivery of beta-galactosidase to mouse brain via the blood-brain barrier transferrin receptor. J Pharmacol Exp Ther 2005 Jun; 313: 1075–81PubMedCrossRefGoogle Scholar
  105. 105.
    Lee HJ, Zhang Y, Zhu C, et al. Imaging brain amyloid of Alzheimer disease in vivo in transgenic mice with an Abeta peptide radiopharmaceutical. J Cereb Blood Flow Metab 2002 Feb; 22: 223–31PubMedCrossRefGoogle Scholar
  106. 106.
    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 2001 Jan; 889: 49–56PubMedCrossRefGoogle Scholar
  107. 107.
    Zhang Y, Pardridge WM. 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 2001 Jun; 32: 1378–84PubMedCrossRefGoogle Scholar
  108. 108.
    Wu D, Pardridge WM. Neuroprotection with noninvasive neurotrophin delivery to the brain. Proc Natl Acad Sci U S A 1999 Jan; 96: 254–9PubMedCrossRefGoogle Scholar
  109. 109.
    Kurihara A, Pardridge WM. Imaging brain tumors by targeting peptide radiopharmaceuticals through the blood-brain barrier. Cancer Res 1999 Dec; 59: 6159–63PubMedGoogle Scholar
  110. 110.
    Song BW, Vinters HV, Wu D, et al. 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 2002 May; 301: 605–10PubMedCrossRefGoogle Scholar
  111. 111.
    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 1996 Oct; 279: 770–83Google Scholar
  112. 112.
    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 Apr; 15: 339–50PubMedCrossRefGoogle Scholar
  113. 113.
    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 Jun; 10: 3667–77PubMedCrossRefGoogle Scholar
  114. 114.
    Zhang Y, Zhu C, Pardridge WM. Antisense gene therapy of brain cancer with an artificial virus gene delivery system. Mol Ther 2002 Jul; 6: 67–72PubMedCrossRefGoogle Scholar
  115. 115.
    Boiardi A, Eoli M, Pozzi A, et al. Locally delivered chemotherapy and repeated surgery can improve survival in glioblastoma patients. Ital J Neurol Sci 1999 Feb; 20: 43–8PubMedCrossRefGoogle Scholar
  116. 116.
    Morantz RA, Kimler BF, Vats TS, et al. Bleomycin and brain tumors: a review. J Neurooncol 1983; 1: 249–55PubMedCrossRefGoogle Scholar
  117. 117.
    Patchell RA, Regine WF, Ashton P, et al. A phase I trial of continuously infused intratumoral bleomycin for the treatment of recurrent glioblastoma multiforme. J Neurooncol 2002 Oct; 60: 37–42PubMedCrossRefGoogle Scholar
  118. 118.
    Voulgaris S, Partheni M, Karamouzis M, et al. Intratumoral doxorubicin in patients with malignant brain gliomas. Am J Clin Oncol 2002 Feb; 25: 60–4PubMedCrossRefGoogle Scholar
  119. 119.
    Huang Y, Hayes RL, Wertheim S, et al. Treatment of refractory recurrent malignant glioma with adoptive cellular immunotherapy: a case report. Crit Rev Oncol Hematol 2001 Jul–Aug; 39: 17–23PubMedCrossRefGoogle Scholar
  120. 120.
    Boiardi A, Silvani A, Milanesi I, et al. Local immunotherapy (beta-ifn) and systemic chemotherapy in primary glial tumors. Ital J Neurol Sci 1991 Apr; 12: 163–8PubMedCrossRefGoogle Scholar
  121. 121.
    Scheid WM. Drug delivery to the central nervous system: general principles and relevance to therapy for infections of the central nervous system. Rev Infect Dis 1989; 11Suppl. 7: S1669–90Google Scholar
  122. 122.
    Giussani C, Carrabba G, Pluderi M, et al. Local intracerebral delivery of endogenous inhibitors by osmotic minipumps effectively suppresses glioma growth in vivo. Cancer Res 2003 May; 63: 2499–505PubMedGoogle Scholar
  123. 123.
    Grondin R, Zhang Z, Yi A, et al. Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys. Brain 2002 Oct; 125: 2191–201PubMedCrossRefGoogle Scholar
  124. 124.
    Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 2003 May; 9: 589–95PubMedCrossRefGoogle Scholar
  125. 125.
    Patel NK, Bunnage M, Plaha P, et al. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol 2005 Feb; 57: 298–302PubMedCrossRefGoogle Scholar
  126. 126.
    Slevin JT, Gerhardt GA, Smith CD, et al. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell linederived neurotrophic factor. J Neurosurg 2005 Feb; 102: 216–22PubMedCrossRefGoogle Scholar
  127. 127.
    Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006 Mar; 59: 459–66PubMedCrossRefGoogle Scholar
  128. 128.
    Nutt JG, Burchiel KJ, Cornelia CL. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003 Jan 14; 60: 69–73PubMedCrossRefGoogle Scholar
  129. 129.
    Salvatore MF, Ai Y, Fischer B, et al. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol 2006 Dec; 202: 497–505PubMedCrossRefGoogle Scholar
  130. 130.
    Dang W, Colvin OM, Brem H, et al. Covalent coupling of methotrexate dextran enhances the penetration of cytotoxicity into a tissue like matrix. Cancer Res 1994 Apr; 54: 1729–35PubMedGoogle Scholar
  131. 131.
    Batycky RP, Hanes J, Langer R, et al. A theoretical model of erosion and macromolecular drug release from biodegrading microspheres. J Pharm Sci 1997 Dec; 86: 1464–77PubMedCrossRefGoogle Scholar
  132. 132.
    Benoit JP, Faisant N, Venier-Julienne MC, et al. Development of microspheres for neurological disorders: from basics to clinical applications. J Control Release 2000 Mar; 65: 285–96PubMedCrossRefGoogle Scholar
  133. 133.
    Menei P, Jadaud E, Faisant N, et al. Stereotaxic implantation of 5-fluorouracil-releasing microspheres in malignant glioma. Cancer 2004 Jan; 100: 405–10PubMedCrossRefGoogle Scholar
  134. 134.
    Leong KW, Brott BC, Langer R. Bioerodible polyanhydrides as drug-carrier matrices: I. Characterization, degradation, and release characteristics. J Biomed Mater Res 1985 Oct; 19: 941–55Google Scholar
  135. 135.
    Leong KW, D’Amore PD, Marietta M, et al. Bioerodible polyanhydrides as drug-carrier matrices: II. Biocompatibility and chemical reactivity. J Biomed Mater Res 1986 Jan; 20: 51–64CrossRefGoogle Scholar
  136. 136.
    Brem H, Gabikian P. Biodegradable polymer implants to treat brain tumors. J Control Release 2001 Jul; 74: 63–7PubMedCrossRefGoogle Scholar
  137. 137.
    Newcomb R, Abbruscato TJ, Singh T, et al. Bioavailability of ziconotide in brain: influx from blood, stability and diffusion. Peptides 2000 Apr; 21: 491–501PubMedCrossRefGoogle Scholar
  138. 138.
    Elena B, Alexander VK. Polymers for CNS drug delivery. Pharm Tech. Epub 2007 May 1Google Scholar
  139. 139.
    Umezawa F, Eto Y. Liposome targeting to mouse brain: mannose as a recognition marker. Biochem Biophys Res Comm 1988 Jun; 153: 1038–44PubMedCrossRefGoogle Scholar
  140. 140.
    Aoki H, Kakinuma K, Morita K, et al. Therapeutic efficacy of targeting chemotherapy using local hyperthermia and thermosensitive liposome: evaluation of drug distribution in a rat glioma model. Int J Hyperther 2004 Sep; 20: 595–605CrossRefGoogle Scholar
  141. 141.
    Chekhonin VP, Zhirkov YA, Gurina OI, et al. PEGylated immunoliposomes directed against brain astrocytes. Drug Deliv 2005 Jan–Feb; 12: 1–6PubMedCrossRefGoogle Scholar
  142. 142.
    Pardridge WM. Tyrosine hydroxylase replacement in experimental parkinson’s disease with transvascular gene therapy. NeuroRx 2005 Jan; 2: 129–38PubMedCrossRefGoogle Scholar
  143. 143.
