1. bookVolume 62 (2018): Issue 1 (March 2018)
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year
Open Access

Permeability of the Blood-Brain Barrier and Transport of Nanobodies Across the Blood-Brain Barrier

Published Online: 11 Apr 2018
Volume & Issue: Volume 62 (2018) - Issue 1 (March 2018)
Page range: 59 - 66
Received: 04 Dec 2017
Accepted: 26 Jan 2018
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year

The presence of a blood-brain barrier (BBB) and a blood-cerebrospinal fluid barrier presents animmense challenge for effective delivery of therapeutics to the central nervous system. Many potential drugs, which are effective at their site of action, have failed due to the lack of distribution in sufficient quantity to the central nervous system (CNS). In consequence, many diseases of the central nervous system remain undertreated. Antibodies, IgG for example, are difficult to deliver to the CNS due to their size (~155 kDa), physico-chemical properties and the presence of Fc receptor on the blood-brain barrier. Smaller antibodies, like the recently developed nanobodies, may overcome the obstacle of the BBB and enter into the CNS. The nanobodies are the smallest available antigen-binding fragments harbouring the full antigenbinding capacity of conventional antibodies. They represent a new generation of therapeutics with exceptional properties, such as: recognition of unique epitopes, target specificity, high affinity, high solubility, high stability and high expression yields in cost-effective recombinant production. Their ability to permeate across the BBBmakes thema promising alternative for central nervous system disease therapeutics. In this review, we have systematically presented different aspects of the BBB, drug delivery mechanisms employed to cross the BBB, and finally nanobodies — a potential therapeutic molecule against neuroinfections.


1. Abbott, N. J., Friedman, A., 2012: Overview and introduction: The blood-brain barrier in health and disease. Epilepsia, 53, 1—6.10.1111/j.1528-1167.2012.03696.x362572823134489Search in Google Scholar

2. Abbott, N. J., 1992: Comparative physiology of the bloodbrain barrier. In Bradbury, M. W. B. (Ed.):Physiology and Pharmacology of the Blood-Brain Barrier, Springer Berlin Heidelberg, 371—396.10.1007/978-3-642-76894-1_15Search in Google Scholar

3. Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M., Yusof, S. R., Begley, D. J., 2010: Structure and function of the blood-brain barrier. Neurobiol. Dis., 37, 13—25.10.1016/j.nbd.2009.07.03019664713Open DOISearch in Google Scholar

4. Abbott, N. J., Ronnback, L., Hansson, E., 2006: Astrocyteendothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci., 7, 41—53.10.1038/nrn182416371949Search in Google Scholar

5. Abulrob, A., Sprong, H., Van Bergen, E., Henegouwen, P., Stanimirovic, D., 2005: The blood-brain barrier transmigrating single domain antibody: Mechanisms of transport and antigenic epitopes in human brain endothelial cells. J. Neurochem., 95, 1201—1214.10.1111/j.1471-4159.2005.03463.x16271053Search in Google Scholar

6. Balda, M. S., Matter, K., 2009: Tight junctions and the regulation of gene expression. Biochem. Biophys. Acta, 1788, 761—767.10.1016/j.bbamem.2008.11.02419121284Open DOISearch in Google Scholar

7. Begley, D. J., Brightman, M. W., 2003: Structural and functional aspects of the blood-brain barrier. Prog. Drug Res., 61, 39—78.10.1007/978-3-0348-8049-7_214674608Search in Google Scholar

8. Begley, D. J., 2004: ABC transporters and the blood-brain barrier. Curr. Pharm. Des., 10, 1295—1312.10.2174/138161204338484415134482Search in Google Scholar

9. Begley, D. J., 2004: Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol. Ther., 104, 29—45.10.1016/j.pharmthera.2004.08.00115500907Open DOISearch in Google Scholar

10. Bernacki, J., Dobrowolska, A., Nierwinska, K., Malecki, A., 2008: Physiology and pharmacological role of the bloodbrain barrier. Pharmacol. Rep., 60, 600—622.Search in Google Scholar

