Skip to main content
SpringerLink
Log in

Drug Delivery to the CNS in the Treatment of Brain Tumors: The Sherbrooke Experience

  • Chapter
  • First Online:
Drug Delivery to the Brain

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 33))

  • 1343 Accesses

Abstract

Drug delivery to the central nervous system (CNS) remains a challenge in neuro-oncology. Despite decades of research in this field, no consensus has emerged as to the best approach to tackle this physiological limitation. Moreover, the relevance of doing so is still sometimes questioned in the community. In this paper, we present our experience with CNS delivery strategies that have been developed in the laboratory and have made their way to the clinic in a continuum of translational research. Using the intra-arterial (IA) route as an avenue to deliver chemotherapeutics in the treatment of brain tumors, complemented by an osmotic breach of the blood-brain barrier (BBB) in specific situations, we have developed over the years a comprehensive research effort on this specialized topic. Looking at preclinical work supporting the rationale for this approach and presenting results discussing the safety of the strategy, as well as results obtained in the treatment of malignant gliomas and primary CNS lymphomas, this paper intend to comprehensively summarize our work in this field.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7(1):41–53

    Article  CAS  PubMed  Google Scholar 

  • Angelov L, Doolittle ND, Kraemer DF, Siegal T, Barnett GH, Peereboom DM et al (2009) Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol 27:3503–3509. https://doi.org/10.1200/JCO.2008.19.3789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bairey O, Siegal T (2018) The possible role of maintenance treatment for primary central nervous system lymphoma. Blood Rev 32:378–386. https://doi.org/10.1016/j.blre.2018.03.003

    Article  PubMed  Google Scholar 

  • Bellavance MA, Blanchette M, Fortin D (2008) Recent advances in blood–brain barrier disruption as a CNS delivery strategy. AAPS J 10(1):166–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blanchard J, Mathieu D, Patenaude Y, Fortin D (2006) MR-pathological comparison in F98-Fischer glioma model using a human gantry. Can J Neurol Sci 33:86–91

    Article  PubMed  Google Scholar 

  • Blanchette M, Fortin D (2011) Blood-brain barrier disruption in the treatment of brain tumors. Methods Mol Biol 686:447–463

    Article  CAS  PubMed  Google Scholar 

  • Blanchette M, Pellerin M, Tremblay L, Lepage M, Fortin D (2009) Real-time monitoring of gadolinium Diethylenetriamine penta-acetic acid during osmotic blood-brain barrier disruption using magnetic resonance imaging in normal Wistar rats. Neurosurgery 65: 344–350. discussion 350–51. https://doi.org/10.1227/01.NEU.0000349762.17256.9E

  • Blanchette M, Tremblay L, Lepage M, Fortin D (2014) Impact of drug size on brain tumor and brain parenchyma delivery after a blood-brain barrier disruption. J Cereb Blood Flow Metab 34:820–826. https://doi.org/10.1038/jcbfm.2014.14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boudaiffa B, Cloutier P, Hunting D, Huels MA, Sanche L (2000) Resonant formation of DNA strand breaks by low energy (3-20 eV) electrons. Science 287:1658–1660

    Article  CAS  PubMed  Google Scholar 

  • Boyle FM, Eller SL, Grossman SA (2004) Penetration of intra-arterially administered vincristine in experimental brain tumor. Neuro-oncology 6(4):300–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradbury MWB (1986) Appraisal of the role of endothelial cells and glia in barrier breakdown. In: Suckling AJ, Rumsby MG, Bradbury MWB (eds) The blood-brain barrier in health and disease. Ellis Horwood, Chichester, pp 128–129

    Google Scholar 

  • Brightman MW, Hori M, Rapoport SI, Reese TS, Westergaard E (1973) Osmotic opening of tight junctions in cerebral endothelium. J Comp Neurol 152:317–325

    Article  CAS  PubMed  Google Scholar 

  • Brodie BB, Kurz H, Schanker LS (1960) The importance of dissociation constant and lipid-solubility in influencing the passage of drugs into the cerebrospinal fluid. J Pharmacol 130:20–25

    CAS  Google Scholar 

  • Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES (2011) The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117:5019–5032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charest G, Paquette B, Fortin D, Mathieu D, Sanche L (2010) Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation. J Neurooncol 97:187–193

    Article  CAS  PubMed  Google Scholar 

  • Charest G, Sanche L, Fortin D, Mathieu D, Paquette B (2012) Glioblastoma treatment: bypassing the toxicity of platinum compounds by using liposomal formulation and increasing treatment efficiency with concomitant radiotherapy. Int J Radiat Oncol Biol Phys. https://doi.org/10.1016/j.ijrobp.2011.10.054

  • Charest G, Sanche L, Fortin D, Mathieu D, Paquette B (2013) Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain. J Neurooncol 115(3):365–373. https://doi.org/10.1007/s11060-013-1238-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chicoine MR, Silbergeld DL (1995) Assessment of brain tumor cell motility in vivo and in vitro. J Neurosurg 82:615–622. https://doi.org/10.3171/jns.1995.82.4.0615

    Article  CAS  PubMed  Google Scholar 

  • Choy H (2003) Chemoradiation in cancer therapy. Humana Press, Totowa

    Google Scholar 

  • Cohen Z, Bonvento G, Lacombe P, Hamel E (1996) Serotonin in the regulation of brain microcirculation. Prog Neurobiol 50(4):335–362

    Article  CAS  PubMed  Google Scholar 

  • Cohen Z, Molinatti G, Hamel E (Aug 1997) Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex. J Cereb Blood Flow Metab 17(8):894–904

    Article  CAS  PubMed  Google Scholar 

  • Da Broi M, Jahr G, Beiske K, Holte H, Meling TR (2018) Efficacy of the nordic and the MSKCC chemotherapy protocols on the overall and progression-free survival in intracranial PCNSL. Blood Cells Mol Dis 73:25–32. https://doi.org/10.1016/j.bcmd.2018.08.005

    Article  PubMed  Google Scholar 

  • Darlix A, Zouaoui S, Rigau V, Bessaoud F, Figarella-Branger D, Mathieu-Daude H et al (2017) Epidemiology for primary brain tumors: a nationwide population-based study. J Neuro-Oncol 131:525–546

    Article  CAS  Google Scholar 

  • Davson H, Oldendorf WH (1967) Symposium on membrane transport. Transport in the central nervous system. Proc R Soc Med 60(4):326–329

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Boer AG, Gaillard PJ (2007) Drug targeting to the brain. Annu Rev Pharmacol Toxicol 47:323–355

    Article  PubMed  CAS  Google Scholar 

  • de Boer AG, van der Sandt IC, Gaillard PJ (2003) The role of drug transporters at the blood-brain barrier. Annu Rev Pharmacol Toxicol 43:629–656

    Article  PubMed  CAS  Google Scholar 

  • Deeken JF, Loscher W (2007) The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13(6):1663–1674

    Article  CAS  PubMed  Google Scholar 

  • Doolittle ND, Miner ME, Hall WA et al (2000) Safety and efficacy of a multicenter study using intra-arterial chemotherapy in conjunction with osmotic opening of the blood–brain barrier for the treatment of patients with malignant brain tumors. Cancer 88(3):637–647

    Article  CAS  PubMed  Google Scholar 

  • Doolittle ND, Dosa E, Fu R, Muldoon LL, Maron LM, Lubow MA et al (2013) Preservation of cognitive function in primary CNS lymphoma survivors a median of 12 years after enhanced chemotherapy delivery. J Clin Oncol 31:4026–4027. https://doi.org/10.1200/JCO.2013.52.7747

    Article  PubMed  PubMed Central  Google Scholar 

  • Drapeau A, Fortin D (2015) Chemotherapy delivery strategies to the central nervous system: neither optional nor superfluous. Curr Cancer Drug Targets 15:752–768

    Article  CAS  PubMed  Google Scholar 

  • Drapeau A, Poirier M-B, Madugundu G-S, Wagner RJ, Fortin D (2017) Intra-arterial Temozolomide, osmotic blood-brain barrier disruption and radiotherapy in a rat F98-glioma model. Clin Cancer Drugs 4:1–11. https://doi.org/10.2174/2212697X04666170727152212

    Article  Google Scholar 

  • Eichler AF et al (2011) The biology of brain metastases-translation to new theapies. Nature reviews. Clinical oncology 8:344–356

    Google Scholar 

  • Fabian D, Eibl MPGP, Alnahhas I, Sebastian N, Giglio P, Puduvalli V, Gonzalez J, Palmer JD (2019) Treatment of glioblastoma (GBM) with the addition of Tumor-Treating Fields (TTF): a review. Cancers (Basel) 11:174. https://doi.org/10.3390/cancers11020174

    Article  CAS  Google Scholar 

  • Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K (1988) Structural and functional variations in capillary systems within the brain. Ann NY Acad Sci 529:21–30

    Article  CAS  PubMed  Google Scholar 

  • Fortin D (2004) La barrière hémato-encéphalique : un facteur clé en neuro-oncologie. Rev Neurol 160(5):523–532

    Article  CAS  PubMed  Google Scholar 

  • Fortin D (2012) The blood–brain barrier: its influence in the treatment of brain tumors metastases. Curr Cancer Drug Targets 12(3):247–259

    Article  CAS  PubMed  Google Scholar 

  • Fortin D (2016) Safety of intra-arterial chemotherapy in the treatment of brain tumors. Society for neuro-oncology, presentation

    Google Scholar 

  • Fortin D et al (2014) Intra-arterial carboplatin as a salvage strategy in the treatment of recurrent glioblastoma multiforme. J Neurooncol 119(2):397–403

    Article  CAS  PubMed  Google Scholar 

  • Guo Z, Zhu J, Zhao L, Luo Q, Jin X (2010) Expression and clinical significance of multidrug resistance proteins in brain tumors. J Exp Clin Cancer Res 29:122

    Google Scholar 

  • Iorio-Morin C, Gahide G, Morin C, Vanderweyen D, Roy MA, St-Pierre I, Massicotte-Tisluck K, Fortin D (2021) Management of primary central nervous system lymphoma using intra-arterial chemotherapy with osmotic blood-brain barrier disruption: retrospective analysis of the Sherbrooke cohort. Font Oncol 10:543648

    Article  Google Scholar 

  • Kroll RA, Neuwelt EA (1998) Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 42(5):1083–1099 discussion 1099–1100

    Google Scholar 

  • Lee G, Dallas S, Hong M, Bendayan R (2001) Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev 53:569–596

    Google Scholar 

  • Loscher W, Potschka H (2005) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 1:22–76

    Article  CAS  Google Scholar 

  • Louis DN, Perry A, Reifenberger G, Deimling A, Figarella-Branger D, Cavenee WK et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-

    Article  PubMed  Google Scholar 

  • Mamon HJ, Tepper JE (2014) Combination chemoradiation therapy: the whole is more than the sum of the parts. J Clin Oncol 32:367

    Article  PubMed  Google Scholar 

  • Mathieu D, Lecomte R, Tsanaclis AM, Larouche A, Fortin D (2007) Standardization and detailed characterization of the syngeneic Fischer/F98 glioma model. Can J Neurol Sci 34:296–306

    Article  PubMed  Google Scholar 

  • Muldoon LL, Nilaver G, Kroll RA, Pagel MA, Breakefield XO, Chiocca EA, Davidson BL, Weissleder R, Neuwelt EA (1995) Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus and iron oxide particles to normal rat brain. Am J Pathol 147:1840–1851

    CAS  PubMed  PubMed Central  Google Scholar 

  • Newton HB, Slivka MA, Volpi C et al (2003) Intra-arterial carboplatin and intravenous etoposide for the treatment of metastatic brain tumors. J Neuro-Oncol 61:35–44

    Article  Google Scholar 

  • Newton HB, Figg GM, Slone HW, Bourekas E (2006) Incidence of infusion plan alterations after angiography in patients undergoing intra-arterial chemotherapy for brain tumors. J Neuro-Oncol 78:157–160

    Article  Google Scholar 

  • Pardridge WM (2007) Blood–brain barrier delivery. Drug Discov Today 12(1–2):54–61

    Article  CAS  PubMed  Google Scholar 

  • Pitz MW, Desai A, Grossman SA, Blakeley JO (2011) Tissue concentration of systemically administered antineoplastic agents in human brain tumors. J Neurooncol. https://doi.org/10.1007/s11060-011-0564-y

  • Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34(1):207–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reichel A (2009) Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept. Chem Biodivers 6(11):2030–2049. https://doi.org/10.1002/cbdv.200900103

    Article  CAS  PubMed  Google Scholar 

  • Rezaee M, Hunting DJ, Sanche L (2013) New Insights into the mechanism underlying the synergistic action of ionizing radiation with platinum chemotherapeutic drugs: the role of low-energy electrons. Int J Radiat Oncol Biol Phys 87:847–853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sato S, Kawase T, Harada S, Takayama H, Suga S (1998) Effect of hyperosmotic solutions on human brain tumor vasculature. Acta Neurochir (Wien) 140(11):1135–1141. discussion 1141–1142

    Google Scholar 

  • Shen F, Chu S, Bence AK, Bailey B, Xue X, Erickson PA, Montrose MH, Beck WT, Erickson LC (2008) Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells. J Pharmacol Exp Ther 324(1):95–102

    Article  CAS  PubMed  Google Scholar 

  • Silbergeld DL, Chicoine MR (1997) Isolation and characterization of human malignant glioma cells from histologically normal brain. J Neurosurg 86

    Google Scholar 

  • Smith MW, Gumbleton M (2006) Endocytosis at the blood-brain barrier: from basic understanding to drug delivery strategies. J Drug Target. 14(4):191–214

    Article  CAS  PubMed  Google Scholar 

  • Stern L, Gautier R (1921) Rapports entre le liquide céphalo-rachidien et la circulation sanquine. Arch Int Physiol 17:138–192

    CAS  Google Scholar 

  • Stupp R, Mason W, van de Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  • Tippayamontria T, Kotb R, Paquette B, Sanche L (2013) Efficacy of Cisplatin and lipoplatinâ„¢ in combined treatment with radiation of a colorectal tumor in nude mouse. Anticancer Res 33:3005–3014

    Google Scholar 

  • Tippayamontria T, Kotb R, Sanche L, Paquette B (2014) New therapeutic possibilities of combined treatment of radiotherapy with oxaliplatin and its liposomal formulations Lipoxalâ„¢ in rectal cancer using nude mouse xenograft. Anticancer Res 34(10):5303–5312

    Google Scholar 

  • Tonn JC, Roosen K, Schachenmayr W (1991) Brain Necroses after Intraarterial chemotherapy and irradiation of malignant gliomas–a complication of both ACNU and BCNU? J Neuro-Oncol 11:241–242

    Article  CAS  Google Scholar 

  • Tosoni A, Ermani M, Brandes AA (2004) The pathogenesis and treatment of brain metastases: a comprehensive review. Crit Rev Oncol Hematol 52:199–215

    Article  PubMed  Google Scholar 

  • Van Den Bent MJ (2003) The role of chemotherapy in brain metastases. Eur J Cancer 39(15):2114–2120

    Article  PubMed  CAS  Google Scholar 

  • Westphal M, Maire CL, Lamszus K (2017) EGFR as a target for glioblastoma treatment: an unfulfilled promise. CNS Drugs 31:723–735. https://doi.org/10.1007/s40263-017-0456-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolburg H, Lippoldt A (2002) Tight junctions of the blood-brain barrier: development, composition and regulation. Vascul Pharmacol 38(6):323–337

    Article  CAS  PubMed  Google Scholar 

  • Zheng Y, Hunting DJ, Ayotte P, Sanche L (2008) Role of secondary low-energy electrons in the concomitant chemoradiation therapy of cancer. Phys Rev Lett 100:198101

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Neuro-oncology, Sherbrooke University, Sherbrooke, QC, Canada

    David Fortin

Authors
  1. David Fortin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Fortin .

Editor information

Editors and Affiliations

  1. Research Division of Systems Pharmacology and Pharmacy, Leiden University, Leiden, The Netherlands

    Elizabeth C.M. de Lange

  2. Department of Pharmacy, Uppsala University, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

  3. Biology Discovery, Denali Therapeutics, South San Francisco, CA, USA

    Robert G. Thorne

Rights and permissions

Reprints and permissions

Copyright information

© 2022 American Association of Pharmaceutical Scientists

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Fortin, D. (2022). Drug Delivery to the CNS in the Treatment of Brain Tumors: The Sherbrooke Experience. In: de Lange, E.C., Hammarlund-Udenaes, M., Thorne, R.G. (eds) Drug Delivery to the Brain. AAPS Advances in the Pharmaceutical Sciences Series, vol 33. Springer, Cham. https://doi.org/10.1007/978-3-030-88773-5_18

Download citation

Publish with us

Policies and ethics

Search

Navigation