    Voinea M, Simionescu M. Designing of ‘intelligent’ liposomes for efficient delivery of drugs. J Cell Mol Med 2002 Oct–Dec; 6: 465–74PubMedCrossRefGoogle Scholar
  144. 144.
    Noble CO, Krauze MT, Drummond DC, et al. Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy. Cancer Res 2006 Mar; 66: 2801–6PubMedCrossRefGoogle Scholar
  145. 145.
    Schmidt J, Metselaar JM, Wauben MH, et al. Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis. Brain 2003; 126: 1895–904PubMedCrossRefGoogle Scholar
  146. 146.
    Garcia-Garcia E, Andrieux K, Gil S, et al. Colloidal carriers and blood-brain barrier (BBB) translocation: a way to deliver drugs to the brain? Int J Pharm 2005 May; 298: 274–92PubMedCrossRefGoogle Scholar
  147. 147.
    Koukourakis MI, Koukouraki S, Giatromanolaki A, et al. High intratumoral accumulation of stealth liposomal doxorubicin in sarcomas: rationale for combination with radiotherapy. Acta Oncol 2000; 39: 207–11PubMedCrossRefGoogle Scholar
  148. 148.
    Hau P, Fabel K, Baumgart U, et al. PEGylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Cancer 2004 Mar; 100: 1199–207PubMedCrossRefGoogle Scholar
  149. 149.
    Sugawa N, Ueda S, Nakagawa Y, et al. An antisense EGFR oligonucleotide enveloped in Lipofectin induces growth inhibition in human malignant gliomas in vitro. J Neuro-Oncol 1998 Sep; 39: 237–44CrossRefGoogle Scholar
  150. 150.
    Omori N, Maruyama K, Jin G, et al. Targeting of post-ischemic cerebral endothelium in rat by liposomes bearing polyethylene glycol-coupled transferrin. Neurol Res 2003 Apr; 25: 275–9PubMedCrossRefGoogle Scholar
  151. 151.
    Schmidt J, Metselaar JM, Gold R. Intravenous liposomal prednisolone downregulates in situ TNF-alpha production by Tcells in experimental autoimmune encephalomyelitis. J Histochem Cytochem 2003 Sep; 51: 1241–4PubMedCrossRefGoogle Scholar
  152. 152.
    Yoshida J, Mizuno M, Fujii M, et al. Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes. Hum Gene Ther 2004 Jan; 15: 77–86PubMedCrossRefGoogle Scholar
  153. 153.
    Groll AH, Giri N, Petraitis V, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis 2000 Jul; 182: 274–82PubMedCrossRefGoogle Scholar
  154. 154.
    Mizuno M, Ryuke Y, Yoshida J. Cationic liposomes conjugation to recombinant adenoviral vectors containing herpes simplex virus thymidine kinase gene followed by ganciclovir treatment reduces viral antigenicity and maintains antitumor activity in mouse experimental glioma models. Cancer Gene Ther 2002 Oct; 9: 825–9PubMedCrossRefGoogle Scholar
  155. 155.
    Shi N, Zhang Y, Zhu C, et al. Brain-specific expression of an exogenous gene after i.v. administration. Proc Natl Acad Sci U S A 2001 Oct; 98: 12754–9CrossRefGoogle Scholar
  156. 156.
    Huwyler J, Cerletti A, Fricker G, et al. By-passing of P-glycoprotein using immunoliposomes. J Drug Target 2002 Feb; 10: 73–9PubMedCrossRefGoogle Scholar
  157. 157.
    Wu D, Song BW, Vinters HV, et al. Pharmacokinetics and brain uptake of biotinylated basic fibroblast growth factor conjugated to a blood-brain barrier drug delivery system. J Drug Target 2002 May; 10: 239–45PubMedCrossRefGoogle Scholar
  158. 158.
    Wu D, Boado RJ, Pardridge WM. Pharmacokinetics and blood-brain barrier transport of [3H]-biotinylated phosphorothioate oligodeoxynucleotide conjugated to a vector-mediated drug delivery system. J Pharmacol Exp Ther 1996 Jan; 276: 206–11PubMedGoogle Scholar
  159. 159.
