Intranasal Delivery—A New Therapeutic Approach for Brain Tumors

Intranasal Delivery—A New Therapeutic Approach for Brain Tumors

Frey II William H, Hashizume Rintaro
Published: US Neurology - Volume 4 Issue 2
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Despite significant advances in tumor imaging, neurosurgery, and radiotherapy, the prognosis for patients with malignant gliomas is extremely poor. The five-year survival rate for patients with glioblastoma (GBM), the most aggressive form of malignant glioma, is less than 5% after initial diagnosis.1 Factors that contribute to the dismal prognosis associated with GBM include its infiltrative nature throughout the brain, which limits the effectiveness of local treatment of surgical resection and targeting of radiotherapy, and the blood–brain barrier (BBB), which limits access of systemically administered therapeutics to the tumor. In the past decade a number of drug delivery strategies have been developed to overcome challenges presented by the BBB. In particular, direct drug administration into the brain parenchyma, such as convectionenhanced delivery (CED), has shown promising results in both animal models and clinical trials.2–12 CED is a continuous infusion that uses a convective (versus diffusive) flow to drive the therapeutic agent throughout a larger region of tissue. This technique is well suited for the delivery of liposomes6,9,11–15 and particulate drug carriers,6,9,16,17 which have the potential to provide a sustained level of drug and to reach cellular targets with improved specificity. However, CED requires the use of potentially risky surgical procedures to position the catheter into the patient’s brain parenchyma.18,19 The convective flow to distribute the drug through the implanted catheter leads to measurable and significant inflammation and local edema because the drug solution infuses continuously beyond the tumor boundary into the adjacent normal brain tissue.4,7,9 This ‘spillover’ of drug to unwanted brain regions may be due to the pressure gradient of the convective bulk flow of CED and could lead to neural toxicity.20

One technique that holds promise for bypassing the BBB to deliver drugs to the brain and eliminating the surgical risk and the spillover effect of drug to normal tissue is intranasal delivery. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain because of the unique anatomic connections provided by the olfactory and trigeminal nerves. These nerves connect the nasal mucosa and central nervous system (CNS), allowing them to detect odors and other chemical stimuli.21,22 Intranasally administered drugs reach the brain parenchyma, spinal cord, and cerebrospinal fluid (CSF) within minutes by using an extracellular route through perineural and/or perivascular channels along the olfactory and trigeminal nerves without binding to any receptor or using axonal transport (see Figure 1).23,24 In addition to bypassing the BBB, advantages of intranasal delivery include rapid delivery to the CNS, avoidance of hepatic first-pass drug metabolism, and elimination of the need for systemic delivery, thereby reducing unwanted systemic side effects. Intranasal delivery also provides painless and convenient selfadministration for patients, features that encourage its use for delivering therapeutic agents into the CNS.25 Many therapeutic agents, including growth factors, proteins, peptides, viral vectors, liposomes, and vaccines, have been delivered to the CNS through the nasal route and applied for the treatment of CNS disorders in both animals and humans.21,24,26–39 Thorne et al. reported that insulin-like growth factor-1 can be rapidly transported into the rat brain and upper spinal cord via the olfactory and trigeminal pathways.21 Thorne et al. have recently reported delivery of interferonbeta- 1b to the CNS in monkeys along the same neural pathways.29 In humans, intranasal delivery of insulin has been shown to improve memory in normal adults40 and in patients with early Alzheimer’s disease41,42 without changing blood levels of glucose or insulin.43 Also, intranasal oxytocin has been reported to improve trust in humans.44

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References:
  1. CBTRUS Central Brain Tumor Registry of The United States. Available at: www,cbtrus,org/2007-2008/tables/report/2007/table22.pdf (accessed September 18, 2008).
  2. Huynh GH, Deen DF, Szoka Jr FC, Barriers to carrier mediated drug and gene delivery to brain tumors, J Control Release, 2006;110:236–59.
  3. Ozawa T, Santos RA, LambornK R, et al., In vivo evaluation of the boronated porphyrin TABP-1 in U-87 MG intracerebral human glioblastoma xenografts, Mol Pharm, 2004;1:368–74.
  4. Ozawa T, Gryaznov SM, HuL J, et al., Antitumor effects of specific telomerase inhibitor GRN163 in human glioblastoma xenografts, Neuro-oncol, 2004;6:218–26.
  5. Ozawa T,Afzal J, Lamborn KR, et al., Toxicitybiodistributionand convection-enhanced delivery of the boronated porphyrin BOPP in the 9L intracerebral rat glioma model, Int J Radiat Oncol Biol Phys, 2005;63:247–52.
  6. MacKay JA, Deen DF, Szoka Jr FC, Distribution in brain of liposomes after convection enhanced delivery: modulation by particle chargeparticle diameterand presence of steric coating, Brain Res, 2005;1035:139–53.
  7. KawakamiK M, Kioi, Husain SR, Puri RK, Distribution kinetics of targeted cytotoxin in glioma by bolus or convection-enhanced delivery in a murine model, J Neurosurg, 2004;101:1004–11.
  8. Lidar Z, Mardr 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;100:472–9.
  9. Mamot C, Nguyen JB, Pourdehnad M, et al., Extensive distribution of liposomes in rodent brains and brain tumors following convectionenhanced delivery, J Neurooncol, 2004;68:1–9.
  10. Boiardi A, Eoli M, Salmaggi A, et al., Local drug delivery in recurrent malignant gliomas, Neurol Sci, 2005;26(Suppl. 1):S37–39.
  11. Saito R ,Krauze MT, Noble C, et al., Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains:Implications for local drug delivery, J Neurosci Methods, 2006.
  12. Saito R, Bringas JR, McKnight TR, et al., Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging, Cancer Res, 2004;64:2572–9.
  13. Noble CO, Krauze MT, Drummond DC, et al., Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors:pharmacology and efficacy, Cancer Res, 2006;66:2801–6.
  14. Saito R, Krauze MT, Noble CO, et al., Convection-enhanced delivery of Ls-TPT enables an effectivecontinuouslow-dose chemotherapy against malignant glioma xenograft model, Neuro Oncol, 2006;8:205–14.
  15. Krauze MT, Noble CO, Kawaguchi T, et al., Convection-enhanced delivery of nanoliposomal CPT-11 (irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts, Neuro Oncol, 2007;9:393–403.
  16. Valtonen S, Timonen U, Toivanen P, et al., Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas:a randomized double-blind study, Neurosurgery, 1997;41:44–8, discussion 48–9.
  17. Voges J, Reszka R, Gossmann A, et al., Imaging-guided convectionenhanced delivery and gene therapy of glioblastoma, Ann Neurol, 2003;54:479–87.
  18. Bobo RH, Laske DW, Akbasak A, et al., Convection-enhanced delivery of macromolecules in the brain, Proc Natl Acad Sci U S A, 1994;91:2076–80.
  19. Groothuis DR, The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery, Neuro-oncol, 2000;2:45–59.
  20. Sandberg DI, Edgar MA, Souweidane MM, Convection-enhanced delivery into the rat brainstem, J Neurosurg, 2002;96:885–91.
  21. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH, 2nd delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration, Neuroscience, 2004;127:481–96.
  22. Dhanda D, Frey II WH, Leopold D, Kompella UB, Approaches for drug deposition in the human olfactory epithelium, Drug Delivery, 2006;5:64–72.
  23. Thorne RG, Emory CR, Ala TA, Frey II WH, Quantitative analysis of the olfactory pathway for drug delivery to the brain, Brain Res, 1995;692:278–82.
  24. Thorne RG, Frey II WH, Delivery of neurotrophic factors to the central nervous system:pharmacokinetic considerations, Clin Pharmacokinet, 2001;40:907–46.
  25. Romeo VD, deMeireles J, Sileno AP, et al., Effects of physicochemical properties and other factors on systemic nasal drug delivery, Adv Drug Deliv Rev,1998;29:89–116.
  26. Hanson LR, Frey II WH, Strategies for intranasal delivery of therapeutics for the prevention and treatment of neuroAIDS, J Neuroimmune Pharmacol, 2007;2:81–862.
  27. Liu XF, Fawcett JR, Hanson LR, Frey II WH, The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats, J Stroke Cerebrovasc, 2004;Dis13:16-23.
  28. Zhao HM, Liu XF, Mao XW, Chen CF, Intranasal delivery of nerve growth factor to protect the central nervous system against acute cerebral infarction, Chin Med Sci, 2004;J19:257–61.
  29. Thorne RG, Hanson LR, Ross TM, et al., Delivery of interferon-beta to the monkey nervous system following intranasal administration, Neuroscience, 2008;152:785–97.
  30. Yamada M, Chiba T, Sasabe J, et al., Nasal colivelin treatment ameliorates memory impairment related to Alzheimer’s disease, Neuropsychopharmacology, 2008;33:2020–32.
  31. De Rosa R, Garcia AA, Braschi C, et al., Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice, Proc Natl Acad Sci U S A, 2005;102:3811–16.
  32. Zhang J,Wu X, Qin C, et al., A novel recombinant adeno-associated virus vaccine reduces behavioral impairment and beta-amyloid plaques in a mouse model of Alzheimer’s disease, Neurobiol Dis, 2003;14:365–79.
  33. Lundstrom K, Alphavirus vectors for gene therapy applications, Curr Gene Ther, 2001;1:19–29.
  34. Tafaghodi M, Jaafari MR, Sajadi Tabassi SA, Nasal immunization studies using liposomes loaded with tetanus toxoid and CpG-ODN, Eur J Pharm Biopharm, 2006;64:138–145.
  35. AlsarraI A, Hamed AY, Alanazi FK, Acyclovir liposomes for intranasal systemic delivery: development and pharmacokinetics evaluation, Drug Deliv, 2008;15:313–21.
  36. Sharma S, Mukkur TK, Benson HA, Chen Y, Pharmaceutical aspects of intranasal delivery of vaccines using particulate systems, J Pharm Sci, 2008.
  37. Peek LJ, Middaugh CR, Berkland C, Nanotechnology in vaccine delivery, Adv Drug Deliv Rev, 2008;60:915–28.
  38. Gozes I, Giladi E, Pinhasov A, et al., Activity-dependent neurotrophic factor:intranasal administration of femtomolar-acting peptides improve performance in a water maze, J Pharmacol Exp Ther, 2000;293:1091–8.
  39. Banks WA, During MJ, Niehoff ML, Brain uptake of the glucagon-like peptide-1 antagonist exendin(9-39) after intranasal administration, J Pharmacol Exp Ther, 2004;309:469–75.
  40. Benedict C, Hallschmid M, Hatke A, et al., Intranasal insulin improves memory in humans, Psychoneuroendocrinology, 2004;29:1326–34.
  41. Reger MA,Watson GS, Frey II WH, et al., Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype, Neurobiol Aging, 2006;27:451–8.
  42. Reger MA,Watson GS, Green PS, et al., Intranasal insulin improves cognition and modulates beta-amyloid in early AD, Neurology, 2008;70:440–48.
  43. Born J, Lange T, Kern W, et al., Sniffing neuropeptides: a transnasal approach to the human brain, Nat Neurosci, 2002;5:514–16.
  44. Kosfeld M, Heinrichs M, Zak PJ, et al., Oxytocin increases trust in humans, Nature, 2005;435:673–6.
  45. Wang F, Jiang X, Lu W, Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats, Int J Pharm, 20032;63:1–7.
  46. Sakane T, Yamashita S, Yata N, Sezaki H, Transnasal delivery of 5- fluorouracil to the brain in the rat, J Drug Target, 1999;7:233–40.
  47. Wang D, Gao Y, Yun L, Study on brain targeting of raltitrexed following intranasal administration in rats, Cancer Chemother Pharmacol, 2005;1–8.
  48. Shingaki T, Sakane T, Yamashita S, et al., Transnasal delivery of anticancer drugs to the brain tumor:a new strategy for brain tumor chemotherapy, Drug Delivery System,1999;14:365–71.
  49. Ozduman K,Wollmann G, Piepmeier JM, et al., Systemic vesicular stomatitis virus selectively destroys multifocal glioma and metastatic carcinoma in brain, J Neurosci, 2008;28:1882–93.
  50. Hashizume R, Ozawa T, Gryaznov SM, et al., New therapeutic approach for brain tumors:Intranasal delivery of telomerase inhibitor GRN163, Neuro Oncol, 2008;10:112–20.
  51. da Fonseca CO, Landeiro JA, Clark SS, et al., Recent advances in the molecular genetics of malignant gliomas disclose targets for antitumor agent perillyl alcohol, Surg Neurol, 2006;65(Suppl. 1): S1:2–1:8, discussion S1:8–1:9.
  52. da Fonseca CO, Schwartsmann G, Fischer JN et al., Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas, Surg Neurol, 2008;70:259–66, discussion 266–57.

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