Skip to main content
SpringerLink
Log in

Localized Delivery of Proteins in the Brain: Can Transport Be Customized?

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Certain central nervous system (CNS) diseases are characterized by the degeneration of specific cell populations. One strategy for treating neurodegenerative diseases is long-term, controlled delivery of proteins such as epidermal growth factor (EOF) and nerve growth factor (NGF). Since proteins permeate through brain capillaries very slowly, local administration using polymeric implants, continuous infusion pumps, or transplanted, protein-secreting cells may be required to achieve therapeutic concentrations in the tissue. The efficiency of local distribution, and hence effectiveness of local therapy, depends on the rate of protein migration through tissue. The rate of dispersion of molecules in a quiescent, isotropic medium can be characterized by the molecular diffusion coefficient, D, which can be measured by techniques such as quantitative autoradiography, iontophoresis, and fluorescence photobleaching recovery (FPR). These methods are reviewed, with an emphasis on their application to measurement of D for proteins in the brain. Biophysical techniques yield quantitative descriptions of local protein distribution and may enable discrimination of mechanisms of protein transport in the brain. This capability suggests a new paradigm for design of protein therapies, in which proteins and delivery systems are collectively customized to provide sustained protein availability over predetermined volumes of tissue.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. A.N. Lieberman. First Ever National Institutes of Health Research Planning Workshop on Parkinson's Disease, National Parkinson Foundation (1995).

  2. Progress Report on Alzheimer's Disease. National Institute on Aging (1996).

  3. M. Mouradian, J. Juncos, G. Fabbrini, and T. Chase. Motor fluctuations in Parkinson's disease: Pathogenic and therapeutic studies. Ann. Neurol. 22:475–479 (1987).

    PubMed  Google Scholar 

  4. K. L. Davis, L. J. Thal, E. R. Gamzu, C. S. Davis, R. F. Woolson, S. I. Gracon, D. A. Drachman, L. S. Schneider, P. J. Whitehouse, and T. M. Hoover. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. N. Engl. J. Med. 327:1253–1308 (1992).

    PubMed  Google Scholar 

  5. G. Ferrari, G. Toffano, and S. D. Skaper. Epidermal growth factor exerts neuronotrophic effects on dopaminergic and GABAergic CNS neurons: Comparison with basic fibroblast growth factor. J. Neurosci. Res. 30:493–497 (1991).

    PubMed  Google Scholar 

  6. J. Villares, B. Faucheux, O. Strada, E. Hirsche, Y. Agid, and F. Javoy-Agid. Autoradiographic study of [125I]epidermal growth factor-binding sites in the mesencephalon of control and Parkinsonian brains post-mortem. Brain Res. 628:72–67 (1993).

    PubMed  Google Scholar 

  7. M. Mogi, M. Harada, T. Kondo, P. Riederer, H. Inagaki, M. Minami, and T. Nagatsu. Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from Parkinsonian patients. Neurosci. Let. 180:147–150 (1994).

    Google Scholar 

  8. S. Weiss, C. Dunne, J. Hewson, C. Wohl, M. Wheatley, A.C. Peterson, and B.A. Reynolds. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J. Neurosci. 16:7599–7609 (1996).

    PubMed  Google Scholar 

  9. C. Craig, T. V. C. Morshead, B. Reynolds, S. Weiss, and D. van der Kooy. In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J. Neurosci. 16:2649–2658 (1996).

    PubMed  Google Scholar 

  10. V. Koliatsos, M. Applegate, B. Knusel, E. Junard, L. Burton, W. Mobley, F. Hefti, and D. Price. Recombinant human nerve growth factor prevents retrograde degeneration of axotomized basal forebrain cholinergic neurons in the rat. Exp. Neurol. 112:161–173 (1991).

    PubMed  Google Scholar 

  11. V. E. Koliatsos, B. S. Clatterbuck, G. J. W. Nauta, B. Knusel, L. E. Burton, F. F. Hefti, W. C. Mobley, and D. L. Price. Human nerve growth factor prevents degeneration of basal forebrain cholinergic neurons in primate. Ann. Neurol. 30:831–840 (1991).