    Gosk S, Vermehren C, Storm G, et al. Targeting anti-transferrin receptor antibody (OX26) and OX26-conjugated liposomes to brain capillary endothelial cells using in situ perfusion. J Cereb Blood Flow Metab 2004 Nov; 24: 1193–204PubMedCrossRefGoogle Scholar
  160. 160.
    da Cruz MT, Simoes S, de Lima MC. Improving lipoplexmediated gene transfer into C6 glioma cells and primary neurons. Exp Neurol 2004 May; 187: 65–75PubMedCrossRefGoogle Scholar
  161. 161.
    Matsuo H, Okamura T, Chen J, et al. Efficient introduction of macromolecules and oligonucleotides into brain capillary endothelial cells using HVJ-liposomes. J Drug Target 2000; 8: 207–16PubMedCrossRefGoogle 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 Jun; 10: 3667–77PubMedCrossRefGoogle Scholar
  163. 163.
    Tosi G, Costantino L, Ruozi B, et al. Polymeric nanoparticles for the drug delivery to the central nervous system. Expert Opin Drug Deliv 2008 Feb; 5: 155–74PubMedCrossRefGoogle Scholar
  164. 164.
    Calvo P, Gouritin B, Villarroya H, et al. Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat. Eur J Neurosci 2002 Apr; 15: 1317–26PubMedCrossRefGoogle Scholar
  165. 165.
    Darius J, Meyer FP, Sabel BA, et al. Influence of nanoparticles on the brain-to-serum distribution and the metabolism of valproic acid in mice. J Pharm Pharmacol 2000; 562: 1043–7CrossRefGoogle Scholar
  166. 166.
    Steiniger SC, Kreuter J, Khalansky AS, et al. Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles. Int J Cancer 2004 May; 109: 759–67PubMedCrossRefGoogle Scholar
  167. 167.
    Cui Z, Lockman PR, Atwood CS, et al. Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer’s and other CNS diseases. Eur J Pharm Biopharm 2005 Feb; 59: 263–72PubMedCrossRefGoogle Scholar
  168. 168.
    Costantino L, Gandolfi F, Tosi G, et al. Peptide-derivatized biodegradable nanoparticles able to cross the blood-brain barrier. J Control Release 2005 Nov; 108: 84–96PubMedCrossRefGoogle Scholar
  169. 169.
    Aktas Y, Yemisci M, Andrieux K, et al. Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26. Bioconjugate Chem 2005 Nov–Dec; 16: 1503–11CrossRefGoogle Scholar
  170. 170.
    Tosi G, Costantino L, Rivasi F, et al. Targeting the central nervous system: in vivo experiments with peptide-derivatized nanoparticles loaded with loperamide and rhodamine-123. J Control Release 2007 Sep; 122: 1–9PubMedCrossRefGoogle Scholar
  171. 171.
    Petri B, Bootz A, Khalansky A, et al. Chemotherapy of brain tumour using doxorubicin bound to surfactant-coated poly(butyl cyanoacrylate) nanoparticles: revisiting the role of surfactants. J Control Release 2007 Jan; 117: 51–8PubMedCrossRefGoogle Scholar
  172. 172.
    Blasi P, Giovagnoli S, Schoubben A, et al. Solid lipid nanoparticles for targeted brain drug delivery. Adv Drug Delivery Rev 2007 Jul; 59: 454–77CrossRefGoogle Scholar
  173. 173.
    Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin rationale for use in solid tumours. Drugs 1997; 54Suppl. 4: 15–21PubMedCrossRefGoogle Scholar
  174. 174.
    Owens DE III, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 2006 Jan; 307: 93–102PubMedCrossRefGoogle Scholar
  175. 175.
    Yang S, Zhu J, Lu Y, et al. Body distribution of camptothecin solid lipid nanoparticles after oral administration. Pharm Res 1999 May; 16: 751–7PubMedCrossRefGoogle Scholar
  176. 176.
    Zara GP, Cavalli R, Fundarò A, et al. Pharmacokinetics of doxorubicin incorporated in solid lipid nanospheres (SLN). Pharmacol Res 1999 Sep; 40: 281–6PubMedCrossRefGoogle Scholar
  177. 177.
    Podio V, Zara GP, Carazzonet M, et al. Biodistribution of stealth and non-stealth solid lipid nanospheres after intravenous administration to rats. J Pharm Pharmacol 2000 Sep; 52: 1057–63PubMedCrossRefGoogle Scholar
  178. 178.
    Yang SC, Lu LF, Cai Y, et al. Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain. J Control Release 1999 Jun; 59: 299–307PubMedCrossRefGoogle Scholar
  179. 179.
    Fundarò A, Cavalli R, Bargoni A, et al. Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats. Pharmacol Res 2000 Oct; 42: 337–43Google Scholar
  180. 180.
    Koziara JM, Lockman PR, Allen DD, et al. In situ blood-brain barrier transport of nanoparticles. Pharm Res 2003 Nov; 20: 1772–8PubMedCrossRefGoogle Scholar
  181. 181.
    Koziara JM, Lockman PR, Allen DD, et al. Paclitaxel nanoparticles for the potential treatment of brain tumors. J Control Release 2004 Sep; 99: 259–69PubMedCrossRefGoogle Scholar
  182. 182.
    Lockman PR, Koziara J, Roder KE, et al. In vivo and in vitro assessment of baseline blood brain barrier parameters in the presence of novel nanoparticles. Pharm Res 2003 May; 20: 705–13PubMedCrossRefGoogle Scholar
  183. 183.
    Peira E, Marzola P, Podio V, et al. In vitro and in vivo study of solid lipid nanoparticles loaded with superparamagnetic iron oxide. J Drug Target 2003 Jan; 11: 19–24PubMedCrossRefGoogle Scholar
  184. 184.
    Yang C, Chang CH, Tsai PJ, et al. Nanoparticle-based in vivo investigation on blood-brain barrier permeability following ischemia and reperfusion. Anal Chem 2004 Aug; 76: 4465–71PubMedCrossRefGoogle Scholar
  185. 185.
    Yumi T, Kazuhito T, Mana N, et al. Development of bionanocapsules targeting brain tumors. J Control Release 2007 Sep; 122: 159–64CrossRefGoogle Scholar
  186. 186.
    Vinogradov SV, Batrakova EV, Kabanov AV. Poly(ethylene glycol)-polyethyleneimine nanogel particles: novel drug delivery systems for antisense oligonucleotides. Colloids Surf B: Biointerfaces 1999 Nov; 16: 291–304CrossRefGoogle Scholar
  187. 187.
    Vinogradov SV, Bronich TK, Kabanov AV. Nanosized cationic hydrogels for drug delivery: preparation, properties and interactions with cells. Adv Drug Deliv Rev 2002 Jan; 54: 135–47PubMedCrossRefGoogle Scholar
  188. 188.
    Vinogradov SV, Kohli E, Zeman AD. Cross-linked polymeric nanogel formulations of 5′-triphosphates of nucleoside analogues: role of the cellular membrane in drug release. Mol Pharm 2005 Nov–Dec; 2: 449–61PubMedCrossRefGoogle Scholar
  189. 189.
    Vinogradov SV, Zeman AD, Batrakova EV. Polyplex nanogel formulations for drug delivery of cytotoxic nucleoside analogs. J Control Release 2005 Sep; 107: 143–57PubMedCrossRefGoogle Scholar
  190. 190.
    Vinogradov SV, Batrakova EV, Kabanov AV. Nanogels for oligonucleotide delivery to the brain. Bioconjug Chem 2004 Jan–Feb; 15: 50–60PubMedCrossRefGoogle Scholar
  191. 191.
    Kabanov AV, Batrakova EV. New technologies for drug delivery across the blood brain barrier. Curr Pharm Design 2004; 10: 1355–63CrossRefGoogle Scholar
  192. 192.
    Madrid Y, Langer LF, Brem H, et al. New directions in the delivery of drugs and other substances to the central nervous system. Adv Pharmacol 1991; 22: 299–324PubMedCrossRefGoogle Scholar
  193. 193.
    Leigh K, Elisevich K, Rogers KA. Vascularization and microvascular permeability in solid versus cell-suspension embryonic neural grafts. J Neurosurg 1994 Aug; 81: 272–83PubMedCrossRefGoogle Scholar
  194. 194.
