Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy
Review Article/Themed Issue: Current Advances in CNS Delivery of Therapeutic Molecules Guest Editors: Jean-Michael Scherrman and Themed Issue: Current Advances in CNS Delivery of Therapeutic Molecules Guest Editors: Jean-Michael Scherrman and Craig K. Svens
First Online: 18 March 2008 Received: 06 November 2007 Accepted: 13 February 2008 DOI:
Cite this article as: Bellavance, M., Blanchette, M. & Fortin, D. AAPS J (2008) 10: 166. doi:10.1208/s12248-008-9018-7 Abstract
The blood–brain barrier (BBB) is a complex functional barrier composed of endothelial cells, pericytes, astrocytic endfeets and neuronal cells. This highly organized complex express a selective permeability for molecules that bear, amongst other parameters, adequate molecular weight and sufficient liposolubility. Unfortunately, very few therapeutic agents currently available do cross the BBB and enters the CNS. As the BBB limitation is more and more acknowledged, many innovative surgical and pharmacological strategies have been developed to circumvent it. This review focuses particularly on the osmotic opening of the BBB, a well-documented approach intended to breach the BBB. Since its inception by Rapoport in 1972, pre-clinical studies have provided important information on the extent of BBB permeation. Thanks to Neuwelt and colleagues, the osmotic opening of the BBB made its way to the clinic. However, many questions remain as to the detailed physiology of the procedure, and its best application to the clinic. Using different tools, amongst which MRI as a real-time
in vivo characterization of the BBB permeability and CNS delivery, we attempt to better define the osmotic BBB permeabilization physiology. These ongoing studies are described, and data related to spatial and temporal distribution of a molecule after osmotic BBB breaching, as well as the window of BBB permeabilization, are discussed. We also summarize recent clinical series highlighting promising results in the application of this procedure to maximize delivery of chemotherapy in the treatment of brain tumor patients. Key words blood–brain barrier, blood–brain barrier disruption, brain tumors, CNS delivery MRI References
D. Fortin. Altering the properties of the blood–brain barrier: disruption and permeabilization.
Prog. Drug Res.
Das sauerstoff-bedürfnis des organismus. Eine Farbenanalytische Studie, Hirschwald, Berlin, 1885.
P. Ehrlich. Ueber die beziehungen von chemischer constitution, vertheilung, und pharmakologischen wirkung.
Collected Studies on Immunity, Wiley, Berlin, 1906, pp. 404–442.
E. Goldmann. Vitalfarbung am zentralnervensystem.
Abhandl Konigl preuss Akad Wiss.
W. M. Pardridge. Blood–brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses.
J. Control Release
(3):345–348 (2007), Oct 8.
L. L. Rubin, and J. M. Staddon. The cell biology of the blood–brain barrier.
Annu. Rev. Neurosci.
H. Davson, and W. H. Oldendorf. Symposium on membrane transport. Transport in the central nervous system.
Proc. R. Soc. Med.
4:326–329 (1967), Apr.
Z. Cohen, G. Bonvento, P. Lacombe, and E. Hamel. Serotonin in the regulation of brain microcirculation.
(4):335–362 (1996), Nov.
Z. Cohen, G. Molinatti, and E. Hamel. Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex.
J. Cereb. Blood Flow Metab.
(8):894–904 (1997), Aug.
J. Fenstermacher, P. Gross, N. Sposito, V. Acuff, S. Pettersen, and K. Gruber. Structural and functional variations in capillary systems within the brain.
Ann. N. Y. Acad. Sci.
T. S. Reese, and M. J. Karnovsky. Fine structural localization of a blood–brain barrier to exogenous peroxidase.
J. Cell Biol.
(1):207–217 (1967), Jul.
H. Wolburg, and A. Lippoldt. Tight junctions of the blood–brain barrier: development, composition and regulation.
(6):323–337 (2002), Jun.
N. J. Abbott, L. Ronnback, and E. Hansson. Astrocyte-endothelial interactions at the blood–brain barrier.
Nat. Rev. Neurosci.
(1):41–53 (2006), Jan.
J. F. Deeken, and W. Loscher. The blood–brain barrier and cancer: transporters, treatment, and Trojan horses.
Clin. Cancer Res.
(6):1663–1674 (2007), Mar 15.
M. W. Smith, and M. Gumbleton. Endocytosis at the blood–brain barrier: from basic understanding to drug delivery strategies.
J. Drug Target.
(4):191–214 (2006), May.
R. A. Kroll, and E. A. Neuwelt. Outwitting the blood–brain barrier for therapeutic purposes: osmotic opening and other means.
(5):1083–1099 (1998), May; discussion 1099–1100.
W. M. Pardridge. The blood–brain barrier: bottleneck in brain drug development.
(1):3–14 (2005), Jan.
V. A. Levin. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability.
J. Med. Chem.
(6):682–684 (1980), Jun.
W. M. Pardridge. Blood–brain barrier delivery.
Drug Discov. Today
(1–2):54–61 (2007), Jan.
E. A. Neuwelt.
Implications of the Blood–Brain Barrier and Its Manipulation. Vol 1 and 2, Plenum, New York, 1989.
E. M. Kemper, W. Boogerd, I. Thuis, J. H. Beijnen, and O. van Tellingen. Modulation of the blood–brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours?
Cancer Treat Rev.
(5):415–423 (2004), Aug.
A. K. Ghose, V. N. Viswanadhan, and J. J. Wendoloski. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases.
J. Comb. Chem.
(1):55–68 (1999), Jan.
C. A. Lipinski. Drug-like properties and the causes of poor solubility and poor permeability.
J. Pharmacol. Toxicol. Methods.
(1):235–249 (2000), Jul–Aug.
R. L. Juliano, and V. Ling. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.
Biochim. Biophys. Acta.
(1):152–162 (1976), Nov 11.
C. Cordon-Cardo, J. P. O'Brien, J. Boccia, D. Casals, J. R. Bertino, and M. R. Melamed. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues.
J. Histochem. Cytochem.
(9):1277–1287 (1990), Sep.
S. I. Rapoport, M. Hori, and I. Klatzo. Testing of a hypothesis for osmotic opening of the blood–brain barrier.
Am. J. Physiol.
(2):323–331 (1972), Aug.
W. M. Pardridge. Targeting neurotherapeutic agents through the blood–brain barrier.
(1):35–40 (2002), Jan.
M. W. B. Bradbury. Appraisal of the role of endothelial cells and glia in barrier breakdown. In A. Suckling, M. Rumsby, and M. Bradbury (eds.),
The Blood–Brain Barrier in Health and Disease, Ellis Horwood, Chichester, 1986, pp. 128–129.
W. M. Pardridge. Advances in cell biology of blood–brain barrier transport.
Semin. Cell Biol.
(6):419–426 (1991), Dec.
W. Selman, W. Lust, and R. RA.
Cerebral blood flow, McGraw-Hill, New York, 1996.
S. I. Rapoport. Effect of concentrated solutions on blood–brain barrier.
Am. J. Physiol.
(1):270–274 (1970), Jul.
M. W. Brightman, M. Hori, S. I. Rapoport, T. S. Reese, and E. Westergaard. Osmotic opening of tight junctions in cerebral endothelium.
J. Comp. Neurol.
(4):317–325 (1973), Dec 15.
K. Dorovini-Zis, P. D. Bowman, A. L. Betz, and G. W. Goldstein. Hyperosmotic arabinose solutions open the tight junctions between brain capillary endothelial cells in tissue culture.
(2):383–386 (1984), Jun 8.
D. Fortin, C. Gendron, M. Boudrias, and M. P. Garant. Enhanced chemotherapy delivery by intraarterial infusion and blood–brain barrier disruption in the treatment of cerebral metastasis.
(4):751–760 (2007), Feb 15.
D. Fortin. [The blood–brain barrier should not be underestimated in neuro-oncology].
Rev. Neurol. (Paris). 160(5 Pt 1):523–532 (2004), May.
D. Fortin, E. A. Neuwelt. Therapeutic manipulation of the blood–brain barrier.
Neurobase-neurosurgery. 1st Ed. Medlink CD-ROM.
D. F. Kraemer, D. Fortin, and E. A. Neuwelt. Chemotherapeutic dose intensification for treatment of malignant brain tumors: recent developments and future directions.
Curr. Neurol. Neurosci. Rep.
(3):216–224 (2002), May.
R. Blasberg, D. Groothius, and P. Molnar. A review of hyperosmotic blood–brain barrier disruption in seven experimental brain tumor models. In B. B. Johansson, C. Owman, and H. Widner (eds.),
Vol Pathophysiology of the Blood–Brain Barrier, Elsevier, Amsterdam, 1990, pp. 197–220.
B. Oztas, and M. Kucuk. Intracarotid hypothermic saline infusion: a new method for reversible blood–brain barrier disruption in anesthetized rats.
(3):203–206 (1995), May 12.
R. A. Kroll, M. A. Pagel, L. L. Muldoon, S. Roman-Goldstein, S. A. Fiamengo, and E. A. Neuwelt. Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: a comparison of osmotic
bradykinin modification of the blood–brain and/or blood–tumor barriers.
(4):879–886 (1998), Oct; discussion 886–879.
E. A. Neuwelt, P. A. Barnett, C. I. McCormick, L. G. Remsen, R. A. Kroll, and G. Sexton. Differential permeability of a human brain tumor xenograft in the nude rat: impact of tumor size and method of administration on optimizing delivery of biologically diverse agents.
Clin. Cancer Res.
(6):1549–1555 (1998), Jun.
D. Fortin, R. Adams, and A. Gallez. A blood–brain barrier disruption model eliminating the hemodynamic effect of ketamine.