    PubMed  Google Scholar 

  12. M. H. Tuszynski, G. Buzsaki, and F. H. Gage. Nerve growth factor infusions combined with fetal hippocampal grafts enhance reconstruction of the lesioned septohippocampal projection. Neuroscience 36:33–44 (1990).

    PubMed  Google Scholar 

  13. K. Niijima, G. R. Chalmers, D. A. Peterson, L. J. Fisher, P. H. Patterson, and F. H. Gage. Enhanced survival and neuronal differentiation of adrenal chromaffin cells cografted into the striatum with NGF-producing fibroblasts. J. Neurosci. 15:1180–1194 (1995).

    PubMed  Google Scholar 

  14. L. Olson, L. Backman, T. Ebendal, M. Eriksdotter-Jonhagen, B. Hoffer, C. Humpel, R. Freedman, M. Giacobini, B. Meyerson, A. Nordberg, A. Seiger, I. Stromberg, O. Sydow, A. Tomac, K. Trok, and B. Winblad. Role of growth factors in degeneration and regeneration in the central nervous system; clinical experiences with NGF in Parkinson's and Alzheimer's diseases. J. Neurol. 241:S12–S15 (1994).

    Google Scholar 

  15. J. F. Poduslo, G. L. Curran, and C. T. Berg. Macromolecular permeability across the blood-nerve and blood-brain barriers. Proc. Natl. Acad. Sci. USA 91:5705–5709 (1994).

    PubMed  Google Scholar 

  16. R. Duncan and F. Spreafico. Polymer conjugates. Pharmacokinetic considerations for design and development. Clin. Pharmacokinet. 27:290–306 (1994).

    PubMed  Google Scholar 

  17. C. E. Krewson, R. B. Dause, M. W. Mak, and W. M. Saltzman. Stabilization of nerve growth factor in polymers and in tissues. Biomater. Sci. Polym. Ed. 8:103–117 (1996).

    Google Scholar 

  18. C. E. Krewson and W. M. Saltzman. Nerve growth factor delivery and cell aggregation enhance choline acetyltransferase activity after neural transplantation. Tissue Eng. 2:183–196 (1996).

    Google Scholar 

  19. C. E. Krewson and W. M. Saltzman. Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res. 727: 169–181 (1996).

    PubMed  Google Scholar 

  20. D. Hoffman, L. Wahlberg, and P. Aebischer. NGF released from a polymer matrix prevents loss of ChAT expression in basal forebrain neurons following a fimbria-fornix lesion. Exp. Neurol. 110:39–44 (1990).

    PubMed  Google Scholar 

  21. P. J. Camarata, R. Suryanarayanan, and D. A. Turner. Sustained release of nerve growth factor from biodegradable polymer microspheres. Neurosurgery 30:313–319(1992).

    PubMed  Google Scholar 

  22. L. Williams, S. Varon, G. Peterson, K. Wictorin, W. Fischer, A. Bjorklund, and F. Gage. Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. Proc. Natl. Acad. Sci. USA 83:9231–9235 (1986).

    PubMed  Google Scholar 

  23. P. F. Morrison, D. W. Laske, H. Bobo, E. H. Oldfield, and R. L. Dedrick. High-flow microinfusion: tissue penetration and pharmacodynamics. Am. J. Physiol. 266: R292–R305 (1994).

    PubMed  Google Scholar 

  24. D. M. Lieberman, D. W. Laske, P. F. Morrison, K. S. Bankiewicz, and E. H. Oldfield. Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J. Neursurg. 82:1027–1029 (1995).

    Google Scholar 

  25. M. Rosenberg, T. Friedmann, R. Robertson, M. Tuszynski, J. Wolff, X. Breakefield, and F. Gage. Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. Science 242:1575–1578 (1988).

    PubMed  Google Scholar 

  26. S. R. Winn, J. P. Hammang, D. F. Emerich, A. Lee, R. D. Palmiter, and E.E. Baetge. Polymer-encapsulated cells genetically modified to secrete human nerve growth factor promote the survival of axotomized septal cholinergic neurons. Proc. Natl. Acad. Sci. USA 91:2324–2328 (1994).

    PubMed  Google Scholar 

  27. D. F. Emerich, J. P. Hammang, B. E. E., and S. R. Winn. Implantation of polymer-encapsulated human nerve growth factor-secreting fibroblasts attenuates the behavioral and neuropathological consequences of quinolinic acid injections into rodent striatum. Exp. Neurol. 30:141–150 (1994).