    Lal B, Indurti RR, Couraud PO, et al. Endothelial cell implantation and survival within experimental gliomas. Proc Natl Acad Sci US A 1994 Oct; 91: 9695–9CrossRefGoogle Scholar
  195. 195.
    Snyder EY, Senut MC. The use of non neuronal cells for gene delivery. Neurobiol Dis 1997; 4: 69–102PubMedCrossRefGoogle Scholar
  196. 196.
    Yurek DM, Sladek JR Jr. Dopamine cell replacement: Parkinson’s disease. Annu Rev Neurosci 1990; 13: 415–40PubMedCrossRefGoogle Scholar
  197. 197.
    Santini JT Jr, Cima MJ, Langer R. A controlled-release microchip. Nature 1999 Jan; 397: 335–8PubMedCrossRefGoogle Scholar
  198. 198.
    Thorne RG, Emory CR, Ala TA, et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res 1995 Sep; 692: 278–82PubMedCrossRefGoogle Scholar
  199. 199.
    Thorne RG, Frey II WH. Delivery of neurotropic factore to the central nervous system: pharmacokinetic consideration. Clin Pharmacokinet 2001; 40: 907–46PubMedCrossRefGoogle Scholar
  200. 200.
    Born J, Lange T, Kern W. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002 Jun; 5: 514–6PubMedCrossRefGoogle Scholar
  201. 201.
    Thorne RG, Pronk GJ, Padmanabhan V, et al. Delivery of insulin like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004; 127: 481–96PubMedCrossRefGoogle Scholar
  202. 202.
    Ilium L. Nasal drug delivery: possibilities, problems and solutions. J Control Release 2003 Feb; 87: 187–98CrossRefGoogle Scholar
  203. 203.
    Ilium L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 2000 Jul; 11: 1–18CrossRefGoogle Scholar
  204. 204.
    Quay SC. Successful delivery of apomorphine to the brain following intranasal administration demonstrated in clinical study [online]. Available from URL: [Accessed 2008 Nov 26]
  205. 205.
    Fehm HL, Perras B, Smolnik R, et al. Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology. Eur J Pharmacol 2000 Sep; 405: 43–54PubMedCrossRefGoogle Scholar
  206. 206.
    Perras B, Pannenborg H, Marshall L, et al. Beneficial treatment of age-related sleep disturbances with prolonged intranasal vasopressin. J Clin Psychopharmacol 1999 Feb; 19: 28–36PubMedCrossRefGoogle Scholar
  207. 207.
    Perras B, Marshall L, Kohler G, et al. Sleep and endocrine changes after intranasal administration of growth hormonereleasing hormone in young and aged humans. Psychoneuroendocrinology 1999 Oct; 24: 743–57PubMedCrossRefGoogle Scholar
  208. 208.
    Dahlin M, Bergman U, Jansson B, et al. Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res 2000 Jun; 17: 737–42PubMedCrossRefGoogle Scholar
  209. 209.
    Ulrika W, Elena P, Björn J, et al. Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents. Eur J Pharm Sci 2005 Apr; 24: 565–73CrossRefGoogle Scholar
  210. 210.
    Merkus P. Nose to brain: management forum nasal drug delivery symposium. 2001 Mar 26–27; LondonGoogle Scholar
  211. 211.
    Xiaomei W, Haibing H, Wei L, et al. Evaluation of braintargeting for the nasal delivery of estradiol by the microdialysis method. Int J Pharm 2006 Jul; 317: 40–6CrossRefGoogle Scholar
  212. 212.
    Jian C, Xiaomei W, Juan W. Evaluation of brain targeting for the nasal delivery of ergoloid mesylate by the micro dialysis methods in the rats. Eur J Pharm Biopharm 2008 Mar; 68: 694–700CrossRefGoogle Scholar
  213. 213.
    Gao X, Tao W, Lu W, et al. Lectin-conjugated PEG-PLA nanoparticles: preparation and brain delivery after intra nasal administration. Biomaterials 2006 Jun; 27: 3482–90PubMedCrossRefGoogle Scholar
  214. 214.
