• IBRAHIM AMINU SHEHU School of Allied Health Science, Sharda University, Knowledge Park III 201306, Greater Noida, UP. India
  • MOJAHIDUL ISLAM School of Pharmaceutical Sciences, Lingayas Vidyapeeth University, Faridabad, India
  • VIJENDER SINGH Rakshpal Bahadur Pharmacy Institute, Plot No 04, Knowledge Park III 201306, Greater Noida, UP. India


Brain tumours are the most lethal type of cancer, which is difficult to manage due to the inherent suboptimal bioavailability of the chemotherapy agent at tumour sites, consequent of high levels of protection of physiological blood-brain barrier (BBB), blood tumour barrier (BTB) and blood-cerebrospinal fluid barrier (CSF). Improving the permeability of these barriers would enhance the disease's clinical prognosis and promote patients' quality of life. To this end, scientists have conducted several studies to determine the most suitable route for CNS delivery. Most of which show that the nose-to-brain is proposed to be the most convenient, efficacious and clinically beneficial non-invasive means of delivering chemotherapeutic agents directly to the brain. Therefore, this study compares the therapeutic benefits of intranasal and other conventional brain delivery systems and further evaluates the clinical benefits of using different nanocarriers for brain tumour targeting. However, we surveyed the literature by conducting an in-depth search of the research keywords and their combinations in recognized scientific databases, primarily Science Direct, PubMed, Google Scholar, and Research Gate. Our findings have shown that the nose-to-brain delivery of chemotherapeutics is a breakthrough in bypassing the effects of BBB, BTB, and CSF barriers, improving the delivery of drugs to the brain for specific tumour targeting with desired clinical prognosis.

Keywords: Brain tumours, Glioblastoma, Intranasal route, Conventional delivery, Nanocarriers, Blood-brain barrier, and blood tumor barrier


JEX HS. The edwin smith surgical papyrus: first milestone in the march of medicine. Merck Rep 1951;60:20-2
2. US. National Library of Medicine. Edwin Smith Papyrus. Turn. Pages Online; 2015.
3. The Papyrus Ebers. Translated from the german version. J Am Med Assoc 1932;89:348, 1927.
4. Sudhakar A. History of cancer, ancient and modern treatment methods. J Cancer Sci Ther 2009;1:1-4.
5. Siri FH, Salehiniya H. Pancreatic cancer in iran: an epidemiological review. J Gastrointest Cancer 2020;51:418–24.
6. Miranda Filho A, Piñeros M, Soerjomataram I, Deltour I, Bray F. Cancers of the brain and CNS: Global patterns and trends in incidence. Neuro Oncol 2017;19:270-80.
7. McKean Cowdin R, Razavi P, Preston Martin S. Brain tumors. Int Encycl Public Health; 2016.
8. Alifieris C, Trafalis DT. Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther 2015;152:63-82.
9. Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee SU. Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev 2017;18:3-9.
10. Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz Sloan JS, et al. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev 2014;23:1985–96.
11. Patel AP, Fisher JL, Nichols E, Abd-Allah F, Abdela J, Abdelalim A, et al. Global, regional, and national burden of brain and other CNS cancer, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol 2019;8:459-80.
12. Claus EB, Walsh KM, Wiencke JK, Molinaro AM, Wiemels JL, Schildkraut JM, et al. Survival and low-grade glioma: the emergence of genetic information. Neurosurg Focus 2015;38:E6.
13. Morsy AA, Ng WH oe. Re-do craniotomy for recurrent glioblastoma. CNS Oncol 2015;4:55–7.
14. Gangemi RMR, Griffero F, Marubbi D, Perera M, Capra MC, Malatesta P, et al. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells 2009;27:40-8.
15. Zhang Q, Xiang W, Yi DY, Xue BZ, Wen WW, Abdelmaksoud A, et al. Current status and potential challenges of mesenchymal stem cell-based therapy for malignant gliomas. Stem Cell Res Ther 2018;93:19–31.
16. Mughal AA, Zhang L, Fayzullin A, Server A, Li Y, Wu Y, et al. Patterns of Invasive growth in malignant gliomas-the hippocampus emerges as an invasion-spared brain region. Neoplasia U S 2018;20:643-56.
17. Spadoni I, Fornasa G, Rescigno M. Organ-specific protection mediated by cooperation between vascular and epithelial barriers. Nat Rev Immunol 2017;12:761-73.
18. Wang H, Cai S, Ernstberger A, Bailey BJ, Wang MZ, Cai W, et al. Temozolomide-mediated DNA methylation in human myeloid precursor cells: Differential involvement of intrinsic and extrinsic apoptotic pathways. Clin Cancer Res 2013;19:2699-709.
19. Tiek DM, Rone JD, Graham GT, Pannkuk EL, Haddad BR, Riggins RB. Alterations in cell motility, proliferation, and metabolism in novel models of acquired temozolomide resistant glioblastoma. Sci Rep 2018;8:7222.
20. Sekerdag E, Lule S, Bozdag Pehlivan S, Ozturk N, Kara A, Kaffashi A, et al. A potential non-invasive glioblastoma treatment: nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles. J Controlled Release 2017;261:187-98.
21. Angeli E, Nguyen TT, Janin A, Bousquet G. How to make anticancer drugs cross the blood-brain barrier to treat brain metastases. Int J Mol Sci 2020;21:1–16.
22. Tucker C, Tucker L, Brown K. The intranasal route as an alternative method of medication administration. Crit Care Nurse 2018;38:26-31.
23. Bruinsmann FA, Vaz GR, De Cristo Soares Alves A, Aguirre T, Pohlmann AR, Guterres SS, et al. Nasal drug delivery of anticancer drugs for the treatment of glioblastoma: preclinical and clinical trials. Molecules. 2019;24:4312.
24. Begley DJ. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther 2004;104:29-45.
25. Begley DJ, Brightman MW. Structural and functional aspects of the blood-brain barrier. Prog Drug Res 2003;61:39-78.
26. Comfort C, Garrastazu G, Pozzoli M, Sonvico F. Opportunities and challenges for the nasal administration of nanoemulsions. Curr Top Med Chem 2015;15:356-68.
27. Lee VHL. Enzymatic barriers to peptide and protein absorption. Crit Rev Ther Drug Carrier Syst 1988;5:69-97.
28. Pohlmann AR, Fonseca FN, Paese K, Detoni CB, Coradini K, Beck RC, et al. Poly(?-caprolactone) microcapsules and nanocapsules in drug delivery. Expert Opin Drug Delivery 2013;10:623-38.
29. Frank LA, Contri RV, Beck RCR, Pohlmann AR, Guterres SS. Improving drug biological effects by encapsulation into polymeric nanocapsules. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2015;7:623–39.
30. Sasi S, Joseph SK, Arian AM, Thomas S, VUA, GKA, et al. An updated review on the application of dendrimers as successful nanocarriers for brain delivery of therapeutic moieties. Int J Appl Pharm 2021;13:1–9.
31. Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm 2009;379:146-57.
32. Ostrom QT, Gittleman H, Liao P, Vecchione Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro-Oncol 2017;19:1–88.
33. Molnar P. Classification of primary brain tumors: molecular aspects. In: Garami M. editor. Manag CNS Tumors. InTech; 2011. Available from: [Last accessed on 11 Sep 2020]
34. Nilsson J, Holgersson G, Carlsson T, Henriksson R, Bergström S, Bergqvist M. Incidence trends in high-grade primary brain tumors in males and females. Oncol Lett 2017;13:2831–7.
35. Rezaee A. WHO grading of CNS tumors | Radiology Reference Article | Radiopaedia. Available from: [Last accessed on 11 Sep 2020]
36. Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987;325:253-7.
37. Bicker J, Alves G, Fortuna A, Falcao A. Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems: a review. Eur J Pharm Biopharm 2014;87:409-32.
38. Liu S, Agalliu D, Yu C, Fisher M. The role of pericytes in blood-brain barrier function and stroke. Curr Pharm Des 2012;18:3653-62.
39. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006;7:41-53.
40. Mc Carthy DJ, Malhotra M, O’Mahony AM, Cryan JF, O’Driscoll CM. Nanoparticles and the blood-brain barrier: advancing from in vitro models towards therapeutic significance. Pharm Res 2015;32:1161-85.
41. Pajouhesh H, Lenz GR. Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2005;2:541-53.
42. Warren KE. Beyond the blood: brain barrier: the importance of central nervous system (CNS) pharmacokinetics for the treatment of CNS tumors, including diffuse intrinsic pontine glioma. Front Oncol 2018;8:239.
43. Ganipineni LP, Danhier F, Preat V. Drug delivery challenges and future of chemotherapeutic nanomedicine for glioblastoma treatment. J Controlled Release Elsevier 2018;281:42–57.
44. Li M, Luo Z, Xia Z, Shen X, Cai K. Time-sequenced drug delivery approaches towards effective chemotherapeutic treatment of glioma. Mater Horiz 2017;4:996-77.
45. Lyday RW, Etters AM, Kim C, Magana F, Pontipiedra GM, Singh NKM, et al. PDE5 inhibitors offer novel mechanisms in combination and solo cancer therapy. Curr Cancer Ther Rev 2017;13:107-19.
46. Liu Y, Lu W. Recent advances in brain tumor-targeted nano-drug delivery systems. Expert Opin Drug Delivery 2012;9:671-86.
47. Drug delivery to the central nervous system: a review. Available from: JPPS6/ A.misra/delivery.htm [Last accessed on 13 Sep 2020]
48. Yokoyama Y, Kono T, Aoki M. [A case of allergic granulomatous angitis (author’s transl)]. Nihon Naika Gakkai Zasshi J Japan Soc Intern Med 1975;64:565–73.
49. Einer Jensen N, Hunter R. Counter-current transfer in reproductive biology. Reproduction 2005;129:9–18.
50. Guynn RW, Pieklik JR. Dependence on dose of the acute effects of ethanol on liver metabolism in vivo. J Clin Invest 1975;56:1411–9.
51. Schmoldt A, Benthe HF, Haberland G. Digitoxin metabolism by rat liver microsomes. Biochem Pharmacol 1975;24:1639–41.
52. Fowler NO, McCall D, Chou TC, Holmes JC, Hanenson IB. Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs. Am J Cardiol 1976;37:223–30.
53. Pogodina VV. Elizaveta nilolaevna levkovich. 75th birthday. Acta Virol 1975;19:509.
54. Goss DJ, Parkhurst LJ, Gorisch H. Kinetic light scattering studies on the dissociation of hemoglobin from lumbricus terrestris. Biochemistry 1975;14:5461–4.
55. Lochhead JJ, Davis TP. Perivascular and perineural pathways involved in brain delivery and distribution of drugs after intranasal administration. Pharmaceutics 2019;11:598.
56. Yadav S, Gattacceca F, Panicucci R, Amiji MM. Comparative biodistribution and pharmacokinetic analysis of cyclosporine-a in the brain upon intranasal or intravenous administration in an oil-in-water nanoemulsion formulation. Mol Pharm Am Chem Soc 2015;12:1523–33.
57. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH. 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.
58. Vaidya AV, Shinde UA, Shimpi HH. Preliminary studies on brain targeting of intranasal atomoxetine liposomes. Int J Pharm Pharm 2016;7:286-92.
59. Lim ST, Forbes B, Berry DJ, Martin GP, Brown MB. In vivo evaluation of novel hyaluronan/chitosan microparticulate delivery systems for the nasal delivery of gentamicin in rabbits. Int J Pharm 2002;231:73–82.
60. Rajendran R, Balan R, Ganesan N, Thiruvengadam D. Recent modalities in drug delivery via inhalation therapy–an advanced treatment strategy for pulmonary carcinoma. Int J Pharm Pharm 2015;7:8-21.
61. Lochhead JJ, Wolak DJ, Pizzo ME, Thorne RG. Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration. J Cereb Blood Flow Metab 2015;35:371–81.
62. Alex AT, Joseph A, Shavi G, Rao JV, Udupa N. Development and evaluation of carboplatin-loaded PCL nanoparticles for intranasal delivery. Drug Delivery 2016;23:2144–53.
63. Kanazawa T, Morisaki K, Suzuki S, Takashima Y. Prolongation of life in rats with malignant glioma by intranasal siRNA/Drug codelivery to the brain with cell-penetrating peptide-modified micelles. Mol Pharm 2014;11:1471–8.
64. Nasr M. Development of an optimized hyaluronic acid-based lipidic nanoemulsion co-encapsulating two polyphenols for nose to brain delivery. Drug Delivery 2016;23:1444–52.
65. 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.
66. Cho HY, Wang W, Jhaveri N, Torres S, Tseng J, Leong MN, et al. Perillyl alcohol for the treatment of temozolomide-resistant gliomas. Mol Cancer Ther 2012;11:2462–72.
67. Azambuja JH, Schuh RS, Michels LR, Gelsleichter NE, Beckenkamp LR, Iser IC, et al. Nasal administration of cationic nanoemulsions as CD73-siRNA delivery system for glioblastoma treatment. Thera Approach Mol Neurobiol 2020;57:635–49.
68. Chu L, Wang A, Ni L, Yan X, Song Y, Zhao M, et al. Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting. Drug Delivery 2018;25:1634–41.
69. Colombo M, Figueiro F, de Fraga Dias A, Teixeira HF, Battastini AMO, Koester LS. Kaempferol-loaded mucoadhesive nanoemulsion for intranasal administration reduces glioma growth in vitro. Int J Pharm 2018;543:214–23.
70. Van Woensel M, Wauthoz N, Rosiere R, Mathieu V, Kiss R, Lefranc F, et al. Development of siRNA-loaded chitosan nanoparticles targeting galectin-1 for the treatment of glioblastoma multiforme via intranasal administration. J Controlled Release 2016;227:71–81.
71. Jain DS, Bajaj AN, Athawale RB, Shikhande SS, Pandey A, Goel PN, et al. Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route. Mater Sci Eng C 2016;63:411–21.
72. Mangraviti A, Tzeng SY, Gullotti D, Kozielski KL, Kim JE, Seng M, et al. Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. Biomaterials 2016;100:53–66.
73. Taki H, Kanazawa T, Akiyama F, Takashima Y, Okada H. Intranasal delivery of camptothecin-loaded tat-modified nanomicells for treatment of intracranial brain tumors. Pharmaceuticals 2012;5:1092–102.
74. Sun Y, Shi K, Wan F, Cui F. Methotrexate-loaded microspheres for nose to brain delivery: in vitro/in vivo evaluation. J Drug Delivery Sci Technol 2012;22:167–74.
75. Jr P, M J, A A, Mp J, H C, Boussin FD. Intranasal administration of temozolomide delayed the development of brain tumors initiated by human glioma stem-like cell in nude mice. J Cancer Sci Ther; 2017. p. 9. Available from: [Last accessed on 07 Sep 2020].
76. DA Fonseca CO, Teixeira RM, Silva JCT, DE Saldanha DA Gama Fischer J, Meirelles OC, Landeiro JA, et al. Long-term outcome in patients with recurrent malignant glioma treated with perillyl alcohol inhalation. Anticancer Res 2013;33:5625–31.
77. Da Fonseca CO, Schwartsmann G, Fischer J, Nagel J, Futuro D, Quirico Santos T, et al. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surgical Neurol 2008;70:259-66.
78. Fonseca COD, Silva JT, Lins IR, Simao M, Arnobio A, Futuro D, et al. Correlation of tumor topography and peritumoral edema of recurrent malignant gliomas with therapeutic response to intranasal administration of perillyl alcohol. Invest New Drugs 2009;27:557-64.
79. Da Fonseca CO, Masini M, Futuro D, Caetano R, Rocha Gattass C, Quirico Santos T. Anaplastic oligodendroglioma responding favorably to intranasal delivery of perillyl alcohol: a case report and literature review. Surg Neurol 2006;66:611–5.
80. da Fonseca CO, Schwartsmann G, Fischer J, Nagel J, Futuro D, Quirico Santos T, 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.
81. Chen TC, Da Fonseca CO, Schönthal AH. Intranasal perillyl alcohol for glioma therapy: molecular mechanisms and clinical development. Int J Mol Sci 2018;19:3905.
82. Santos J, Da Cruz WM, Schinthal A, Salazar M, Fontes CA, Quirico Santos T, et al. efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma. Oncol Lett 2017. Available from: 10.3892/ol.2017.7362 [Last accessed on 17 Sep 2020].
83. Patel A, Surti N, Mahajan A. Intranasal drug delivery: Novel delivery route for effective management of neurological disorders. J Drug Delivery Sci Technol 2019;52:130–7.
84. Bhardwaj A, Arora R. Nanoformulations: a novel approach against hypoxia. Manag High Alt Pathophysiol. Elsevier; 2018. p. 231–56. Available from: retrieve/pii/B9780128139998000124 [Last accessed on 12 Sep 2020].
85. Sardoiwala MN, Kaundal B, Roy Choudhury S. Development of engineered nanoparticles expediting diagnostic and therapeutic applications across blood–brain barrier. Handb Nanomater Ind Appl Elsevier; 2018. p. 696–709. Available from: [Last accessed on 12 Sep 2020].
86. Chatterjee B, Gorain B, Mohananaidu K, Sengupta P, Mandal UK, Choudhury H. Targeted drug delivery to the brain via intranasal nanoemulsion. Int J Pharm 2019;565:258–68.
87. Ansari R, Sadati SM, Mozafari N, Ashrafi H, Azadi A. Carbohydrate polymer-based nanoparticle application in drug delivery for CNS-related disorders. Eur Polym J 2020;128:109607.
88. Agrawal M, Saraf S, Saraf S, Dubey SK, Puri A, Gupta U, et al. Stimuli-responsive In situ gelling system for nose-to-brain drug delivery. J Controlled Release 2020;327:235–65.
89. Tsai HC, Imae T. Fabrication of dendrimers toward biological application. Prog Mol Biol Transl Sci Elsevier; 2011. p. 101–40. Available from: pii/B9780124160200000036 [Last accessed on 12 Sep 2020].
39 Views | 11 Downloads
How to Cite
SHEHU, I. A., ISLAM, M., & SINGH, V. (2021). NOSE-TO-BRAIN DELIVERY, A ROUTE OF CHOICE FOR TARGETING BRAIN TUMORS. International Journal of Applied Pharmaceutics, 13(3), 39-46.
Review Article(s)