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Journal of Neuro-Oncology

, Volume 95, Issue 3, pp 317–329 | Cite as

Targeted delivery of bleomycin to the brain using photo-chemical internalization of Clostridium perfringens epsilon prototoxin

  • Henry Hirschberg
  • Michelle J. Zhang
  • H. Michael Gach
  • Francisco A. Uzal
  • Qian Peng
  • Chung-Ho Sun
  • David Chighvinadze
  • Steen J. Madsen
Laboratory Investigation - Human/animal tissue

Abstract

Cells infiltrating into normal brain from malignant brain tumors are protected by the blood brain barrier (BBB) which prevents the delivery and limits the effects of anti-tumor agents. We have evaluated the ability of photochemical internalization (PCI) to limit the effects of an agent known to broadly open the BBB to a target region of the brain. The PCI-based relocation and activation of macromolecules into the cell cytosol has the advantage of minimal side effects since the effect is localized to the area exposed to light, allowing the access of chemotherapeutic agents only to these regions. Non tumor bearing inbred Fisher rats were treated with photosesitizer, and a nontoxic intraperitoneal dose of Clostridium perfringens epsilon prototoxin (ETXp) followed by light exposure. Post-contrast T1 MRI scans were used to monitor the degree BBB disruption. F98 tumor cells were implanted into the brains of other animals that were subsequently treated 24 h later with ETXp-PCI BBB opening followed by the i.p. administration of bleomycin (BLM). PCI delivery of ETXp at low fluence levels demonstrated significant MRI enhancement. No effect on the BBB was observed if photosesitizer and light was given in the absence ETXp. The survival of animals implanted with F98 tumor cells was significantly extended following ETXp-PCI BBB opening and BLM therapy compared to controls. PCI delivered ETXp was effective in opening the BBB in a limited region of the brain. ETXp-PCI mediated BBB opening clearly increased the efficacy of BLM therapy.

Keywords

Blood brain barrier Brain tumor Bleomycin Photochemical internalization PDT Clostridium perfringens prototoxin Targeted opening 

Notes

Acknowledgments

The authors are grateful for the support of the Nevada Cancer Institute which sponsored this research through the NVCI Collaborative Grant Program. Henry Hirschberg is grateful for the support of the Norwegian Radium Hospital Research Foundation. Portions of this work were made possible through access to the Laser Microbeam and Medical Program (LAMMP) and the Chao Cancer Center Optical Biology Shared Resource at the University of California, Irvine.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

References

  1. 1.
    Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:1405–1409CrossRefPubMedGoogle Scholar
  2. 2.
    Huber J, Egleton R, Davis T (2001) Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci 24:719–725. doi: 10.1016/S0166-2236(00)02004-X CrossRefPubMedGoogle Scholar
  3. 3.
    Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13. doi: 10.1016/j.nbd.2003.12.016 CrossRefPubMedGoogle Scholar
  4. 4.
    Abbott N, Romero I (1996) Transporting therapeutics across the blood-brain barrier. Mol Med Today 2:106–113. doi: 10.1016/1357-4310(96)88720-X CrossRefPubMedGoogle Scholar
  5. 5.
    Kemper E, Boogerd W, Thuis I, Beijnen J, Tellingen O (2004) Modulation of the blood–brain barrier in oncology: therapeutic opportunities for the treatment of brain tumors. Cancer Treat Rev 30:415–423. doi: 10.1016/j.ctrv.2004.04.001 CrossRefPubMedGoogle Scholar
  6. 6.
    Abbott N (2005) Physiology of the blood-brain barrier and its consequences for drug transport to the brain. Int Congr Ser 1277:3–18. doi: 10.1016/j.ics.2005.02.008 CrossRefGoogle Scholar
  7. 7.
    Pardridge W (2005) The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2:3–14. doi: 10.1602/neurorx.2.1.3 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Jolliet-Riant P, Tillementi JP (1999) Drug transfer across the blood–brain barrier and improvement of brain delivery. Fundam Clin Pharmacol 13:16–26CrossRefPubMedGoogle Scholar
  9. 9.
    Doolittle ND, Miner ME, Hall WA, Siegal T, Jerome E, Osztie E, McAllister LD, Bubalo JS, Kraemer DF, Fortin D, Nixon R, Muldoon LL, Neuwelt EA (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. doi: 10.1002/(SICI)1097-0142(20000201)88:3<637::AID-CNCR22>3.0.CO;2-Y CrossRefPubMedGoogle Scholar
  10. 10.
    Rand RW, Kreitman RJ, Patronas N, Varricchio F, Pastan I, Puri RK (2000) Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma. Clin Cancer Res 6(6):2157–2165PubMedGoogle Scholar
  11. 11.
    Sampson JH, Akabani G, Archer GE et al (2003) Progress report of a phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol 65(1):27–35. doi: 10.1023/A:1026290315809 CrossRefPubMedGoogle Scholar
  12. 12.
    Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91:2076–2080. doi: 10.1073/pnas.91.6.2076 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lieberman DM, Laske DW, Morrison PF, Bankiewicz KS, Oldfield EH (1995) Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:1021–1029CrossRefPubMedGoogle Scholar
  14. 14.
    Lidar Z, Mardor Y, Jonas T, Pfeffer R, Faibel M, Hadani M, Ram Z (2004) Convection-enhanced delivery of paclitaxel for the treatment of recurrent glioblastoma. A phase I/II clinical study. J Neurosurg 100:472–479CrossRefPubMedGoogle Scholar
  15. 15.
    Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black KL, Sisti M, Brem S, Mohr G, Muller P, Morawetz R, Schold SC, Polymer-Brain Tumor Treatment Group (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345(8956):1008–1012. doi: 10.1016/S0140-6736(95)90755-6 CrossRefPubMedGoogle Scholar
  16. 16.
    Lawson HC, Sampath P, Bohan E, Park MC, Hussain N, Olivi A, Weingart J, Kleinberg L, Brem H (2007) Interstitial chemotherapy for malignant gliomas: the Johns Hopkins experience. J Neurooncol 83(1):61–70. doi: 10.1007/s11060-006-9303-1 CrossRefPubMedGoogle Scholar
  17. 17.
    Choi JJ, Pernot M, Small SA, Konofagou EE (2007) Noninvasive, transcranial and localized opening of the blood-brain barrier using focused ultrasound in mice. Ultrasound Med Biol 33(1):95–104. doi: 10.1016/j.ultrasmedbio.2006.07.018 CrossRefPubMedGoogle Scholar
  18. 18.
    Treat LH, McDannold N, Vykhodtseva N, Zhang Y, Tam K, Hynynen K (2007) Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer 121:901–907. doi: 10.1002/ijc.22732 CrossRefPubMedGoogle Scholar
  19. 19.
    Worthington R, Mulders M (1975) The effect of Clostridium perfringens epsilon toxin on the blood brain barrier of mice. Onderstepoort J Vet Res 42:25–28PubMedGoogle Scholar
  20. 20.
    Nagahama M, Sakurai J (1991) Distribution of labeled Clostridium perfringens epsilon toxin in mice. Toxicon 29:211–217. doi: 10.1016/0041-0101(91)90105-Z CrossRefPubMedGoogle Scholar
  21. 21.
    Dorca-Arévalo J, Soler-Jover A, Gibert M, Popoff M, Martín-Satué M, Blasi J (2008) Binding of epsilon-toxin from Clostridium perfringens in the nervous system. Vet Microbiol 131:14–25. doi: 10.1016/j.vetmic.2008.02.015 CrossRefPubMedGoogle Scholar
  22. 22.
    Zhu C, Ghabriel M, Blumbergs P, Reilly P, Manavis J, Youssef J, Hatami S, Finnie J (2001) Clostridium perfringens prototoxin-induced alteration of endothelial barrier antigen (EBA) immunoreactivity at the blood–brain barrier (BBB). Exp Neurol 169:72–82. doi: 10.1006/exnr.2001.7652 CrossRefPubMedGoogle Scholar
  23. 23.
    Berg K, Selbo PK, Prasmickaite L, Tjelle TE, Sandvig K, Moan J, Gaudernack G, Fodstad O, Kjølsrud S, Anholt H, Rodal GH, Rodal SK, Høgset A (1999) Photochemical internalization: a novel technology for delivery of macromolecules into cytosol. Cancer Res 59:1180–1183PubMedGoogle Scholar
  24. 24.
    Dietze A, Peng Q, Selbo PK, Kaalhus O, Muller C, Bown S, Berg K (2005) Enhanced photodynamic destruction of a transplantable fibrosarcoma using photochemical internalisation of gelonin. Br J Cancer 92:2004–2009. doi: 10.1038/sj.bjc.6602600 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Selbo PK, Kaalhus O, Sivam G, Berg K (2001) 5-Aminolevulinic acid-based photochemical internalization of the immunotoxin MOC31-gelonin generates synergistic cytotoxic effects in vitro. Photochem Photobiol 74(2):303–310. doi: 10.1562/0031-8655(2001)074<0303:AABPIO>2.0.CO;2 CrossRefPubMedGoogle Scholar
  26. 26.
    Selbo PK, Sivam G, Fodstad Ø, Sandvig K, Berg K (2000) Photochemical internalisation increases the cytotoxic effect of the immunotoxin MOC31-gelonin. Int J Cancer 87:853–859. doi: 10.1002/1097-0215(20000915)87:6<853::AID-IJC15>3.0.CO;2-0 CrossRefPubMedGoogle Scholar
  27. 27.
    Prasmickaite L, Høgset A, Selbo P, Engesæter B, Hellum M, Berg K (2002) Photochemical disruption of endocytic vesicles before delivery of drugs: a new strategy for cancer therapy. Br J Cancer 86:652–657. doi: 10.1038/sj.bjc.6600138 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hirschberg H, Uzal FA, Chighvinadze D, Zhang MJ, Peng Q, Madsen SJ (2008) Disruption of the blood-brain barrier following ALA-mediated photodynamic therapy. Lasers Surg Med 40(8):535–542CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Barth RF (1998) Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol 36:91–102. doi: 10.1023/A:1005805203044 CrossRefPubMedGoogle Scholar
  30. 30.
    Hirschberg H, Sun CH, Krasieva T, Madsen SJ (2006) Effects of ALA-mediated photodynamic therapy on the invasiveness of human glioma cells. Lasers Surg Med 38(10):939–945CrossRefPubMedGoogle Scholar
  31. 31.
    Michl P, Buchholz M, Rolke M et al (2001) Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology 121:678–684. doi: 10.1053/gast.2001.27124 CrossRefPubMedGoogle Scholar
  32. 32.
    Kominsky SL, Vali M, Korz D, Gabig TG, Weitzman SA, Argani P, Sukumar S (2004) Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am J Pathol 164(5):1627–1633CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kominsky SL, Tyler B, Sosnowski J, Brady K, Doucet M, Nell D, Smedley JG 3rd, McClane B, Brem H, Sukumar S (2007) Clostridium perfringens enterotoxin as a novel-targeted therapeutic for brain metastasis. Cancer Res 67(17):7977–7982CrossRefPubMedGoogle Scholar
  34. 34.
    Buxton D (1976) Use of horseradish peroxidase to study the antagonism of Clostridium welchii (Cl. perfringens) type D epsilon toxin in mice by the formalinized epsilon prototoxin. J Comp Pathol 86:67–72. doi: 10.1016/0021-9975(76)90029-3 CrossRefPubMedGoogle Scholar
  35. 35.
    Fingar VH (1996) Vascular effects of photodynamic therapy. J Clin Laser Med Surg 14:323–328PubMedGoogle Scholar
  36. 36.
    Snyder JW, William R, Greco WR, Bellnier DA, Vaughan L, Henderson BW (2003) Photodynamic therapy: a means to enhanced drug delivery to tumors. Cancer Res 63:8126–8131PubMedGoogle Scholar
  37. 37.
    Barth RF, Yang W, Coderre JA (2003) Rat brain tumor models to assess the efficacy of boron neutron capture therapy: a critical evaluation. J Neurooncol 62(1–2):61–74PubMedGoogle Scholar
  38. 38.
    Giese A, Bjerkvig R, Berens ME, Westphal M (2003) Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 21(8):1624–1636. doi: 10.1200/JCO.2003.05.063 CrossRefPubMedGoogle Scholar
  39. 39.
    Madsen SJ, Sun C-H, Tromberg BJ, Hirschberg H (2001) Development of a novel balloon applicator for optimizing light delivery in photodynamic therapy. Lasers Surg Med 29:406–412. doi: 10.1002/lsm.10005 CrossRefPubMedGoogle Scholar
  40. 40.
    Inamura T, Nomura T, Bartus RT et al (1994) Intracarotid infusion of RMP-7, a bradykinin analog: a method for selective drug delivery to brain tumors. J Neurosurg 81:752–758CrossRefPubMedGoogle Scholar
  41. 41.
    Matsukado K, Inamura T, Nakano S et al (1996) Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7. Neurosurgery 39:125–133. doi: 10.1097/00006123-199607000-00025 CrossRefPubMedGoogle Scholar
  42. 42.
    Matsukado K, Sugita M, Black K (1998) Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas. Brain Res 792:10–15. doi: 10.1016/S0006-8993(97)01502-3 CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2009

Authors and Affiliations

  • Henry Hirschberg
    • 1
    • 2
  • Michelle J. Zhang
    • 2
  • H. Michael Gach
    • 3
  • Francisco A. Uzal
    • 4
  • Qian Peng
    • 5
  • Chung-Ho Sun
    • 1
  • David Chighvinadze
    • 2
  • Steen J. Madsen
    • 2
  1. 1.Beckman Laser InstituteUniversity of CaliforniaIrvineUSA
  2. 2.Department of Health Physics and Diagnostic SciencesUniversity of NevadaLas VegasUSA
  3. 3.Nevada Cancer InstituteLas VegasUSA
  4. 4.School of Veterinary MedicineUniversity of California, DavisSan BernardinoUSA
  5. 5.Department of PathologyThe Norwegian Radium HospitalOsloNorway

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