    Gao X, Wu B, Zhang Q, et al. Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with the wheat germ agglutinin following intranasal administration. J Control Release 2007 Aug; 121: 156–67PubMedCrossRefGoogle Scholar
  215. 215.
    Gao X, Chen J, Tao W, et al. UEA I-bearing nanoparticles for brain delivery following intranasal administration. Int J Pharm 2007 Aug; 340: 207–15PubMedCrossRefGoogle Scholar
  216. 216.
    Illum L. Nasal drug delivery: new development strategies. Drug Discov Today 2002; 7: 1184–9PubMedCrossRefGoogle Scholar
  217. 217.
    Krauze MT, Saito R, Noble C, et al. Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen. Exp Neurol 2005; 196: 104–11PubMedCrossRefGoogle Scholar
  218. 218.
    Debinski W, Gibo DM, Puri RK. Novel way to increase targeting specificity to a human glioblastoma-associated receptor for interleukin 13. Int J Cancer 1998; 76: 547–51PubMedCrossRefGoogle Scholar
  219. 219.
    Debinski W, Obiri NI, Powers SK, et al. Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. Clin Cancer Res 1995 Nov; 1: 1253–8PubMedGoogle Scholar
  220. 220.
    Debinski W, Gibo DM, Hulet SW, et al. Receptor for interleukin 13 is a marker and therapeutic target for human high-grade gliomas. Clin Cancer Res 1999 May; 5: 985–90PubMedGoogle Scholar
  221. 221.
    Debinski W, Slagle B, Gibo DM, et al. Expression of a restrictive receptor for Interleukin 13 is associated with glial transformation. J Neurooncol 2000 Jun; 48: 103–11PubMedCrossRefGoogle Scholar
  222. 222.
    Kunwar S. Convection enhanced delivery of I13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. Acta Neurochir 2003; 88 Suppl.: 105–11Google Scholar
  223. 223.
    Hall WA, Godai A, Juell S, et al. In vitro efficacy of transferrintoxinconjugates against glioblastoma multiforme. J Neurosurg 1992 May; 76: 838–44PubMedCrossRefGoogle Scholar
  224. 224.
    Martell LA, Agrawal A, Ross DA. Efficacy of transferrin receptor-targeted immunotoxins in brain tumor cell lines and pediatric brain tumors. Cancer Res 1993 Mar; 53: 1348–53PubMedGoogle Scholar
  225. 225.
    Buchwald P, Bodor N. A simple, predictive, structure-based skin permeability model. J Pharm Pharmacol 2001 Aug; 53: 1087–98PubMedCrossRefGoogle Scholar
  226. 226.
    Krewson CE, Klarman ML, Saltzman WM. Distribution of nerve growth factor following direct delivery to brain interstitium. Brain Res 1995 May; 680: 196–206PubMedCrossRefGoogle Scholar
  227. 227.
    Rietman JS, Geertzen JH. Efficacy of intrathecal baclofen delivery in the management of severe spasticity in upper motor neuron syndrome. Acta Neurotic Suppl 2007; 97 (Pt 1): 205–11CrossRefGoogle Scholar
  228. 228.
    Winkelmüller M, Winkelmüller W. Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J Neurosurg 1996 Sep; 85: 458–67PubMedCrossRefGoogle Scholar
  229. 229.
    Varelas PN, Rehman M, Pierce W, et al. Vancomycin-resistant enterococcal meningitis treated with intrathecal streptomycin. Clin Neurol Neurosurg 2008 Apr; 110(4): 376–80PubMedCrossRefGoogle Scholar
  230. 230.
    Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 1975 Oct; 195: 73–83PubMedGoogle Scholar
  231. 231.
    Huang TY, Arita N, Hayakawa T, et al. ACNU, MTX and 5-FU penetration of rat brain tissue and tumors. J Neurooncol 1999; 45: 9–17PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Mayur M. Patel
    • 1
  • Bhoomika R. Goyal
    • 1
  • Shraddha V. Bhadada
    • 1
  • Jay S. Bhatt
    • 1
  • Avani F. Amin
    • 1
  1. 1.Institute of PharmacyNirma University of Science and TechnologyAhmedabadIndia

Personalised recommendations