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PMID: 17619996 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Review

Blood-brain barrier transport of therapeutics via receptor-mediation.

Pharmaceutical research ·Vol. 24 ·No. 9 ·2007-09-00 ·Pages 1759-71

Jones AR, Shusta EV

Abstract

Drug delivery to the brain is hindered by the presence of the blood-brain barrier (BBB). Although the BBB restricts the passage of many substances, it is actually selectively permeable to nutrients necessary for healthy brain function. To accomplish the task of nutrient transport, the brain endothelium is endowed with a diverse collection of molecular transport systems. One such class of transport system, known as a receptor-mediated transcytosis (RMT), employs the vesicular trafficking machinery of the endothelium to transport substrates between blood and brain. If appropriately targeted, RMT systems can also be used to shuttle a wide range of therapeutics into the brain in a noninvasive manner. Over the last decade, there have been significant developments in the arena of RMT-based brain drug transport, and this review will focus on those approaches that have been validated in an in vivo setting.

MeSH Terms
Animals Bacterial Proteins/administration & dosage Biological Transport Blood-Brain Barrier Brain/metabolism Drug Delivery Systems Humans Low Density Lipoprotein Receptor-Related Protein-1/physiology Low Density Lipoprotein Receptor-Related Protein-2/physiology Receptor, Insulin/physiology Receptors, Cell Surface/physiology Receptors, Transferrin/physiology
Chemicals
Bacterial Proteins Low Density Lipoprotein Receptor-Related Protein-1 Low Density Lipoprotein Receptor-Related Protein-2 Receptors, Cell Surface Receptors, Transferrin CRM197 (non-toxic variant of diphtheria toxin) Receptor, Insulin
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Jones Angela R
Department of Chemical and Biological Engineering, University of Wisconsin-Madison, 1415 Engineering Drive, Madison, Wisconsin 53706, USA.
Shusta Eric V
References (97)
97 references, click to expand
  1. Molecular and cellular mechanisms of receptor-mediated endocytosis.
    DNA Cell Biol. 1991 Jul-Aug;10(6):399-409 PMID: 1648927
  2. Immunogens consisting of oligosaccharides from the capsule of Haemophilus influenzae type b coupled to diphtheria toxoid or the toxin protein CRM197.
    J Clin Invest. 1985 Jul;76(1):52-9 PMID: 3874882
  3. Receptor-mediated gene targeting to tissues in vivo following intravenous administration of pegylated immunoliposomes.
    Pharm Res. 2001 Aug;18(8):1091-5 PMID: 11587478
  4. Tyrosine hydroxylase and Parkinson's disease.
    Mol Neurobiol. 1998 Jun;16(3):285-309 PMID: 9626667
  5. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier.
    J Drug Target. 2002 Jun;10(4):317-25 PMID: 12164380
  6. 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 1;100(7):1804-12 PMID: 9312181
  7. Vector-mediated drug delivery to the brain.
    Adv Drug Deliv Rev. 1999 Apr 5;36(2-3):299-321 PMID: 10837722
  8. Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis.
    Circulation. 2005 May 3;111(17):2241-9 PMID: 15851587
  9. Intravenous administration of a transferrin receptor antibody-nerve growth factor conjugate prevents the degeneration of cholinergic striatal neurons in a model of Huntington disease.
    Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9077-80 PMID: 8090772
  10. Basic fibroblast growth factor promotes in vivo cerebral angiogenesis in chronic forebrain ischemia.
    Brain Res. 1991 Sep 6;558(2):315-20 PMID: 1723639
  11. 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(6):1378-84 PMID: 11387502
  12. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer.
    Clin Cancer Res. 2004 Jun 1;10(11):3667-77 PMID: 15173073
  13. Targeted delivery across the blood-brain barrier.
    Expert Opin Drug Deliv. 2005 Mar;2(2):299-309 PMID: 16296755
  14. Blood-brain barrier transcytosis of insulin in developing rabbits.
    Brain Res. 1987 Sep 8;420(1):32-8 PMID: 3315116
  15. Biodistribution of polysorbate 80-coated doxorubicin-loaded [14C]-poly(butyl cyanoacrylate) nanoparticles after intravenous administration to glioblastoma-bearing rats.