11. Boado, R. J., Hui, E. K. W., Lu, J. Z., Pardridge, W. M., 2012: Glycemic control and chronic dosing of Rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor. Drug Metabolism and Disposition, 40, 2021—2025.10.1124/dmd.112.046375346382222822036Open DOISearch in Google Scholar

12. Carman, C. V., Springer, T. A., 2008: Trans-cellular migration: cell-cell contacts get intimate. Current Opinion in Cell Biology, 20, 533—540.10.1016/j.ceb.2008.05.007Open DOISearch in Google Scholar

13. Charles, A. Janeway, J., Travers, P., Walport, M., Shlomchik, M. J., 2001: The structure of a typical antibody molecule. In Immunobiology, the Immune System in Health and Disease, 5th edition., Garland Science Publishing, New York, 600 pp.Search in Google Scholar

14. Clark, D. E., 2003: In silico prediction of blood-brain barrier permeation. Drug Discovery Today, 8, 927—933.10.1016/S1359-6446(03)02827-7Search in Google Scholar

15. Comor, L., Dolinska, S., Bhide, K., Pulzova, L., Jiménez-Munguía, I., Bencurova, E., et al., 2017: Joining the in vitro immunization of alpaca lymphocytes and phage display: rapid and cost effective pipeline for sdAb synthesis. Microb. Cell Fact., 16,10.1186/s12934-017-0630-zSearch in Google Scholar

16. Cooper, P. R., Ciambrone, G. J., Kliwinski, C. M., Maze, E., Johnson, L., et al., 2013: Efflux of monoclonal antibodies from rat brain by neonatal Fc receptor. Brain Res., 1534, 13—21.10.1016/j.brainres.2013.08.035Open DOISearch in Google Scholar

17. Dauchy, S., Miller, F., Couraud, P. O., Weaver, R. J., Weksler, B., Romero, I. A., et al., 2009: Expression and transcriptional regulation of ABC transporters and cytochromes P450 in hCMEC/D3 human cerebral microvascular endothelial cells. Biochem. Pharmacol., 77, 897—909.10.1016/j.bcp.2008.11.001Search in Google Scholar

18. Elgert, K. D., 2009:Immunology: Understanding the immune system, 2nd edn., Wiley-Blackwell, New Jersey, 726.Search in Google Scholar

19. Engelhardt, B., Wolburg, H., 2004: Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house ? Eur. J. Immunol., 34, 2955—2963.10.1002/eji.200425327Open DOISearch in Google Scholar

20. Farrington, G. K., Caram-Salas, N., Haqqani, A. S., Brunette, E., Eldredge, J., Pepinsky, B., et al., 2014: A novel platform for engineering blood-brain barrier-crossing bispecific biologics. FASEB J., 28, 4764—4778.10.1096/fj.14-253369Open DOISearch in Google Scholar

21. Gaillard, P. J., Brink, A., de Boer, A. G., 2005: Diphtheria toxin receptor-targeted brain drug delivery. Int. Congr. Ser., 1277, 185—198.10.1016/j.ics.2005.02.022Open DOISearch in Google Scholar

22. Ghassabeh, G. H., Muyldermans, S., Saerens, D., 2010: Nanobodies, single-domain antigen-binding fragments of camelid heavy-chain antibodies. In Shire, S. J., Gombotz, W., Bechtold-Peters, K., Andya, J. (Eds.):Current Trends in Monoclonal Antibody Development and Manufacturing. Springer New York, 29—48.10.1007/978-0-387-76643-0_3Search in Google Scholar

23. Gingrich, M. B., Traynelis, S. F., 2000: Serine proteases and brain damage - is there a link ? Trends Neurosci., 23, 399—407.10.1016/S0166-2236(00)01617-9Open DOISearch in Google Scholar

