Diffusion of macromolecules in the brain: Implications for drug delivery

Molecular Pharmaceutics

Volumn 10, Issue 5, 2013, Pages 1492-1504

  Wolak, Daniel J ^a   Thorne, Robert G ^a  

^a UNIVERSITY OF WISCONSIN MADISON   (United States)

Author keywords

central nervous system; diffusion; distribution; drug delivery; extracellular space; macromolecules; proteins

Indexed keywords

BOVINE SERUM ALBUMIN; DEXTRAN; EPIDERMAL GROWTH FACTOR; INULIN; LACTALBUMIN; LACTOFERRIN; MACROGOL; NANOPARTICLE; NERVE GROWTH FACTOR; OVALBUMIN; POLY[N (2 HYDROXYPROPYL)METHACRYLAMIDE]; QUANTUM DOT; SUCROSE; TRANSFERRIN; VIRUS VECTOR; MACROMOLECULE;

BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; DRUG CLEARANCE; DRUG CONJUGATION; DRUG DELIVERY SYSTEM; DRUG DIFFUSION; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG SCREENING; DRUG TRANSPORT; EXTRACELLULAR SPACE; HUMAN; MACROMOLECULE; NEUROLOGIC DISEASE; NONHUMAN; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; REVIEW; ADMINISTRATION AND DOSAGE; ANATOMY AND HISTOLOGY; ANIMAL; BIOLOGICAL MODEL; BRAIN; CENTRAL NERVOUS SYSTEM DISEASES; METABOLISM; PHARMACOKINETICS; PHYSIOLOGY; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; BIOLOGICAL TRANSPORT; BLOOD-BRAIN BARRIER; BRAIN; CENTRAL NERVOUS SYSTEM DISEASES; DRUG DELIVERY SYSTEMS; EXTRACELLULAR SPACE; HUMANS; MACROMOLECULAR SUBSTANCES; MODELS, NEUROLOGICAL;

EID: 84877292573     PISSN: 15438384     EISSN: 15438392     Source Type: Journal    
DOI: 10.1021/mp300495e     Document Type: Review

References (105)

1. Brain Facts. http://www.brainfacts.org/ (accessed Aug 23, 2012).
2. Pangalos, M. N.; Schechter, L. E.; Hurko, O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition Nat. Rev. Drug Discovery 2007, 6 (7) 521-32
3. Thorne, R. G.; Frey, W. H., 2nd Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations Clin. Pharmacokinet. 2001, 40 (12) 907-46
4. Nagahara, A. H.; Tuszynski, M. H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders Nat. Rev. Drug Discovery 2011, 10 (3) 209-19
5. Neuwelt, E.; Abbott, N. J.; Abrey, L.; Banks, W. A.; Blakley, B.; Davis, T.; Engelhardt, B.; Grammas, P.; Nedergaard, M.; Nutt, J.; Pardridge, W.; Rosenberg, G. A.; Smith, Q.; Drewes, L. R. Strategies to advance translational research into brain barriers Lancet Neurol. 2008, 7 (1) 84-96
6. Abbott, N. J.; Patabendige, A. A.; Dolman, D. E.; Yusof, S. R.; Begley, D. J. Structure and function of the blood-brain barrier Neurobiol. Dis. 2010, 37 (1) 13-25
7. Pardridge, W. M. The blood-brain barrier: bottleneck in brain drug development NeuroRx 2005, 2 (1) 3-14
8. Neuwelt, E. A.; Bauer, B.; Fahlke, C.; Fricker, G.; Iadecola, C.; Janigro, D.; Leybaert, L.; Molnar, Z.; O'Donnell, M. E.; Povlishock, J. T.; Saunders, N. R.; Sharp, F.; Stanimirovic, D.; Watts, R. J.; Drewes, L. R. Engaging neuroscience to advance translational research in brain barrier biology Nat. Rev. Neurosci. 2011, 12 (3) 169-82
9. Banks, W. A. Characteristics of compounds that cross the blood-brain barrier BMC Neurol. 2009, 9 (Suppl. 1) S3
10. Peters, A.; Palay, S. F.; Webster, H. D. The Fine Structure of the Nervous System: Neurons and Their Supporting Cells, 3 rd ed.; Oxford University Press: New York, 1991.
11. The Human Nervous System; Paxinos, G.; Mai, J. K., Eds.; Elsevier: Amsterdam, 2004.
12. Junqueria, L. C.; Carneiro, J.; Kelly, R. O. Basic Histology; Appleton & Large: Norwalk, CT, 1992.
13. Kandel, E. R.; Schwartz, J. H.; Jessel, T. M.; Siegelbaum, S. A.; Hudspeth, A. J. Principles of Neural Science; 5 th ed.; McGraw-Hill Medical: New York, 2013.
14. Oberheim, N. A.; Wang, X.; Goldman, S.; Nedergaard, M. Astrocytic complexity distinguishes the human brain Trends Neurosci. 2006, 29 (10) 547-53
15. Jabr, F. Know Your Neurons: What Is the Ratio of Glia to Neurons in the Brain? http://blogs.scientificamerican.com/brainwaves/2012/06/13/know-your- neurons-what-is-the-ratio-of-glia-to-neurons-in-the-brain/ (accessed Dec 14, 2012).
16. Azevedo, F. A.; Carvalho, L. R.; Grinberg, L. T.; Farfel, J. M.; Ferretti, R. E.; Leite, R. E.; Jacob Filho, W.; Lent, R.; Herculano-Houzel, S. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain J. Comp. Neurol. 2009, 513 (5) 532-41
17. Pelvig, D. P.; Pakkenberg, H.; Stark, A. K.; Pakkenberg, B. Neocortical glial cell numbers in human brains Neurobiol. Aging 2008, 29 (11) 1754-62
18. Oberheim, N. A.; Goldman, S. A.; Nedergaard, M. Heterogeneity of astrocytic form and function Methods Mol. Biol. 2012, 814, 23-45
19. Van Harreveld, A. The extracellular space in the vertebrate central nervous system. In The Structure and Function of Nervous Tissue; Bourne, G. H., Ed.; Academic: New York, 1972; Vol. IV, pp 447-511.
20. Nicholson, C.; Sykova, E. Extracellular space structure revealed by diffusion analysis Trends Neurosci. 1998, 21 (5) 207-15
21. Nicholson, C. Diffusion and related transport mechanisms in brain tissue Rep. Prog. Phys. 2001, 64 (7) 815-84
22. Sykova, E.; Nicholson, C. Diffusion in brain extracellular space Physiol. Rev. 2008, 88 (4) 1277-340
23. Schlageter, K. E.; Molnar, P.; Lapin, G. D.; Groothuis, D. R. Microvessel organization and structure in experimental brain tumors: microvessel populations with distinctive structural and functional properties Microvasc. Res. 1999, 58 (3) 312-28
24. Mabuchi, T.; Lucero, J.; Feng, A.; Koziol, J. A.; del Zoppo, G. J. Focal cerebral ischemia preferentially affects neurons distant from their neighboring microvessels J. Cereb. Blood Flow Metab. 2005, 25 (2) 257-66
25. Rusakov, D. A.; Kullmann, D. M. Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation J. Neurosci. 1998, 18 (9) 3158-70
26. Rusakov, D. A.; Savtchenko, L. P.; Zheng, K.; Henley, J. M. Shaping the synaptic signal: molecular mobility inside and outside the cleft Trends Neurosci. 2011, 34 (7) 359-69
27. Vargova, L.; Sykova, E. Extracellular space diffusion and extrasynaptic transmission Physiol. Res. 2008, 57 (Suppl. 3) S89-99
28. Coggan, J. S.; Bartol, T. M.; Esquenazi, E.; Stiles, J. R.; Lamont, S.; Martone, M. E.; Berg, D. K.; Ellisman, M. H.; Sejnowski, T. J. Evidence for ectopic neurotransmission at a neuronal synapse Science 2005, 309 (5733) 446-51
29. Matsui, K.; Jahr, C. E.; Rubio, M. E. High-concentration rapid transients of glutamate mediate neural-glial communication via ectopic release J. Neurosci. 2005, 25 (33) 7538-47
30. Kinney, J. P.; Spacek, J.; Bartol, T. M.; Bajaj, C. L.; Harris, K. M.; Sejnowski, T. J. Extracellular sheets and tunnels modulate glutamate diffusion in hippocampal neuropil J. Comp. Neurol. 2013, 521 (2) 448-64
31. Briscoe, J.; Lawrence, P. A.; Vincent, J. P. Generation and Interpretation of Morphogen Gradients; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 2010.
32. Kuffler, S. W.; Potter, D. D. Glia in the Leech Central Nervous System: Physiological Properties and Neuron-Glia Relationship J. Neurophysiol. 1964, 27, 290-320
33. Wyckoff, R. W.; Young, J. Z. The motorneuron surface Proc. R. Soc. London, Ser. B 1956, 144 (917) 440-50
34. Villegas, G. M.; Fernandez, J. Permeability to thorium dioxide of the intercellular spaces of the frog cerebral hemisphere Exp. Neurol. 1966, 15 (1) 18-36
35. Hansen, A. J. Effect of anoxia on ion distribution in the brain Physiol. Rev. 1985, 65 (1) 101-48
36. Vorisek, I.; Sykova, E. Ischemia-induced changes in the extracellular space diffusion parameters, K+, and pH in the developing rat cortex and corpus callosum J. Cereb. Blood Flow Metab. 1997, 17 (2) 191-203
37. Horstmann, E.; Meves, H. Die Feinstruktur des molekularen Rindengraues und ihre physiologische Bedeutung Z. Zellforsch. 1959, 49, 569-604
38. Trubatch, J.; Loud, A. V.; Van Harreveld, A. Quantitative stereological evaulation of KC1-induced ultrastructural changes in frog brain Neuroscience 1977, 2 (6) 963-74
39. Nicholson, C.; Phillips, J. M. Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum J. Physiol. 1981, 321, 225-57
40. Lehmenkuhler, A.; Sykova, E.; Svoboda, J.; Zilles, K.; Nicholson, C. Extracellular space parameters in the rat neocortex and subcortical white matter during postnatal development determined by diffusion analysis Neuroscience 1993, 55 (2) 339-51
41. Sykova, E.; Vorisek, I.; Antonova, T.; Mazel, T.; Meyer-Luehmann, M.; Jucker, M.; Hajek, M.; Ort, M.; Bures, J. Changes in extracellular space size and geometry in APP23 transgenic mice: a model of Alzheimer's disease Proc. Natl. Acad. Sci. U.S.A. 2005, 102 (2) 479-84
42. Thorne, R. G.; Nicholson, C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space Proc. Natl. Acad. Sci. U.S.A. 2006, 103 (14) 5567-72
43. Dityatev, A.; Schachner, M. Extracellular matrix molecules and synaptic plasticity Nat. Rev. Neurosci. 2003, 4 (6) 456-68
44. Thorne, R. G.; Lakkaraju, A.; Rodriguez-Boulan, E.; Nicholson, C. In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate Proc. Natl. Acad. Sci. U.S.A. 2008, 105 (24) 8416-21
45. Dityatev, A.; Seidenbecher, C. I.; Schachner, M. Compartmentalization from the outside: the extracellular matrix and functional microdomains in the brain Trends Neurosci. 2010, 33 (11) 503-12
46. Novak, U.; Kaye, A. H. Extracellular matrix and the brain: components and function J. Clin. Neurosci. 2000, 7 (4) 280-90
47. Abbott, N. J. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology Neurochem. Int. 2004, 45 (4) 545-52
48. Rosenberg, G. A.; Kyner, W. T.; Estrada, E. Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions Am. J. Physiol. 1980, 238 (1) F42-9
49. Ichimura, T.; Fraser, P. A.; Cserr, H. F. Distribution of extracellular tracers in perivascular spaces of the rat brain Brain Res. 1991, 545 (1-2) 103-13
50. Fenstermacher, J.; Kaye, T. Drug ″diffusion″ within the brain Ann. N.Y. Acad. Sci. 1988, 531, 29-39
51. Weiss, T. F. Cellular biophysics; MIT Press: Cambridge, MA, 1996.
52. Berg, H. C. Random Walks in Biology; Princeton University Press: Princeton, NJ, 1993.
53. Bear, J. Dynamics of Fluids in Porous Media; American Elsevier Pub. Co.: New York, 1972.
54. Iliff, J. J.; Wang, M.; Liao, Y.; Plogg, B. A.; Peng, W.; Gundersen, G. A.; Benveniste, H.; Vates, G. E.; Deane, R.; Goldman, S. A.; Nagelhus, E. A.; Nedergaard, M. A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid beta Sci. Transl. Med. 2012, 4 (147) 147ra111
55. Foley, C. P.; Nishimura, N.; Neeves, K. B.; Schaffer, C. B.; Olbricht, W. L. Real-Time Imaging of Perivascular Transport of Nanoparticles During Convection-Enhanced Delivery in the Rat Cortex Ann. Biomed. Eng. 2012, 40 (2) 292-303
56. Pollock, H.; Hutchings, M.; Weller, R. O.; Zhang, E. T. Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes J Anat 1997, 191 (Part 3) 337-46
57. Hille, B. Ion Channels of Excitable Membranes, 3 rd ed.; Sinauer: Sunderland, MA, 2001.
58. Hrabetova, S.; Hrabe, J.; Nicholson, C. Dead-space microdomains hinder extracellular diffusion in rat neocortex during ischemia J. Neurosci. 2003, 23 (23) 8351-9
59. Levin, V. A.; Fenstermacher, J. D.; Patlak, C. S. Sucrose and inulin space measurements of cerebral cortex in four mammalian species Am. J. Physiol. 1970, 219 (5) 1528-33
60. Patlak, C. S.; Fenstermacher, J. D. Measurements of dog blood-brain transfer constants by ventriculocisternal perfusion Am. J. Physiol. 1975, 229 (4) 877-84
61. Kessler, J. A.; Fenstermacher, J. D.; Owens, E. S. Spinal subarachnoid perfusion of rhesus monkeys Am. J. Physiol. 1976, 230 (3) 614-8
62. Rall, D. P.; Oppelt, W. W.; Patlak, C. S. Extracellular space of brain as determined by diffusion of inulin from the ventricular system Life Sci. 1962, 2, 43-48
63. Lux, H. D.; Neher, E. The equilibration time course of (K +) 0 in cat cortex Exp. Brain Res. 1973, 17 (2) 190-205
64. Nicholson, C.; Tao, L. Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging Biophys. J. 1993, 65 (6) 2277-90
65. Tao, L.; Nicholson, C. The three-dimensional point spread functions of a microscope objective in image and object space J. Microsc. 1995, 178 (Part 3) 267-71
66. Cragg, S. J.; Nicholson, C.; Kume-Kick, J.; Tao, L.; Rice, M. E. Dopamine-mediated volume transmission in midbrain is regulated by distinct extracellular geometry and uptake J. Neurophysiol. 2001, 85 (4) 1761-71
67. Tao, L.; Nicholson, C. Diffusion of albumins in rat cortical slices and relevance to volume transmission Neuroscience 1996, 75 (3) 839-47
68. Thorne, R. G.; Hrabetova, S.; Nicholson, C. Diffusion of epidermal growth factor in rat brain extracellular space measured by integrative optical imaging J. Neurophysiol. 2004, 92 (6) 3471-81
69. Thorne, R. G.; Hrabetova, S.; Nicholson, C. Diffusion measurements for drug design Nat. Mater. 2005, 4 (10) 713 author reply 714
70. Xiao, F.; Nicholson, C.; Hrabe, J.; Hrabetova, S. Diffusion of flexible random-coil dextran polymers measured in anisotropic brain extracellular space by integrative optical imaging Biophys. J. 2008, 95 (3) 1382-92
71. Prokopova-Kubinova, S.; Vargova, L.; Tao, L.; Ulbrich, K.; Subr, V.; Sykova, E.; Nicholson, C. Poly[N-(2-hydroxypropyl)methacrylamide] polymers diffuse in brain extracellular space with same tortuosity as small molecules Biophys. J. 2001, 80 (1) 542-8
72. Stroh, M.; Zipfel, W. R.; Williams, R. M.; Webb, W. W.; Saltzman, W. M. Diffusion of nerve growth factor in rat striatum as determined by multiphoton microscopy Biophys. J. 2003, 85 (1) 581-8
73. Stroh, M.; Zipfel, W. R.; Williams, R. M.; Ma, S. C.; Webb, W. W.; Saltzman, W. M. Multiphoton microscopy guides neurotrophin modification with poly(ethylene glycol) to enhance interstitial diffusion Nat. Mater. 2004, 3 (7) 489-94
74. Scimemi, A.; Tian, H.; Diamond, J. S. Neuronal Transporters Regulate Glutamate Clearance, NMDA Receptor Activation, and Synaptic Plasticity in the Hippocampus (November, pg 14581, 2009) J. Neurosci. 2010, 30 (29) 9954-6
75. Binder, D. K.; Papadopoulos, M. C.; Haggie, P. M.; Verkman, A. S. In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching J. Neurosci. 2004, 24 (37) 8049-56
76. Papadopoulos, M. C.; Binder, D. K.; Verkman, A. S. Enhanced macromolecular diffusion in brain extracellular space in mouse models of vasogenic edema measured by cortical surface photobleaching FASEB J. 2005, 19 (3) 425-7
77. Papadopoulos, M. C.; Kim, J. K.; Verkman, A. S. Extracellular space diffusion in central nervous system: anisotropic diffusion measured by elliptical surface photobleaching Biophys. J. 2005, 89 (5) 3660-8
78. Thiagarajah, J. R.; Kim, J. K.; Magzoub, M.; Verkman, A. S. Slowed diffusion in tumors revealed by microfiberoptic epifluorescence photobleaching Nat. Methods 2006, 3 (4) 275-80
79. Zador, Z.; Magzoub, M.; Jin, S.; Manley, G. T.; Papadopoulos, M. C.; Verkman, A. S. Microfiberoptic fluorescence photobleaching reveals size-dependent macromolecule diffusion in extracellular space deep in brain FASEB J. 2008, 22 (3) 870-9
80. Axelrod, D.; Koppel, D. E.; Schlessinger, J.; Elson, E.; Webb, W. W. Mobility measurement by analysis of fluorescence photobleaching recovery kinetics Biophys. J. 1976, 16 (9) 1055-69
81. Lochhead, J. J.; Thorne, R. G. Intranasal delivery of biologics to the central nervous system Adv. Drug Delivery Rev. 2012, 64 (7) 614-28
82. Kakee, A.; Terasaki, T.; Sugiyama, Y. Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier J. Pharmacol. Exp. Ther. 1996, 277 (3) 1550-9
83. Groothuis, D. R.; Vavra, M. W.; Schlageter, K. E.; Kang, E. W.; Itskovich, A. C.; Hertzler, S.; Allen, C. V.; Lipton, H. L. Efflux of drugs and solutes from brain: the interactive roles of diffusional transcapillary transport, bulk flow and capillary transporters J. Cereb. Blood Flow Metab. 2007, 27 (1) 43-56
84. Ziegler, R. J.; Salegio, E. A.; Dodge, J. C.; Bringas, J.; Treleaven, C. M.; Bercury, S. D.; Tamsett, T. J.; Shihabuddin, L.; Hadaczek, P.; Fiandaca, M.; Bankiewicz, K.; Scheule, R. K. Distribution of acid sphingomyelinase in rodent and non-human primate brain after intracerebroventricular infusion Exp. Neurol. 2011, 231 (2) 261-71
85. Ghersi-Egea, J. F.; Finnegan, W.; Chen, J. L.; Fenstermacher, J. D. Rapid distribution of intraventricularly administered sucrose into cerebrospinal fluid cisterns via subarachnoid velae in rat Neuroscience 1996, 75 (4) 1271-88
86. Powell, E. M.; Sobarzo, M. R.; Saltzman, W. M. Controlled release of nerve growth factor from a polymeric implant Brain Res. 1990, 515 (1-2) 309-11
87. Saltzman, W. M.; Radomsky, M. L. Drugs Released from Polymers-Diffusion and Elimination in Brain-Tissue Chem. Eng. Sci. 1991, 46 (10) 2429-44
88. Jain, A.; Jain, S. K. PEGylation: an approach for drug delivery. A review Crit. Rev. Ther. Drug Carrier Syst. 2008, 25 (5) 403-47
89. Harris, J. M.; Chess, R. B. Effect of pegylation on pharmaceuticals Nat. Rev. Drug Discovery 2003, 2 (3) 214-21
90. Nelson, A. L. Antibody fragments: hope and hype MAbs 2010, 2 (1) 77-83
91. Yokota, T.; Milenic, D. E.; Whitlow, M.; Schlom, J. Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms Cancer Res. 1992, 52 (12) 3402-8
92. Jain, R. K. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors Cancer Res. 1990, 50 (3 Suppl.) 814s-819s
93. Kume-Kick, J.; Mazel, T.; Vorisek, I.; Hrabetova, S.; Tao, L.; Nicholson, C. Independence of extracellular tortuosity and volume fraction during osmotic challenge in rat neocortex J. Physiol. 2002, 542 (Part 2) 515-27
94. Burger, C.; Nguyen, F. N.; Deng, J.; Mandel, R. J. Systemic mannitol-induced hyperosmolality amplifies rAAV2-mediated striatal transduction to a greater extent than local co-infusion Mol. Ther. 2005, 11 (2) 327-31
95. Mastakov, M. Y.; Baer, K.; Xu, R.; Fitzsimons, H.; During, M. J. Combined injection of rAAV with mannitol enhances gene expression in the rat brain Mol. Ther. 2001, 3 (2) 225-32
96. Mastakov, M. Y.; Baer, K.; Kotin, R. M.; During, M. J. Recombinant adeno-associated virus serotypes 2- and 5-mediated gene transfer in the mammalian brain: quantitative analysis of heparin co-infusion Mol. Ther. 2002, 5 (4) 371-80
97. Hamilton, J. F.; Morrison, P. F.; Chen, M. Y.; Harvey-White, J.; Pernaute, R. S.; Phillips, H.; Oldfield, E.; Bankiewicz, K. S. Heparin coinfusion during convection-enhanced delivery (CED) increases the distribution of the glial-derived neurotrophic factor (GDNF) ligand family in rat striatum and enhances the pharmacological activity of neurturin Exp. Neurol. 2001, 168 (1) 155-61
98. Yu, Y. J.; Zhang, Y.; Kenrick, M.; Hoyte, K.; Luk, W.; Lu, Y.; Atwal, J.; Elliott, J. M.; Prabhu, S.; Watts, R. J.; Dennis, M. S. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target Sci. Transl. Med. 2011, 3 (84) 84ra44
99. El-Kareh, A. W.; Secomb, T. W. Theoretical models for drug delivery to solid tumors Crit. Rev. Biomed. Eng. 1997, 25 (6) 503-71
100. Lim, S. T.; Airavaara, M.; Harvey, B. K. Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS Pharmacol. Res. 2010, 61 (1) 14-26
101. Dickson, P. I.; Chen, A. H. Intrathecal enzyme replacement therapy for mucopolysaccharidosis I: translating success in animal models to patients Curr. Pharm. Biotechnol. 2011, 12 (6) 946-55
102. Robert, R.; Wark, K. L. Engineered antibody approaches for Alzheimer's disease immunotherapy Arch. Biochem. Biophys. 2012, 526 (2) 132-8
103. Zhang, Y.; Pardridge, W. M. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier J. Neuroimmunol. 2001, 114 (1-2) 168-72
104. Cserr, H. F.; Cooper, D. N.; Suri, P. K.; Patlak, C. S. Efflux of radiolabeled polyethylene glycols and albumin from rat brain Am. J. Physiol. 1981, 240 (4) F319-28
105. Zhang, Y.; Pardridge, W. M. Rapid transferrin efflux from brain to blood across the blood-brain barrier J. Neurochem. 2001, 76 (5) 1597-600