    Google Scholar 

  28. J. H. Kordower, S. R. Winn, Y.-T. Liu, E. J. Mufson, J. R. Sladek, J. P. Hammang, E. E. Baetge, and D. F. Emerich. The aged monkey basal forebrain: Rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor. Proc. Natl. Acad. Sci. USA 91:10898–10902 (1994).

    PubMed  Google Scholar 

  29. J. H. Kordower, J. M. Rosenstein, T. J. Collier, M. A. Burke, E. Y. Chen, J. M. Li, L. Martel, A. E. Levey, E. J. Mufson, T. B. Freeman, and C. W. Olanow. Functional fetal nigral grafts in a patient with Parkinson's Disease — chemoanatomic, ultrastructural, and metabolic studies. J. Comp. Neurol. 370:203–230 (1996).

    PubMed  Google Scholar 

  30. M. J. Mahoney, and W. M. Saltzman. Controlled release of proteins to tissue transplants for the treatment of neurodegenerative disorders. J. Pharm. Sci. 85: 1276–1281. (1996).

    PubMed  Google Scholar 

  31. L. T. Baxter, and R. K. Jain. Transport of fluid and macromolecules in tumors I. Role of interstitial pressure and convection. Microvasc. Res. 37:77–104 (1989).

    PubMed  Google Scholar 

  32. C. P. Geer, and S. A. Grossman. Extracellular fluid flow along white matter tracts in brain: a potentially important mechanism for dissemination of primary brain tumors. Proc. ASCO 12:177 (1993).

    Google Scholar 

  33. L. Fung, M. Shin, B. Tyler, H. Brem, and W. M. Saltzman. Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharm. Res. 13:671–682 (1996).

    PubMed  Google Scholar 

  34. S. Yamada, M. DePasquale, C. S. Patlak, and H. F. Cserr. Albumin outflow into deep cervical lymph from different regions of rabbit brain. Am. J. Physiol. 261:H1197–H1204 (1991).

    PubMed  Google Scholar 

  35. M. A. Clauss, and R. K. Jain. Interstitial transport of rabbit and sheep antibodies in normal and neoplastic tissues. Cancer Res. 50:3487–3492 (1990).

    PubMed  Google Scholar 

  36. K. D. Anderson, R. F. Alderson, C. A. Altar, P. S. Distefano, T. L. Corcoran, R. M. Lindsay, and S. J. Wiegand. Differential distribution of exogenous BDNF, NGF, and NT-3 in the brain corresponds to the relative abundance and distribution of high-affinity and low-affinity neurotrophin receptors. J. Comp. Neurol. 357:296–317 (1995).

    PubMed  Google Scholar 

  37. M. Mak, L. Fung, J. F. Strasser, and W. M. Saltzman. Distribution of drugs following controlled delivery to the brain interstitium. J. Neurooncol. 26:91–102 (1995).

    PubMed  Google Scholar 

  38. W. M. Saltzman. Antibodies for treating and preventing disease: the potential role of polymeric controlled release. Crit. Rev. Ther. Drug Carrier Syst. 10:111–142 (1993).

    PubMed  Google Scholar 

  39. W. M. Saltzman and M. L. Radomsky. Drugs released from polymers: diffusion and elimination in brain tissue. Chem. Eng. Sci. 46:2429–2444 (1991).

    Google Scholar 

  40. E. W. Thiele. Relation between catalytic activity and size of particle. Ind. Eng. Chem. 31:916 (1939).

    Google Scholar 

  41. V. Levin, J. Fenstermacher, and C. Patlak. Sucrose and inulin space measurements of cerebral cortex in four mammalian species. Am. J. Physiol. 219: 1528–1533 (1970).

    PubMed  Google Scholar 

  42. K. H. Dykstra, J. K. Hsiao, P. F. Morrison, P. M. Bungay, I. N. Mefford, M. M. Scully, and R. L. Dedrick. Quantitative examination of tissue concentration profiles associated with microdialysis. J. Neurochem. 58:931–940 (1992).