    J Drug Target. 2006 Feb;14(2):97-105 PMID: 16608736
  16. Transferrin receptors in rat central nervous system. An immunocytochemical study.
    J Neurol Sci. 1990 Aug;98(1):81-90 PMID: 2230832
  17. Brain drug delivery of small molecules using immunoliposomes.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14164-9 PMID: 8943078
  18. The blood-brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells.
    J Neurochem. 2005 Nov;95(4):1201-14 PMID: 16271053
  19. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier.
    Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4771-5 PMID: 2052557
  20. Body distribution of polysorbate-80 and doxorubicin-loaded [14C]poly(butyl cyanoacrylate) nanoparticles after i.v. administration in rats.
    J Drug Target. 2005 Dec;13(10):535-42 PMID: 16390814
  21. Targeted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles.
    J Drug Target. 2006 Jan;14(1):45-53 PMID: 16603451
  22. Pharmacokinetics and saturable blood-brain barrier transport of biotin bound to a conjugate of avidin and a monoclonal antibody to the transferrin receptor.
    Drug Metab Dispos. 1994 Jan-Feb;22(1):99-105 PMID: 8149897
  23. Fusion antibody for Alzheimer's disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation.
    Bioconjug Chem. 2007 Mar-Apr;18(2):447-55 PMID: 17315944
  24. Selection of phage-displayed llama single-domain antibodies that transmigrate across human blood-brain barrier endothelium.
    FASEB J. 2002 Feb;16(2):240-2 PMID: 11772942
  25. Pharmacokinetics and delivery of tat and tat-protein conjugates to tissues in vivo.
    Bioconjug Chem. 2001 Nov-Dec;12(6):995-9 PMID: 11716691
  26. 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(10):1766-75 PMID: 15471847
  27. 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(4):339-50 PMID: 15053859
  28. Molecular Trojan horses for blood-brain barrier drug delivery.
    Curr Opin Pharmacol. 2006 Oct;6(5):494-500 PMID: 16839816
  29. Serum proteins as drug carriers of anticancer agents: a review.
    Drug Deliv. 1998;5(4):281-99 PMID: 19569996
  30. Pharmacologic effects in vivo in brain by vector-mediated peptide drug delivery.
    Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2618-22 PMID: 8385339
  31. An antibody-avidin fusion protein specific for the transferrin receptor serves as a delivery vehicle for effective brain targeting: initial applications in anti-HIV antisense drug delivery to the brain.
    J Immunol. 1999 Oct 15;163(8):4421-6 PMID: 10510383
  32. Mining a yeast library for brain endothelial cell-binding antibodies.
    Nat Methods. 2007 Feb;4(2):143-5 PMID: 17206151
  33. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse.
    J Pharmacol Exp Ther. 2000 Mar;292(3):1048-52 PMID: 10688622
  34. The blood-brain barrier and brain drug delivery.
    J Nanosci Nanotechnol. 2006 Sep-Oct;6(9-10):2712-35 PMID: 17048477
  35. Changes in the business of culture.
    Nat Biotechnol. 2004 Nov;22(11):1355-6 PMID: 15529153
  36. Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier.
    J Cell Sci. 2004 Oct 1;117(Pt 21):5071-8 PMID: 15383619
  37. Enhanced uptake of rsCD4 across the rodent and primate blood-brain barrier after conjugation to anti-transferrin receptor antibodies.
    J Pharmacol Exp Ther. 1996 May;277(2):1067-75 PMID: 8627518
  38. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes.
    Nature. 1985 Feb 28-Mar 6;313(6005):756-61 PMID: 2983222
  39. Influence of particle size on transport of methotrexate across blood brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles.
    Int J Pharm. 2006 Mar 9;310(1-2):213-9 PMID: 16426779
  40. Imaging gene expression in the brain in vivo in a transgenic mouse model of Huntington's disease with an antisense radiopharmaceutical and drug-targeting technology.
    J Nucl Med. 2002 Jul;43(7):948-56 PMID: 12097468
  41. Immunogenicity of engineered antibodies.
    Methods. 2005 May;36(1):3-10 PMID: 15848070
  42. Transferrin receptor on endothelium of brain capillaries.
    Nature. 1984 Nov 8-14;312(5990):162-3 PMID: 6095085
  43. Endocytosis at the blood-brain barrier: from basic understanding to drug delivery strategies.
    J Drug Target. 2006 May;14(4):191-214 PMID: 16777679
  44. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles.
