Skip to main content
Neurotherapeutics logoLink to Neurotherapeutics
. 2009 Jul;6(3):539–546. doi: 10.1016/j.nurt.2009.04.004

Novel drug delivery strategies in neuro-oncology

Dani S Bidros 1, Michael A Vogelbaum 1,
PMCID: PMC5084189  PMID: 19560743

Summary

Treatment of malignant gliomas represents one of the most formidable challenges in oncology. Despite treatment with surgery, radiation therapy, and chemotherapy, the prognosis remains poor, particularly for glioblastoma, which has a median survival of 12 to 15 months. An important impediment to finding effective treatments for malignant gliomas is the presence of the blood brain barrier, which serves to prevent delivery of potentially active therapeutic compounds. Multiple efforts are focused on developing strategies to effectively deliver active drugs to brain tumor cells. Blood brain barrier disruption and convection-enhanced delivery have emerged as leading investigational delivery techniques for the treatment of malignant brain tumors. Clinical trials using these methods have been completed, with mixed results, and several more are being initiated. In this review, we describe the clinically available methods used to circumvent the blood brain barrier and summarize the results to date of ongoing and completed clinical trials.

Key Words: Convection-enhanced delivery, blood brain barrier disruption, brain neoplasm, drug delivery system

References

  • 1.Central Brain Tumor Registry of the United States (CBTRUS): Statistical report: primary brain tumors in the United States, 2000–2004. Chicago, Central Brain Tumor Registry of the United States, 2005.
  • 2.Central Nervous System Cancers Practice Guidelines in Oncology. Vol 2. Jenkintown, PA: National Comprehensive Cancer Network; 2005. [DOI] [PubMed]
  • 3.Nieder C, Grosu AL, Molls M. A comparison of treatment results for recurrent malignant gliomas. Cancer Treatment Rev. 2000;26:397–409. doi: 10.1053/ctrv.2000.0191. [DOI] [PubMed] [Google Scholar]
  • 4.Nicholas MK, Prados MD, Larson DA, Gutin PH, et al. Malignant astrocytomas. In: Black PMCL, Loeffler JS, et al., editors. Cancer of the nervous system. Cambridge: Blackwell Science; 1997. pp. 464–491. [Google Scholar]
  • 5.Greenwood J. Experimental manipulation of the blood-brain and blood-retinal barriers. In: Bradbury MWB, editor. the physiology and pharmacology of the blood-brain barrier. Germany: Springer-Verlag; 1992. pp. 459–486. [Google Scholar]
  • 6.Neuwelt EA. Mechanisms of disease: The blood-brain barrier. Neurosurgery. 2004;54:131–142. doi: 10.1227/01.NEU.0000097715.11966.8E. [DOI] [PubMed] [Google Scholar]
  • 7.Rapoport SL, Robinson PJ. Tight-junctional modification as the basis of osmotic opening of the blood-brain barrier. Ann NY Acad Sci. 1987;481:250–267. doi: 10.1111/j.1749-6632.1986.tb27155.x. [DOI] [PubMed] [Google Scholar]
  • 8.Williams PC, Henner WD, Roman-Goldstein S, et al. Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain tumor barrier in the treatment of intracranial neoplasms. Neurosurgery. 1995;37:17–28. doi: 10.1227/00006123-199507000-00003. [DOI] [PubMed] [Google Scholar]
  • 9.Neuwelt EA, Frenkel EP, Rapoport SI, et al. Effect of osmotic blood-brain barrier disruption on methotrexate pharmacokinetics in the dog. Neurosurgery. 1980;7:36–43. doi: 10.1227/00006123-198007000-00006. [DOI] [PubMed] [Google Scholar]
  • 10.Dahlborg SA, Henner WD, Crossen JR, et al. Non-AIDS primary CNS lymphoma: The first example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J Sci Am. 1996;2:168–174. [PubMed] [Google Scholar]
  • 11.Kraemer DF, Fortin D, Doolittle ND, et al. Association of total dose intensity of chemotherapy in primary CNS lymphoma (human non-AIDS) and survival. Neurosurgery. 2001;48:1033–1041. doi: 10.1097/00006123-200105000-00013. [DOI] [PubMed] [Google Scholar]
  • 12.McAllister LD, Doolittle ND, Guastadisegni PE, et al. Cognitive outcomes and long-term follow-up after enhanced chemotherapy delivery for primary central nervous system lymphomas. Neurosurgery. 2000;46:51–61. doi: 10.1097/00006123-200001000-00010. [DOI] [PubMed] [Google Scholar]
  • 13.Neuwelt EA, Goldman DL, Dahlborg SA, et al. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: Prolonged survival and preservation of cognitive function. J Clin Oncol. 1991;9:1580–1590. doi: 10.1200/JCO.1991.9.9.1580. [DOI] [PubMed] [Google Scholar]
  • 14.Neuwelt EA, Barnett PA, Glasberg M, et al. Pharmacology and neurotoxicity of Cis-diamminedichloroplatinum, bleomycin, 5-fluorouracil, and cyclophosphamide administration following osmotic blood-brain barrier modification. Cancer Res. 1983;43:5278–5285. [PubMed] [Google Scholar]