    PubMed  Google Scholar 

  43. J. F. Strasser, L. K. Fung, S. Eller, S. A. Grossman, and W. M. Saltzman. Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and tracers in the rabbit brain following interstitial delivery by biodegradable polymer implants. J. Pharm. Exp. Ther. 275:1647–1655 (1995).

    Google Scholar 

  44. W. Dang and W. M. Saltzman. Dextran retention in the rat brain following controlled release from a polymer. Biotech. Prog. 8:527–532 (1992).

    Google Scholar 

  45. W. M. Saltzman, M. L. Radomsky, K. J. Whaley, and R. A. Cone. Antibody diffusion in human cervical mucus. Biophys. J. 66:508–515 (1994).

    PubMed  Google Scholar 

  46. M. L. Radomsky, K. J. Whaley, R. A. Cone, and W. M. Saltzman. Macromolecules released from polymers: diffusion into unstirred fluids. Biomat. 11:619–624 (1990).

    Google Scholar 

  47. K. Groebe, S. Erz, and W. Mueller-Klieser. Glucose diffusion coefficients determined from concentration profiles in EMT6 tumor spheroids incubated in radioactively labeled L-glucose. Adv. Exp. Med. Biol. 361:619–25 (1994).

    PubMed  Google Scholar 

  48. B. Bjelke, R. England, C. Nicholson, M. E. Rice, J. Lindberg, M. Zoli, L. F. Agnati, and K. Fuxe. Long distance pathways of diffusion for dextran along fibre bundles in brain. Relevance for volume transmission. Neuroreport 6:1005–1009 (1995).

    PubMed  Google Scholar 

  49. S. Popov and M. M. Poo. Diffusional transport of macromolecules in developing nerve processes. J. Neurosci. 12:77–85 (1992).

    PubMed  Google Scholar 

  50. S. Terada, T. Nakata, A. Peterson, and N. Hirokawa. Visualization of slow axonal transport in vivo. Science 273:784–788 (1996).

    PubMed  Google Scholar 

  51. S. Johanson, M. Crouch, and I. Hendry. Retrograde axonal transport of signal transduction proteins in rat sciatic nerve. Brain. Res. 690:55–63 (1995).

    PubMed  Google Scholar 

  52. L. Tao and C. Nicholson. Diffusion of albumins in rat cortical slices and relevance to volume transmission. Neuroscience 75:839–847 (1996).

    PubMed  Google Scholar 

  53. V. A Levin, J. D. Fenstermacher, and C. S. Patlak. Sucrose and inulin space measurements of cerebral cortex in four mammalian species. Am. J. Physiol. 219:1528–1533 (1970).

    PubMed  Google Scholar 

  54. J. Fenstermacher and T. Kaye. Drug “diffusion” within the brain. Ann. NY Acad. Sci. 531:29–39 (1988).

    PubMed  Google Scholar 

  55. L. Nugent and R. Jain. Extravascular diffusion in normal and neoplastic tissues. Cancer Res. 44:238–244 (1984).

    PubMed  Google Scholar 

  56. R. K. Jain. Barriers to drug delivery in solid tumors. Sci. Amer. 271:58–65 (1994).

    Google Scholar 

  57. R. Williams, D. Piston, and W. Webb. Two-photon molecular excitation provides intrinsic 3-dimensional resolution for laser-based microscopy and microphotochemistry. FASEB J. 8:804–13 (1994).

    PubMed  Google Scholar 

  58. C. Xu, W. Zipfel, J. Shear, R. M. Williams, and W. W. Webb. Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy. Proc. Natl. Acad. Sci. USA 93:10763–10768 (1996).

    PubMed  Google Scholar 

  59. S. Maiti, J. B. Shear, R. Williams, W. Zipfel, and W. W. Webb. Measuring serotonin distribution in live cells with three-photon excitation. Science 275:530–532 (1997).

    PubMed  Google Scholar 

  60. D. Berk, F. Yuan, M. Leunig, and R. Jain. Fluorescence photobleaching with spatial fourier analysis: measurement of diffusion in light-scattering media. Biophys. J. 65:2428–2436 (1933).

    Google Scholar 

  61. D. Axelrod, D. Koppel, J. Schlessinger, E. Elson, and W. Webb. Mobility measurement by analysis of fluorescence photobleaching recovery kinetics. Biophys. J. 16:1055–1069 (1976).

    PubMed  Google Scholar 

  62. E. M. Johnson, D. A. Berk, R. Jain, and W. M. Deen. Hindered diffusion in agarose gels: test of the effective medium model. Biophys. J. 70:1017–1026 (1996).

    PubMed  Google Scholar 

  63. J. Jarnefelt, T. Laurent, and R. Rigler. Diffusion of fluoresceinlabelled molecules in suspensions of erythrocyte ghosts. FEBS Lett. 242:129–133 (1988).

    PubMed  Google Scholar 

  64. E.D. Salmon, W. M. Saxton, R. J. Leslie, M. L. Karow, and J. R. McIntosh. Diffusion coefficient of fluorescein-labeled tubulin in the cytoplasm of embryonic cells of a sea urchin: video image analysis of fluorescence redistribution after photobleaching. J. Cell Biol. 99:2157–2164 (1984).

    PubMed  Google Scholar 

  65. C. Nicholson. Ion-selective microelectrodes and diffusion measurements as tools to explore the brain cell microenvironment. J. Neurosci. Methods 48:199–213(1993).

    PubMed  Google Scholar 

  66. C. Nicholson and J. M. Phillips. Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J. Physiol. 321:225–257 (1981).

    PubMed  Google Scholar 

  67. J. A. Lundbaek and A. J. Hansen. Brain interstitial volume fraction and tortuosity in anoxia. Evaluation of the ion-selective microelectrode method. Acta Physiol. Scand., 146:473–484. (1992).

    PubMed  Google Scholar 

  68. M. E. Rice and C. Nicholson. Diffusion characteristics and extracellular volume fraction during normoxia and hypoxia in slices of rat neostriatum. J. Neurophys., 65:264–272. (1991)

    Google Scholar 

  69. R. S. Kelly and R. M. Wightman. Detection of dopamine overflow and diffusion with voltammetry in slices of rat brain. Brain Res., 423:79–87. (1987).

    PubMed  Google Scholar 

  70. B. Reisfeld, S. Blackband, V. Calhoun, S. Grossman, S. Eller, and K. Leong. The use of magnetic resonance imaging to track controlled drug release and transport in the brain. Magn. Reson. Imaging, 11:247–52. (1993).

    PubMed  Google Scholar 

  71. C. E. Krewson, M. L. Klarman, and W. M. Saltzman. Distribution of nerve growth factor following direct delivery to brain interstitium. Brain Res., 680:196–206. (1995).

    PubMed  Google Scholar 

  72. I. A. Ferguson, J. B. Schweitzer, P. F. Barlett, and E. M. Johnson. Receptor-mediated retrograde transport in CNS neurons after intraventricular administration of NGF and growth factors. J. Comp. Neurol., 313:680–692. (1991).

    PubMed  Google Scholar 

  73. K. J. Bridges, Harford, G. Ashwell, and R. D. Klausner. Fate of receptor and ligand during endocytosis of asialoglycoproteins by isolated hepatocytes. Proc. Natl. Acad. Sci. USA, 79:350–354. (1982).

    PubMed  Google Scholar 

  74. D. A. Lauffenburger and J. J. Linderman. Receptors: models for binding, trafficking, and signaling, Oxford University Press, New York, 1993.

    Google Scholar 

  75. L. Chu, H. S. Wiley, and D. A. Lauffenburger. Endocytic relay as a potential means for enhancing ligand transport through cellular tissue matrices: analysis and possible implications for drug delivery. Tissue Eng., 2:17–37. (1996).

    Google Scholar 

  76. A. Wells, J. B. Welsh, C. S. Lazar, H. S. Wiley, G. N. Gill, and M. G. Rosenfeld. Ligand-induced transformation by a noninternalized epidermal growth factor receptor. Science, 247:962–964. (1990).

    PubMed  Google Scholar 

  77. D. Lauffenburger, L. Chu, A. French, G. Oehrtman, C. Reddy, A. Wells, S. Niyogi, and W. HS. Engineering dynamics of growth factors and other therapeutic ligands. Biotech. and Bioeng., 52:61–80. (1996).

    Google Scholar 

  78. L. Chu, M.-S. Yi, H. S. Wiley, and D. A. Lauffenburger. Ligand transport through cellular matrices and the role of receptor-mediated trafficking. Proc. Top. Conf. Biomat.,:306–308. (1997).

    Google Scholar 

  79. M. van den Heuvel, R. Nusse, P. Johnston, and P. A. Lawrence. Distribution of the wingless gene produce in Drosophila embryos: a protein involve in cell-cell communication. Cell, 59:739–749. (1989).

    PubMed  Google Scholar 

  80. F. Gonzalez, L. Swales, A. Bejsovec, H. Skaer, and A. Martinez. Secretion and movement of wingless protein in the epidermis of the Drosophila embryo. Mech. Dev., 35:43–54. (1991).

    PubMed  Google Scholar 

  81. A. Bejsovec and E. Wieschaus. Signaling activities of the Drosophila wingless gene are separately mutable and appear to be transduces at the cell surface. Genetics, 139:309–320. (1995).

    PubMed  Google Scholar 

  82. C. E. Krewson, R. Dause, M. Mak, and W. M. Saltzman. Stabilization of nerve growth factor in controlled release polymers and in tissue. Biomater. Sci. Polym. Ed., 8:103–117. (1996).

    Google Scholar 

  83. P. Olsson, A. Lindstrom, and J. Carlsson. Internalization and excretion of epidermal growth factor-dextran-associated radioactivity in cultured human squamous-carcinoma cells. Int. J. Cancer, 56:529–537. (1994).

    PubMed  Google Scholar 

  84. W. Dang, O. M. Colvin, H. Brem, and W. M. Saltzman. Covalent coupling of methotrexate to dextran enhances the penetration of cytotoxicity into a tissue-like matrix. Cancer Res., 54:1729–1735. (1994).

    PubMed  Google Scholar 

  85. D. H. Ho, N. S. Brown, A. Yen, R. Holmes, M. Keating, A. Abuchowski, R. A. Newman, and I. H. Krakoff. Clinical pharmacology of polyethylene glycol-L-asparaginase. Drug Metab. Dispos. 14:349–352. (1986).

    PubMed  Google Scholar 

  86. M. S. Hershfield, R. H. Buckley, M. L. Greenberg, A. L. Melton, R. Schiff, C. Hatem, J. Kurtzberg, M. L. Markert, R. H. Kobayashi, A. L. Kobayashi, and A. Abuchowski. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N. Engl. J. Med., 316:589–596. (1987).

    PubMed  Google Scholar 

  87. H. Brem, S. Piantadosi, P. C. Burger, M. Walker, R. Selker, N. A. Vick, K. Black, M. Sisti, S. Brem, G. Mohr, P. Muller, R. Morawetz, S. C. Schold, and P.-B.T.T. Group. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet, 345:1008–1012. (1995).

    PubMed  Google Scholar 

  88. J. Winkler, G. A. Ramirez, H. G. Kuhn, D. A. Peterson, P. A. Day-Lollini, G. R. Stewart, M. H. Tuszynski, F. H. Gage, and L. J. Thal. Reversible Schwann cell hyperplasia and sprouting of sensory and sympathetic neutites after intraventricular administration of nerve growth factor. Ann. Neurol., 41:83–93. (1997).

    Google Scholar 

  89. T. Arakawa and C. Frieden. The use of the fluorescence photobleaching recovery technique to study the self-assembly of tubulin. Anal. Biochem., 146:134–142. (1985).

    PubMed  Google Scholar 

  90. C. Nicholson and L. Tao. Diffusion properties of brain tissue measured with electrode methods and prospects for optical analysis. In U. Dirnagl (eds), Optical Imaging of Brain Function and Metabolism, Plenum Press, New York, 1993.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemical Engineering, Cornell University, Ithaca, New York, 14853

    Michael F. Haller & W. Mark Saltzman

Authors
  1. Michael F. Haller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Mark Saltzman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W. Mark Saltzman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haller, M.F., Saltzman, W.M. Localized Delivery of Proteins in the Brain: Can Transport Be Customized?. Pharm Res 15, 377–385 (1998). https://doi.org/10.1023/A:1011911912174

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1011911912174

Search

Navigation