Can. J. Neurol. Sci.
(2):248–253 (2004), May.
L. G. Remsen, M. A. Pagel, C. I. McCormick, S. A. Fiamengo, G. Sexton, and E. A. Neuwelt. The influence of anesthetic choice, PaCO2, and other factors on osmotic blood–brain barrier disruption in rats with brain tumor xenografts.
(3):559–567 (1999), Mar.
M. K. Gumerlock, and E. A. Neuwelt. The effects of anesthesia on osmotic blood–brain barrier disruption.
(2):268–277 (1990), Feb.
D. Fortin, C. I. McCormick, L. G. Remsen, R. Nixon, and E. A. Neuwelt. Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood–brain barrier modification to enhance delivery, using propofol for general anesthesia, in a rat model.
(1):199–207 (2000), Jul.
W. C. Cosolo, P. Martinello, W. J. Louis, and N. Christophidis. Blood–brain barrier disruption using mannitol: time course and electron microscopy studies.
Am. J. Physiol.
(2 Pt 2):R443–447 (1989), Feb.
S. Roman-Goldstein, D. A. Clunie, J. Stevens,
. Osmotic blood–brain barrier disruption: CT and radionuclide imaging.
AJNR Am. J. Neuroradiol.
(3):581–590 (1994), Mar.
R. A. Rawson. The binding of T-1824 and structurally related diazo dyes by the plasma proteins.
Am. J. Physiol.
F. B. Freedman, and J. A. Johnson. Equilibrium and kinetic properties of the Evans blue–albumin system.
Am. J. Physiol.
(3):675–681 (1969), Mar.
A. W. Vorbrodt, D. H. Dobrogowska, M. Tarnawski, and A. S. Lossinsky. A quantitative immunocytochemical study of the osmotic opening of the blood–brain barrier to endogenous albumin.
(12):792–800 (1994), Dec.
N. D. Doolittle, M. E. Miner, W. A. Hall,
. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood–brain barrier for the treatment of patients with malignant brain tumors.
(3):637–647 (2000), Feb 1.
D. Fortin, L. D. McAllister, G. Nesbit,
. Unusual cervical spinal cord toxicity associated with intra-arterial carboplatin, intra-arterial or intravenous etoposide phosphate, and intravenous cyclophosphamide in conjunction with osmotic blood brain–barrier disruption in the vertebral artery.
AJNR Am. J. Neuroradiol.
(10):1794–1802 (1999), Nov–Dec.
S. C. Saris, R. G. Blasberg, R. E. Carson,
. Intravascular streaming during carotid artery infusions. Demonstration in humans and reduction using diastole-phased pulsatile administration.
(5):763–772 (1991), May.
S. I. Rapoport. Modulation of blood–brain barrier permeability.
J. Drug Target
L. D. McAllister, N. D. Doolittle, P. E. Guastadisegni,
. Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma.
(1):51–60 (2000), Jan; discussion 60-51.
D. F. Kraemer, D. Fortin, N. D. Doolittle, and E. A. Neuwelt. Association of total dose intensity of chemotherapy in primary central nervous system lymphoma (human non-acquired immunodeficiency syndrome) and survival.
(5):1033–1040 (2001), May discussion 1040–1031.
P. C. Williams, W. D. Henner, S. Roman-Goldstein,
. Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood–brain tumor barrier in the treatment of intracranial neoplasms.
(1):17–27 (1995), Jul; discussion 27–18.
D. Fortin, A. Desjardins, A. Benko, T. Niyonsega, and M. Boudrias. Enhanced chemotherapy delivery by intraarterial infusion and blood–brain barrier disruption in malignant brain tumors: the Sherbrooke experience.
(12):2606–2615 (2005), Jun 15.
M. Huncharek, and J. Muscat. Treatment of recurrent high grade astrocytoma; results of a systematic review of 1,415 patients.
(2B):1303–1311 (1998), Mar–Apr.
M. Huncharek, J. Muscat, and J. F. Geschwind. Multi-drug
single agent chemotherapy for high grade astrocytoma; results of a meta-analysis.
(6B):4693–4697 (1998), Nov–Dec.
L. A. Stewart. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials.
(9311):1011–1018 (2002), Mar 23.
R. Stupp, P. Y. Dietrich, S. Ostermann Kraljevic,
. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide.
J. Clin. Oncol.
(5):1375–1382 (2002), Mar 1.
W. A. Hall, N. D. Doolittle, M. Daman,
. Osmotic blood–brain barrier disruption chemotherapy for diffuse pontine gliomas.
(3):279–284 (2006), May.
J. L. Finlay, and S. Zacharoulis. The treatment of high grade gliomas and diffuse intrinsic pontine tumors of childhood and adolescence: a historical—and futuristic—perspective.
(3):253–266 (2005), Dec.
PubMed CrossRef Copyright information
© American Association of Pharmaceutical Scientists 2008