  • 15.Cloughesy TF, Black KL. Pharmacological blood-brain barrier modification for selective drug delivery. J Neurooncol. 1995;26:125–132. doi: 10.1007/BF01060218. [DOI] [PubMed] [Google Scholar]
  • 16.Bartus RT, Elliott PJ, Dean RL, et al. Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7. Exp Neurol. 1996;142:14–28. doi: 10.1006/exnr.1996.0175. [DOI] [PubMed] [Google Scholar]
  • 17.Ford J, Osborn C, Barton T, Bleehan NM. A phase I study of intravenous RMP-7 with carboplatin in patients with progression of malignant glioma. Eur J Cancer. 1998;34:1807–1811. doi: 10.1016/S0959-8049(98)00155-5. [DOI] [PubMed] [Google Scholar]
  • 18.Hynynen K, Clement GT, McDonald N, et al. 500-element ultrasound phased array system for noninvasive focal surgery of the brain: A preliminary rabbit study with ex vivo human skulls. Magn Reson Med. 2004;52:100–107. doi: 10.1002/mrm.20118. [DOI] [PubMed] [Google Scholar]
  • 19.Hynynen K, McDannold N, Vykhodtseva N, et al. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology. 2001;220:640–646. doi: 10.1148/radiol.2202001804. [DOI] [PubMed] [Google Scholar]
  • 20.Treat LH, McDannold N, Hynynen K. Transcranial MRI-guided focused ultrasound-induced blood-brain barrier opening in rats (2:998–1000). IEEE Ultrasonics Symposium, Montreal, Canada, August 24–27, 2004.
  • 21.Clement GT, Hynynen K. A noninvasive method for focusing ultrasound through the human skull. Phys Med Biol. 2000;47:1219–1236. doi: 10.1088/0031-9155/47/8/301. [DOI] [PubMed] [Google Scholar]
  • 22.Brem H, Mahaley MS, Vick NA, et al. Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg. 1991;74:441–446. doi: 10.3171/jns.1991.74.3.0441. [DOI] [PubMed] [Google Scholar]
  • 23.Westphal M, Ram Z, Riddle V, Hilt D, Bortey E, Executive Committee of the, Gliadel Study Group Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 2006;148(3):269–275. doi: 10.1007/s00701-005-0707-z. [DOI] [PubMed] [Google Scholar]
  • 24.Walter KA, Cahan MA, Gur A, et al. Interstitial Taxol delivered from a biodegradable polymer implant against experimental malignant glioma. Cancer Res. 1994;54:2207–2212. [PubMed] [Google Scholar]
  • 25.Watts MC, Lesniak MS, Burke M, et al. Controlled release of Adriamycin in the treatment of malignant glioma (poster). In: American Association of Neurological Surgeons Annual Meeting, Denver, CO, 1997.
  • 26.Menei P, Venier MC, Gamelin E, et al. Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: a pilot study. Cancer. 1999;86:325–330. doi: 10.1002/(SICI)1097-0142(19990715)86:2<325::AID-CNCR17>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  • 27.Tajika Y, Muragaki Y, Hiyama H, et al. Local chemotherapy with slowly-releasing anticancer drug polymers for malignant brain tumors. J Control Fel. 1994;32:1–8. [Google Scholar]
  • 28.DeMeco F, Li KW, Tyler BM, et al. Local delivery of mitoxantrone for the treatment of malignant brain tumors in rats. J Neurosurg. 2002;97:1173–1178. doi: 10.3171/jns.2002.97.5.1173. [DOI] [PubMed] [Google Scholar]
  • 29.Bobo RH, Laske DW, Akbasak A, et al. Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci. 1994;15(6):2076–2080. doi: 10.1073/pnas.91.6.2076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Cunningham J, Pivirotto P, Bringas I, et al. Biodistribution of adeno-associated virus type-2 in nonhuman primates after convection-enhanced delivery to brain. Mol Ther. 2008;16(7):1267–1275. doi: 10.1038/mt.2008.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Lonser RR, Walbridge S, Garmestani K, et al. Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg. 2002;97(4):905–913. doi: 10.3171/jns.2002.97.4.0905. [DOI] [PubMed] [Google Scholar]
  • 32.Chen MY, Lonser RR, Morrison PF, et al. Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg. 1999;90(2):315–320. doi: 10.3171/jns.1999.90.2.0315. [DOI] [PubMed] [Google Scholar]
  • 33.Vogelbaum MA. Convection enhanced delivery for the treatment of malignant gliomas: symposium review. J Neurooncol. 2005;73(1):57–69. doi: 10.1007/s11060-004-2243-8. [DOI] [PubMed] [Google Scholar]
  • 34.Raghavan R, Brady ML, Rodriquez-Ponce MI, Hartlep A, Pedain C, Sampson JH. Convection-enhanced delivery of therapeutics for brain disease, and its optimization. Neurosurg Focus. 2006;20(4):E12–E12. doi: 10.3171/foc.2006.20.4.7. [DOI] [PubMed] [Google Scholar]
  • 35.Oh S, Odland R, Wilson S, et al. Improved distribution of small molecules and viral vectors in the murine brain using a hollow fiber catheter. J Neurosurg. 2007;107:568–577. doi: 10.3171/JNS-07/09/0568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Hadaczek P, Kohutnicka M, Krauze MT, et al. Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain. Hum Gene Ther. 2006;17(3):291–302. doi: 10.1089/hum.2006.17.291. [DOI] [PubMed] [Google Scholar]
  • 37.Sanftner LM, Sommer JM, Suzuki BM, et al. AAV2-mediated gene delivery to monkey putamen: evaluation of an infusion device and delivery parameters. Exp Neurol. 2005;194(2):476–483. doi: 10.1016/j.expneurol.2005.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Lidar Z, Mardor Y, Jonas T, et al. Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg. 2004;100(3):472–479. doi: 10.3171/jns.2004.100.3.0472. [DOI] [PubMed] [Google Scholar]
  • 39.Kaiser MG, Parsa AT, Fine RL, et al. Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model. Neurosurgery. 2000;47(6):1391–1398. doi: 10.1097/00006123-200012000-00026. [DOI] [PubMed] [Google Scholar]
  • 40.Saito R, Krauze MT, Noble CO, et al. Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model. Neuro Oncol. 2006;8(3):205–214. doi: 10.1215/15228517-2006-001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Laske DW, Youle RJ, Oldfield EH. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med. 1997;3:1362–1368. doi: 10.1038/nm1297-1362. [DOI] [PubMed] [Google Scholar]
  • 42.Weaver M, Laske DW. Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol. 2002;65(1):3–13. doi: 10.1023/A:1026246500788. [DOI] [PubMed] [Google Scholar]
  • 43.Kunwar S. Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. Acta Neurochir. 2003;88:105–111. doi: 10.1007/978-3-7091-6090-9_16. [DOI] [PubMed] [Google Scholar]
  • 44.Debinski W, Obiri N, Pastan I, et al. A novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin is highly cytotoxic to human carcinoma cells expressing receptors for interleukin 13 and interleukin 4. J Biol Chem. 1995;270:16775–16780. doi: 10.1074/jbc.270.15.8797. [DOI] [PubMed] [Google Scholar]
  • 45.Debinski W, Obiri N, Powers S, et al. Human glioma cells over-express receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. Clin Cancer Res. 1995;1:1253–1258. [PubMed] [Google Scholar]
  • 46.Kunwar S, Chang SM, Prados MD, et al. Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies. Neurosurg Focus. 2006;20(4):E15–E15. [PubMed] [Google Scholar]
  • 47.Vogelbaum MA. Convection enhanced delivery for treating brain tumors and selected neurological disorders: symposium review. J Neurooncol. 2007;83:97–109. doi: 10.1007/s11060-006-9308-9. [DOI] [PubMed] [Google Scholar]
  • 48.Kunwar S, Westphal M, Medhorn M, et al. 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). Abstract from the Twelfth Annual Meeting of the Society for Neuro-Oncology; October, 2007.
  • 49.Vogelbaum MA, Sampson JH, Kunwar S, et al. Convection-enhanced delivery of cintredekin besudotox (interleukin-13-PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: phase 1 study of final safety results. Neurosurgery. 2007;61:1031–1038. doi: 10.1227/01.neu.0000303199.77370.9e. [DOI] [PubMed] [Google Scholar]
  • 50.Kawakami M, Kawakami K, Puri RK. Interleukin-4-pseudomonas exotoxiu chimeric fusion protein for malignant glioma therapy. J Neurooncol. 2003;5(1):15–25. doi: 10.1023/A:1026294416718. [DOI] [PubMed] [Google Scholar]
  • 51.Weber FW, Floeth F, Asher A, et al. Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma. Acta Neurochir Suppl. 2003;88:93–103. doi: 10.1007/978-3-7091-6090-9_15. [DOI] [PubMed] [Google Scholar]
  • 52.Rand RW, Kreitman RJ, Patronas N, et al. Intratumoral administration of recombinant circularly permuted interleukin-4-pseudomonas exotoxin in patients with high-grade glioma. Clin Cancer Res. 2000;6(6):2157–2165. [PubMed] [Google Scholar]
  • 53.Weber F, Asher A, Bucholz R, et al. Safety, toleratbility, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neurooncol. 2003;64(1–2):125–137. doi: 10.1007/BF02700027. [DOI] [PubMed] [Google Scholar]
  • 54.Wong AJ, Bigner SH, Bigner DD, et al. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci. 1987;84(19):6899–6903. doi: 10.1073/pnas.84.19.6899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Sampson JH, Akabani G, Archer GE, et al. 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. 2003;65(1):27–35. doi: 10.1023/A:1026290315809. [DOI] [PubMed] [Google Scholar]
  • 56.Schlingensiepen KH, Fischer-Blass B, Schmaus S, et al. Antisense therapeutics for tumor treatment: the TGF-beta 2 inhibitor AP 12009 in clinical development against malignant tumors. Recent Results Cancer Res. 2008;177:137–150. doi: 10.1007/978-3-540-71279-4_16. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES