Advertisement

Journal of Neuro-Oncology

, Volume 95, Issue 2, pp 185–197 | Cite as

Non-PEGylated liposomes for convection-enhanced delivery of topotecan and gadodiamide in malignant glioma: initial experience

  • Amy Y. Grahn
  • Krystof S. Bankiewicz
  • Millicent Dugich-Djordjevic
  • John R. Bringas
  • Piotr Hadaczek
  • Greg A. Johnson
  • Simon Eastman
  • Matthias Luz
Laboratory Investigation - Human/animal Tissue

Abstract

Convection-enhanced delivery (CED) of highly stable PEGylated liposomes encapsulating chemotherapeutic drugs has previously been effective against malignant glioma xenografts. We have developed a novel, convectable non-PEGylated liposomal formulation that can be used to encapsulate both the topoisomerase I inhibitor topotecan (topoCED™) and paramagnetic gadodiamide (gadoCED™), providing an ideal basis for real-time monitoring of drug distribution. Tissue retention of topoCED following single CED administration was significantly improved relative to free topotecan. At a dose of 10 μg (0.5 mg/ml), topoCED had a half-life in brain of approximately 1 day and increased the area under the concentration–time curve (AUC) by 28-fold over free topotecan (153.8 vs. 5.5 μg day/g). The combination of topoCED and gadoCED was found to co-convect well in both naïve rat brain and malignant glioma xenografts (correlation coefficients 0.97–0.99). In a U87MG cell assay, the 50% inhibitory concentration (IC50) of topoCED was approximately 0.8 μM at 48 and 72 h; its concentration–time curves were similar to free topotecan and unaffected by gadoCED. In a U87MG intracranial rat xenograft model, a two-dose CED regimen of topoCED co-infused with gadoCED greatly increased median overall survival at dose levels of 0.5 mg/ml (29.5 days) and 1.0 mg/ml (33.0 days) vs. control (20.0 days; P < 0.0001 for both comparisons). TopoCED at higher concentrations (1.6 mg/ml) co-infused with gadoCED showed no evidence of histopathological changes attributable to either agent. The positive results of tissue pharmacokinetics, co-convection, cytotoxicity, efficacy, and lack of toxicity of topoCED in a clinically meaningful dose range, combined with an ideal matched-liposome paramagnetic agent, gadoCED, implicates further clinical applications of this therapy in the treatment of malignant glioma.

Keywords

Brain tumor Convection-enhanced delivery Topotecan Gadodiamide Liposome 

Notes

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.
    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi: 10.1056/NEJMoa043330 CrossRefPubMedGoogle Scholar
  2. 2.
    Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578CrossRefPubMedGoogle Scholar
  3. 3.
    Rapisarda A, Zalek J, Hollingshead M et al (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1α protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 64:6845–6848. doi: 10.1158/0008-5472.CAN-04-2116 CrossRefPubMedGoogle Scholar
  4. 4.
    Marchesini R, Colombo A, Caserini C et al (1996) Interaction of ionizing radiation with topotecan in two human tumor cell lines. Int J Cancer 66:342–346. doi: 10.1002/(SICI)1097-0215(19960503)66:3<342::AID-IJC13>3.0.CO;2-D CrossRefPubMedGoogle Scholar
  5. 5.
    Schmidt F, Rieger J, Wischhusen J, Naumann U, Weller M (2001) Glioma cell sensitivity to topotecan: the role of p53 and topotecan-induced DNA damage. Eur J Pharmacol 412:21–25. doi: 10.1016/S0014-2999(00)00923-7 CrossRefPubMedGoogle Scholar
  6. 6.
    Mainwaring MG, Gomez SP, Marsh RD, Chen S (2001) Sequential temozolomide followed by topotecan in the treatment of glioblastoma multiforme. Proc Am Soc Clin Oncol 20:245 (abstract)Google Scholar
  7. 7.
    Fisher BJ, Scott C, Macdonald DR, Coughlin C, Curran WJ (2001) Phase I study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group Trial 9507. J Clin Oncol 19:1111–1117CrossRefPubMedGoogle Scholar
  8. 8.
    Fisher B, Won M, MacDonald D, Johnson DW, Roa W (2002) Phase II study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group 9513. Int J Radiat Oncol Biol Phys 53:980–986. doi: 10.1016/S0360-3016(02)02817-1 CrossRefPubMedGoogle Scholar
  9. 9.
    Grabenbauer GG, Anders K, Fietkau RJ et al (2002) Prolonged infusional topotecan and accelerated hyperfractionated 3d-conformal radiation in patients with newly diagnosed glioblastoma-a phase I study. J Neurooncol 60:269–275. doi: 10.1023/A:1021100413142 CrossRefPubMedGoogle Scholar
  10. 10.
    Lesimple T, Hassel MB, Gedouin D et al (2003) Phase I study of topotecan in combination with concurrent radiotherapy in adults with glioblastoma. J Neurooncol 65:141–148. doi: 10.1023/B:NEON.0000003647.66788.3b CrossRefPubMedGoogle Scholar
  11. 11.
    Gross MW, Altscher R, Brandtner M et al (2005) Open-label simultaneous radio-chemotherapy of glioblastoma multiforme with topotecan in adults. Clin Neurol Neurosurg 107:207–213. doi: 10.1016/j.clineuro.2004.07.016 CrossRefPubMedGoogle Scholar
  12. 12.
    Pipas JM, Meyer LP, Rhodes CH, Cromwell LD, McDonnell CE, Kingman LS, Rigas JR, Fadul CE (2005) A phase II trial of paclitaxel and topotecan with filgrastim in patients with recurrent or refractory glioblastoma multiforme or anaplastic astrocytoma. J Neurooncol 71:301–305. doi: 10.1007/s11060-004-2026-2 CrossRefPubMedGoogle Scholar
  13. 13.
    Walter KA, Tamargo RJ, Olivi A, Burger PC, Brem H (1995) Intratumoral chemotherapy. Neurosurgery 37:1129–1145. doi: 10.1097/00006123-199512000-00013 CrossRefGoogle Scholar
  14. 14.
    Lieberman DM, Laske DW, Morrison PF et al (1995) Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:1021–1029CrossRefPubMedGoogle Scholar
  15. 15.
    Croteau D, Walbridge S, Morrison PF et al (2005) Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer. J Neurosurg 102:90–97CrossRefPubMedGoogle Scholar
  16. 16.
    Lonser RR, Walbridge S, Garmestani K et al (2002) Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg 97:905–913CrossRefPubMedGoogle Scholar
  17. 17.
    Bobo RH, Laske DW, Akbasak A et al (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
  18. 18.
    Morrison PF, Laske DW, Bobo H et al (1994) High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266:R292–R305PubMedGoogle Scholar
  19. 19.
    Vogelbaum MA (2007) Convection enhanced delivery for treating brain tumors and selected neurological disorders: symposium review. J Neurooncol 83:97–109. doi: 10.1007/s11060-006-9308-9 CrossRefPubMedGoogle Scholar
  20. 20.
    Moog R, Burger AM, Brandl M et al (2002) Change in pharmacokinetics and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels. Cancer Chemother Pharmacol 49:356–366. doi: 10.1007/s00280-002-0428-4 CrossRefPubMedGoogle Scholar
  21. 21.
    Saito R, Krauze MT, Noble CO et al (2006) Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model. Neuro-oncology 8:205–214. doi: 10.1215/15228517-2006-001 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Noble CO, Krauze MT, Drummond DC et al (2006) Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy. Cancer Res 66:2801–2806. doi: 10.1158/0008-5472.CAN-05-3535 CrossRefPubMedGoogle Scholar
  23. 23.
    Woodle MC, Lasic DD (1992) Sterically stabilized liposomes. Biochim Biophys Acta 1113:171–199CrossRefPubMedGoogle Scholar
  24. 24.
    Ishida T, Kiwada H (2008) Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes. Int J Pharm 354:56–62. doi: 10.1016/j.ijpharm.2007.11.005 CrossRefPubMedGoogle Scholar
  25. 25.
    Szebeni J, Baranyi L, Savay S et al (2002) Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies. J Liposome Res 12:165–172. doi: 10.1081/LPR-120004790 CrossRefPubMedGoogle Scholar
  26. 26.
    Szebeni J (2005) Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology 216:106–121. doi: 10.1016/j.tox.2005.07.023 CrossRefPubMedGoogle Scholar
  27. 27.
    Saito R, Krauze MT, Noble CO et al (2006) Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains: implications for local drug delivery. J Neurosci Methods 154:225–232. doi: 10.1016/j.jneumeth.2005.12.027 CrossRefPubMedGoogle Scholar
  28. 28.
    Mamot C, Nguyen JB, Pourdehnad M et al (2004) Extensive distribution of liposomes in rodent brains and brain tumors following convection-enhanced delivery. J Neurooncol 68:1–9. doi: 10.1023/B:NEON.0000024743.56415.4b CrossRefPubMedGoogle Scholar
  29. 29.
    Saito R, Bringas JR, McKnight TR et al (2004) Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res 64:2572–2579. doi: 10.1158/0008-5472.CAN-03-3631 CrossRefPubMedGoogle Scholar
  30. 30.
    Krauze MT, Forsayeth J, Park JW, Bankiewicz KS (2006) Real-time imaging and quantification of brain delivery of liposomes. Pharm Res 23:2493–2504. doi: 10.1007/s11095-006-9103-5 CrossRefPubMedGoogle Scholar
  31. 31.
    Krauze MT, Vandenberg SR, Yamashita Y et al (2008) Safety of real-time convection-enhanced delivery of liposomes to primate brain: a long-term retrospective. Exp Neurol 210:638–644. doi: 10.1016/j.expneurol.2007.12.015 CrossRefPubMedGoogle Scholar
  32. 32.
    Murad GJ, Walbridge S, Morrison PF et al (2006) Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to pseudomonas exotoxin. Clin Cancer Res 12:3145–3151. doi: 10.1158/1078-0432.CCR-05-2583 CrossRefPubMedGoogle Scholar
  33. 33.
    Broaddus WC (2007) Convection enhanced delivery 3rd international symposium, trial update: TransMID. Available at http://cms.clevelandclinic.org/neuroscience/documents/1340%20Broaddus%20Update%20on%20TransMID%20Trial.pdf. Accessed 11 Feb 2008
  34. 34.
    Kunwar S, Westphal M, Medhorn M et al (2007) Results from PRECISE: a randomized phase 3 study in patients with first recurrent glioblastoma multiforme (GBM) comparing cintredekin besudotox (CB) administered via convection-enhanced delivery (CED) with Gliadel Wafers (GW). Neuro-oncology 9:531 (abstract)Google Scholar
  35. 35.
    Sampson JH, Raghavan R, Brady ML et al (2007) Clinical utility of a patient-specific algorithm for simulating intracerebral drug infusions. Neuro-oncology 9:343–353. doi: 10.1215/15228517-2007-007 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Krauze MT, Noble CO, Kawaguchi T et al (2007) Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts. Neuro-oncology 9:393–403. doi: 10.1215/15228517-2007-019 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nakashio A, Fujita N, Tsuruo T (2002) Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K-Akt signaling pathway. Int J Cancer 98:36–41. doi: 10.1002/ijc.10166 CrossRefPubMedGoogle Scholar
  38. 38.
    Saito R, Krauze MT, Bringas JR et al (2005) Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain. Exp Neurol 196:381–389. doi: 10.1016/j.expneurol.2005.08.016 CrossRefPubMedGoogle Scholar
  39. 39.
    Dickensen PJ, LeCouteur RA, Higgins RJ et al (2008) Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging. J Neurosurg 108:989–998. doi: 10.3171/JNS/2008/108/5/0989 CrossRefGoogle Scholar
  40. 40.
    Yamashita Y, Krauze MT, Kawaguchi T et al (2007) Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts. Neuro-oncology 9:20–28. doi: 10.1215/15228517-2006-016 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2009

Authors and Affiliations

  • Amy Y. Grahn
    • 1
  • Krystof S. Bankiewicz
    • 3
  • Millicent Dugich-Djordjevic
    • 2
  • John R. Bringas
    • 3
  • Piotr Hadaczek
    • 3
  • Greg A. Johnson
    • 1
  • Simon Eastman
    • 4
  • Matthias Luz
    • 1
  1. 1.MedGenesis Therapeutix IncVictoriaCanada
  2. 2.NeurocoreSan DiegoUSA
  3. 3.Department of Neurological Surgery, Brain Tumor Research CenterUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Northern Lipids IncBurnabyCanada

Personalised recommendations