24. Hamers-Casterman, C., Atarhouch, T., Muyldermans, S., Robinson, G., Hammers, C., Bajyana Songa, E., et al., 1993: Naturally occurring antibodies devoid of light chains. Nature, 363, 446—8.10.1038/363446a08502296Search in Google Scholar

25. Jain, K. K., 2012: Nanobiotechnology-based strategies for crossing the blood-brain barrier. Nanomedicine, 7, 1225—1233.10.2217/nnm.12.8622931448Open DOISearch in Google Scholar

26. Li, T., Bourgeois, J. P., Celli, S., Glacial, F., Le Sourd, A. M., Mecheri, S., et al., 2012: Cell-penetrating anti-GFAP VHH and corresponding fluorescent fusion protein VHH-GFP spontaneously cross the blood-brain barrier and specifically recognize astrocytes: application to brain imaging. FASEB J., 26, 3969—3979.10.1096/fj.11-20138422730440Open DOISearch in Google Scholar

27. Lim, D. A., Huang, Y.-C., Alvarez-Buylla, A., 2007: The adult neural stem cell niche: lessons for future neural cell replacement strategies. Neurosurg. Clin. N. Am., 18, 81—92, ix.10.1016/j.nec.2006.10.00217244556Open DOISearch in Google Scholar

28. Liu, X., Tu, M., Kelly, R. S., Chen, C., Smith, B. J., 2004: Development of a computational approach to predict blood-brain barrier permeability. Drug Metab. Dispos., 32, 132—139.10.1124/dmd.32.1.13214709630Open DOISearch in Google Scholar

29. McManus, S., Riechmann, L., 1991: Use of 2D NMR, protein engineering, and molecular modelling to study the haptenbinding site of an antibody Fv fragment against 2-phenyloxazolone. Biochemistry, 30, 5851—5857.10.1021/bi00238a0072043627Open DOISearch in Google Scholar

30. Milenic, D. E., Yokota, T., Filpula, D. R., Finkelman, A. J., Dodd, S. W., Wood, J. F., et al., 1991: Construction, binding properties, metabolism, and tumour targeting of a singlechain Fv derived from the pancarcinoma monoclonal antibody CC49. Cancer Res., 51, 6363—6371.Search in Google Scholar

31. Mitic, L. L., Van Itallie, C. M., Anderson, J M., 2000: Molecular physiology and pathophysiology of tight junctions I. Tight junction structure and function: lessons from mutant animals and proteins. Am. J. Physiol. Gastrointest. Liver Physiol., 279, G250—254.10.1152/ajpgi.2000.279.2.G25010915631Search in Google Scholar

32. Muoio, V., Persson, P. B., Sendeski, M. M., 2014: The neurovascular unit - concept review. Acta Physiol., 210, 790—798.10.1111/apha.1225024629161Search in Google Scholar

33. Muruganandam, A., Tanha, J., Narang, S., Stanimirovic, D., 2002: Selection of phage-displayed llama single-domain antibodies that transmigrate across human blood-brain barrier endothelium. FASEB J., 16, 240—242.10.1096/fj.01-0343fje11772942Open DOISearch in Google Scholar

34. Muyldermans, S., 2013: Nanobodies: natural single-domain antibodies. Annu. Rev. Biochem., 82, 775—797.10.1146/annurev-biochem-063011-09244923495938Open DOISearch in Google Scholar

35. Nadal, A., Fuentes, E., Pastor, J., McNaughton, P. A., 1995: Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes. Proc. Natl. Acad. Sci. USA, 92, 1426—1430.10.1073/pnas.92.5.1426Open DOISearch in Google Scholar

36. Nag, S., Begley, D. J., 2005: Blood brain barrier, exchange of metabolites and gases. In Kalimo, H. (Ed.):Pathology and Genetics: Cerebrovascular Diseases. ISN Neuropath. Press, 22—29.Search in Google Scholar

37. Nakagawa, S., Deli, M. A., Kawaguchi, H., Shimizudani, T., Shimono, T., Kittel, A., et al., 2009: A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem. Int., 54, 253—263.10.1016/j.neuint.2008.12.002Search in Google Scholar