    Pharm Res. 1999 Oct;16(10):1564-9 PMID: 10554098
  45. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains.
    Proc Natl Acad Sci U S A. 1984 Nov;81(21):6851-5 PMID: 6436822
  46. 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 15;97(6):1376-86 PMID: 17286273
  47. Characterization, receptor mapping and blood-brain barrier transcytosis of antibodies to the human transferrin receptor.
    J Pharmacol Exp Ther. 1996 Sep;278(3):1491-8 PMID: 8819537
  48. 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(6):807-16 PMID: 7667183
  49. Antisense imaging of gene expression in the brain in vivo.
    Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14709-14 PMID: 11106372
  50. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway.
    Pharmacol Rev. 2002 Dec;54(4):561-87 PMID: 12429868
  51. Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles.
    Int J Cancer. 2004 May 1;109(5):759-67 PMID: 14999786
  52. Organ-specific gene expression in the rhesus monkey eye following intravenous non-viral gene transfer.
    Mol Vis. 2003 Oct 3;9:465-72 PMID: 14551536
  53. Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles.
    Pharm Res. 1997 Mar;14(3):325-8 PMID: 9098875
  54. Distribution and number of transferrin receptors in Parkinson's disease and in MPTP-treated mice.
    Exp Neurol. 1991 Oct;114(1):73-81 PMID: 1915737
  55. Developmental changes in transferrin and iron uptake by the brain in the rat.
    Brain Res Dev Brain Res. 1990 Aug 1;55(1):35-42 PMID: 2208639
  56. Antisense gene therapy of brain cancer with an artificial virus gene delivery system.
    Mol Ther. 2002 Jul;6(1):67-72 PMID: 12095305
  57. Intravenous nonviral gene therapy causes normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism.
    Hum Gene Ther. 2003 Jan 1;14(1):1-12 PMID: 12573054
  58. Human blood-brain barrier transferrin receptor.
    Metabolism. 1987 Sep;36(9):892-5 PMID: 3306281
  59. Transferrin-antibody fusion proteins are effective in brain targeting.
    Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2820-4 PMID: 7708731
  60. Biodegradable polymeric nanoparticles as drug delivery devices.
    J Control Release. 2001 Jan 29;70(1-2):1-20 PMID: 11166403
  61. 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. 1995 Oct 24;92(22):10227-31 PMID: 7479757
  62. Mechanism and developmental changes in iron transport across the blood-brain barrier.
    Dev Neurosci. 2002;24(2-3):106-13 PMID: 12401948
  63. Covalent linkage of apolipoprotein e to albumin nanoparticles strongly enhances drug transport into the brain.
    J Pharmacol Exp Ther. 2006 Jun;317(3):1246-53 PMID: 16554356
  64. Brain-specific expression of an exogenous gene after i.v. administration.
    Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12754-9 PMID: 11592987
  65. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy.
    Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11460-4 PMID: 1763060
  66. Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to beta-glucuronidase requires early initiation of enzyme replacement therapy.
    Pediatr Res. 1999 Jun;45(6):838-44 PMID: 10367775
  67. Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion.
    Brain Res. 2006 Sep 21;1111(1):227-9 PMID: 16884698
  68. 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(2):605-10 PMID: 11961063
  69. Global non-viral gene transfer to the primate brain following intravenous administration.
    Mol Ther. 2003 Jan;7(1):11-8 PMID: 12573613
  70. Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier.
    Biotechnol Bioeng. 2007 Feb 1;96(2):381-91 PMID: 16937408
  71. Nanoparticles, a drug carrier system to pass the blood-brain barrier, permit central analgesic effects of i.v. dalargin injections.
    Brain Res. 1996 Feb 26;710(1-2):121-4 PMID: 8963650
  72. Drug transport to brain with targeted nanoparticles.
    NeuroRx. 2005 Jan;2(1):108-19 PMID: 15717062
  73. Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels.
    J Clin Invest. 1997 Jan 1;99(1):14-8 PMID: 9011568
  74. Delivery of peptides and proteins through the blood-brain barrier.
    Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):247-79 PMID: 11259843
  75. 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(3):239-45 PMID: 12075825
  76. Direct evidence that polysorbate-80-coated poly(butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles.
    Pharm Res. 2003 Mar;20(3):409-16 PMID: 12669961
  77. Endocytosis and transcytosis of an immunoliposome-based brain drug delivery system.
    J Drug Target. 2000;8(6):435-46 PMID: 11328669
  78. Efficient cancer therapy with a nanobody-based conjugate.
    Cancer Res. 2004 Apr 15;64(8):2853-7 PMID: 15087403
  79. An attempt to directly trace polymeric nanoparticles in vivo with electron microscopy.
    J Control Release. 2006 Oct 27;115(3):259-65 PMID: 17010467
  80. CRM197 (nontoxic diphtheria toxin): effects on advanced cancer patients.
    Cancer Immunol Immunother. 2004 Nov;53(11):1041-8 PMID: 15168087
  81. High transcytosis of melanotransferrin (P97) across the blood-brain barrier.
    J Neurochem. 2002 Nov;83(4):924-33 PMID: 12421365
  82. Engineered antibody fragments and the rise of single domains.
    Nat Biotechnol. 2005 Sep;23(9):1126-36 PMID: 16151406
  83. 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(1):77-83 PMID: 8858978
  84. Delivery of hydrophobised 5-fluorouracil derivative to brain tissue through intravenous route using surface modified nanogels.
    J Drug Target. 2006 Feb;14(2):87-95 PMID: 16608735
  85. Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles).
    Brain Res. 1995 Mar 13;674(1):171-4 PMID: 7773690
  86. Transferrin-loaded nido-carborane liposomes: tumor-targeting boron delivery system for neutron capture therapy.
    Bioconjug Chem. 2006 Sep-Oct;17(5):1314-20 PMID: 16984142
  87. Drug delivery of antisense molecules to the brain for treatment of Alzheimer's disease and cerebral AIDS.
    J Pharm Sci. 1998 Nov;87(11):1308-15 PMID: 9811482
  88. Combined use of carboxyl-directed protein pegylation and vector-mediated blood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenous administration.
    Pharm Res. 1998 Apr;15(4):576-82 PMID: 9587954
  89. Insulin and insulin receptors in rodent brain.
    Diabetologia. 1981 Mar;20 Suppl:268-73 PMID: 7014325
  90. 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. 1999 May-Jun;10(3):502-11 PMID: 10346884
  91. Receptor mediated delivery of daunomycin using immunoliposomes: pharmacokinetics and tissue distribution in the rat.
    J Pharmacol Exp Ther. 1997 Sep;282(3):1541-6 PMID: 9316870
  92. Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor.
    Pharm Res. 2000 Mar;17(3):266-74 PMID: 10801214
  93. Imaging brain amyloid of Alzheimer disease in vivo in transgenic mice with an Abeta peptide radiopharmaceutical.
    J Cereb Blood Flow Metab. 2002 Feb;22(2):223-31 PMID: 11823720
  94. Transferrin and transferrin receptor function in brain barrier systems.
    Cell Mol Neurobiol. 2000 Feb;20(1):77-95 PMID: 10690503
  95. Delivery of beta-galactosidase to mouse brain via the blood-brain barrier transferrin receptor.
    J Pharmacol Exp Ther. 2005 Jun;313(3):1075-81 PMID: 15718287
  96. Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier.
    Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12658-63 PMID: 15314220
  97. Iron and transferrin uptake by brain and cerebrospinal fluid in the rat.
    Brain Res. 1992 Oct 2;592(1-2):8-16 PMID: 1450923
Article Info
Journal
Pharmaceutical research
Abbr.
Pharm Res
ISSN
0724-8741
DOI
10.1007/s11095-007-9379-0
Published
2007-09-00
Epub
2007-00-10
Pages
1759-71
Language
English
Region
United States
NLM ID
8406521
PMCID
PMC2685177
Subset
IM
Grants
NINDS NIH HHS · R01 NS052649 · United States
NINDS NIH HHS · R01 NS052649-03 · United States
NINDS NIH HHS · NS052649 · United States
External Links
PubMed source DOI: 10.1007/s11095-007-9379-0 PMC Full Text View journal details
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