38. Padlan, E. A., 1994: Anatomy of the antibody molecule. Mol. Immunol., 31, 169—217.10.1016/0161-5890(94)90001-9Open DOISearch in Google Scholar

39. Pardridge, W. M., 2012: Drug transport across the bloodbrain barrier. J. Cereb. Blood Flow Metab., 32, 1959—1972.10.1038/jcbfm.2012.126Search in Google Scholar

40. Porter, R. R., 1973: Structural studies of immunoglobulins. Science, 180, 713—716.10.1126/science.180.4087.713Search in Google Scholar

41. Rennels, M. L., Gregory, T. F., Fujimoto, K., 1983: Innervation of capillaries by local neurons in the cat hypothalamus: A light microscopic study with horseradish peroxidase. J. Cereb. Blood Flow Metab., 3, 535—542.10.1038/jcbfm.1983.82Search in Google Scholar

42. Riechmann, L., Cavanagh, J., McManus, S., 1991: Uniform labelling of a recombinant antibody Fv-fragment with 15N and 13C for heteronuclear NMR spectroscopy. FEBS Lett., 287, 185—188.10.1016/0014-5793(91)80047-7Search in Google Scholar

43. Rissiek, B., Koch-Nolte, F., Magnus, T., 2014: Nanobodies as modulators of inflammation: potential applications for acute brain injury. Front. Cell. Neurosci., 8, 344.10.3389/fncel.2014.00344420452125374510Search in Google Scholar

44. Saunders, N. R., Liddelow, S. A., Dziegielewska, K. M., 2012: Barrier mechanisms in the developing brain. Front. Pharmacol., 3, 46.10.3389/fphar.2012.00046331499022479246Search in Google Scholar

45. Smith, Q. R., Rapoport, S. I., 1986: Cerebrovascular permeability coefficients to sodium, potassium, and chloride. J. Neurochem., 46, 1732—42.10.1111/j.1471-4159.1986.tb08491.x3084708Search in Google Scholar

46. Utsumi, S., Karush, F., 1964: The subunits of purified rabbit antibody. Biochemistry, 3, 1329—1338.10.1021/bi00897a024Open DOISearch in Google Scholar

47. Wang, D., El-Amouri, S. S., Dai, M., Kuan, C. Y., Hui, D. Y., Brady, R. O., et al., 2013: Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood-brain barrier. Proc. Natl. Acad. Sci. USA, 110, 2999—3004.10.1073/pnas.1222742110Search in Google Scholar

48. Wolburg, H., Lippoldt, A., 2002: Tight junctions of the blood-brain barrier: development, composition and regulation. Vascul. Pharmacol., 38, 323—337.10.1016/S1537-1891(02)00200-8Search in Google Scholar

49. Wolburg, H., Noell, S., Mack, A., Wolburg-Buchholz, K., Fallier-Becker, P., 2009: Brain endothelial cells and the gliovascular complex. Cell Tissue Res., 335, 75—96.10.1007/s00441-008-0658-918633647Search in Google Scholar

50. Wolburg, H., Wolburg-Buchholz, K., Engelhardt, B., 2005: Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact. Acta Neuropathol., 109, 181—190.10.1007/s00401-004-0928-x15549331Search in Google Scholar

51. Wu, A. M., Senter, P. D., 2005: Arming antibodies: prospects and challenges for immunoconjugates. Nat. Biotechnol., 23, 1137—1146.10.1038/nbt114116151407Open DOISearch in Google Scholar

52. Xiao, G., Gan, L.-S., 2013: Receptor-mediated endocytosis and brain delivery of therapeutic biologics. Int. J. Cell Biol., 2013, 14.10.1155/2013/703545369309923840214Search in Google Scholar

53. Yokota, T., Milenic, D. E., Whitlow, M., Schlom, J., 1992: Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res., 52, 3402—3408.Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo