Therapeutic Intranasal Delivery for Alzheimer’s Disease

  • Xinxin Wang
  • Fangxia Guan
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


Alzheimer’s disease (AD) is an age-related detrimental neurodegenerative disorder with no effective treatment, which is clinically characterized by progressive memory decline and cognitive dysfunction, altered decision making, apraxia, language disturbances, etc., and often histologically manifested by the deposition of amyloid-beta (Aβ) plaques and the formation of neurofibrillary tangles. AD is a global health crisis, currently, more than 35 million people worldwide were estimated to be afflicted by AD, and the number is expect to increase with the aging of the society. Current therapy is based on neurotransmitter or enzyme replacement/modulation, and recently, stem cells therapy is proposed as a promising strategy for AD. However, effective strategies for AD treatment has not been achieved. One of the major problems is the blood–brain barrier (BBB), which hampers drug delivery into the brain. Intranasal (IN) route will overcome this obstacle by delivering drugs or cells directly to the central nervous system (CNS) through the olfactory and trigeminal neural pathways. Here, we demonstrate how intranasal delivery systems works and its advantages and disadvantages. Moreover, we discuss and summarize some latest findings on IN delivery of drug and cell in AD models, with a focus on the potential efficacy of treatments for AD.


Intranasal delivery Therapy Alzheimer’s disease 


  1. 1.
    Sindi S, Mangialasche F, Kivipelto M. Advances in the prevention of Alzheimer’s disease. F1000Prime Rep. 2015;7:50.CrossRefGoogle Scholar
  2. 2.
    Hu J, Lin T, Gao Y, et al. The resveratrol trimer miyabenol C inhibits beta-secretase activity and beta-amyloid generation. PLoS One. 2015;10(1):e0115973.CrossRefGoogle Scholar
  3. 3.
    Sood S, Jain K, Gowthamarajan K. Intranasal therapeutic strategies for management of Alzheimer’s disease. J Drug Target. 2014;22(4):279–94.CrossRefGoogle Scholar
  4. 4.
    Xiao C, Davis FJ, Chauhan BC, et al. Brain transit and ameliorative effects of intranasally delivered anti-amyloid-beta oligomer antibody in 5XFAD mice. J Alzheimers Dis. 2013;35(4):777–88.CrossRefGoogle Scholar
  5. 5.
    Jogani VV, Shah PJ, Mishra P, et al. Nose-to-brain delivery of tacrine. J Pharm Pharmacol. 2007;59(9):1199–205.CrossRefGoogle Scholar
  6. 6.
    Jogani VV, Shah PJ, Mishra P, et al. Intranasal mucoadhesive microemulsion of tacrine to improve brain targeting. Alzheimer Dis Assoc Disord. 2008;22(2):116–24.CrossRefGoogle Scholar
  7. 7.
    Luppi B, Bigucci F, Corace G, et al. Albumin nanoparticles carrying cyclodextrins for nasal delivery of the anti-Alzheimer drug tacrine. Eur J Pharm Sci. 2011;44(4):559–65.CrossRefGoogle Scholar
  8. 8.
    Leonard AK, Sileno AP, MacEvilly C, et al. Development of a novel high-concentration galantamine formulation suitable for intranasal delivery. J Pharm Sci. 2005;94(8):1736–46.CrossRefGoogle Scholar
  9. 9.
    Leonard AK, Sileno AP, Brandt GC, et al. In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo. Int J Pharm. 2007;335(1–2):138–46.CrossRefGoogle Scholar
  10. 10.
    Hanafy AS, Farid RM, ElGamal SS. Complexation as an approach to entrap cationic drugs into cationic nanoparticles administered intranasally for Alzheimer’s disease management: preparation and detection in rat brain. Drug Dev Ind Pharm. 2015;41(12):2055–68.CrossRefGoogle Scholar
  11. 11.
    Yang ZZ, Zhang YQ, Wu K, et al. Tissue distribution and pharmacodynamics of rivastigmine after intranasal and intravenous administration in rats. Curr Alzheimer Res. 2012;9(3):315–25.CrossRefGoogle Scholar
  12. 12.
    Shah BM, Misra M, Shishoo CJ, et al. Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization. Drug Deliv. 2015;22(7):918–30.CrossRefGoogle Scholar
  13. 13.
    Arumugam K, Subramanian GS, Mallayasamy SR, et al. A study of rivastigmine liposomes for delivery into the brain through intranasal route. Acta Pharm. 2008;58(3):287–97.CrossRefGoogle Scholar
  14. 14.
    Fazil M, Md S, Haque S, et al. Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting. Eur J Pharm Sci. 2012;47(1):6–15.CrossRefGoogle Scholar
  15. 15.
    Hussain MA, Mollica JA. Intranasal absorption of physostigmine and arecoline. J Pharm Sci. 1991;80(8):750–1.CrossRefGoogle Scholar
  16. 16.
    Dahlin M, Bjork E. Nasal administration of a physostigmine analogue (NXX-066) for Alzheimer’s disease to rats. Int J Pharm. 2001;212(2):267–74.CrossRefGoogle Scholar
  17. 17.
    Zhao Y, Yue P, Tao T, et al. Drug brain distribution following intranasal administration of Huperzine A in situ gel in rats. Acta Pharmacol Sin. 2007;28(2):273–8.CrossRefGoogle Scholar
  18. 18.
    Illum L. Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems? J Pharm Sci. 2007;96(3):473–83.CrossRefGoogle Scholar
  19. 19.
    Muntimadugu E, Dhommati R, Jain A, et al. Intranasal delivery of nanoparticle encapsulated tarenflurbil: a potential brain targeting strategy for Alzheimer’s disease. Eur J Pharm Sci. 2016;92:224–34.CrossRefGoogle Scholar
  20. 20.
    Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in Alzheimer’s disease. Neurobiol Aging. 1996;17(1):123–30.CrossRefGoogle Scholar
  21. 21.
    Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10):1326–34.CrossRefGoogle Scholar
  22. 22.
    Zhang C, Chen J, Feng C, et al. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer’s disease. Int J Pharm. 2014;461(1–2):192–202.CrossRefGoogle Scholar
  23. 23.
    de la Monte SM. Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer’s disease therapeutics. Aging Health. 2012;8(1):61–4.CrossRefGoogle Scholar
  24. 24.
    Hanson LR, Fine JM, Renner DB, et al. Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice. Drug Deliv Transl Res. 2012;2(3):160–8.CrossRefGoogle Scholar
  25. 25.
    Guo C, Wang T, Zheng W, et al. Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 2013;34(2):562–75.CrossRefGoogle Scholar
  26. 26.
    Fine JM, Forsberg AC, Stroebel BM, et al. Intranasal deferoxamine affects memory loss, oxidation, and the insulin pathway in the streptozotocin rat model of Alzheimer’s disease. J Neurol Sci. 2017;380:164–71.CrossRefGoogle Scholar
  27. 27.
    Wong LR, Ho PC. Role of serum albumin as a nanoparticulate carrier for nose-to-brain delivery of R-flurbiprofen: implications for the treatment of Alzheimer’s disease. J Pharm Pharmacol. 2017;70(1):59–69.CrossRefGoogle Scholar
  28. 28.
    Lou G, Zhang Q, Xiao F, et al. Intranasal administration of TAT-haFGF((1)(4)(-)(1)(5)(4)) attenuates disease progression in a mouse model of Alzheimer’s disease. Neuroscience. 2012;223:225–37.CrossRefGoogle Scholar
  29. 29.
    Chen X, Zhi F, Jia X, et al. Enhanced brain targeting of curcumin by intranasal administration of a thermosensitive poloxamer hydrogel. J Pharm Pharmacol. 2013;65(6):807–16.CrossRefGoogle Scholar
  30. 30.
    Sood S, Jain K, Gowthamarajan K. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment. Colloids Surf B: Biointerfaces. 2014;113:330–7.CrossRefGoogle Scholar
  31. 31.
    Elnaggar YSR, Etman SM, Abdelmonsif DA, et al. Intranasal piperine-loaded chitosan nanoparticles as brain-targeted therapy in Alzheimer’s disease: optimization, biological efficacy, and potential toxicity. J Pharm Sci. 2015;104(10):3544–56.CrossRefGoogle Scholar
  32. 32.
    Danielyan L, Klein R, Hanson LR, et al. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res. 2010;13(2–3):195–201.CrossRefGoogle Scholar
  33. 33.
    Chen XQ, Fawcett JR, Rahman YE, et al. Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimer’s Dis. 1998;1(1):35–44.CrossRefGoogle Scholar
  34. 34.
    Capsoni S, Covaceuszach S, Ugolini G, et al. Delivery of NGF to the brain: intranasal versus ocular administration in anti-NGF transgenic mice. J Alzheimer’s Dis. 2009;16(2):371–88.CrossRefGoogle Scholar
  35. 35.
    Capsoni S, Marinelli S, Ceci M, et al. Intranasal “painless” human Nerve Growth Factor [corrected] slows amyloid neurodegeneration and prevents memory deficits in App X PS1 mice. PLoS One. 2012;7(5):e37555.CrossRefGoogle Scholar
  36. 36.
    Reuss B, und Halbach OVB. Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res. 2003;313(2):139–57.CrossRefGoogle Scholar
  37. 37.
    Meng T, Cao Q, Lei P, et al. Tat-haFGF14-154 upregulates ADAM10 to attenuate the Alzheimer phenotype of APP/PS1 mice through the PI3K-CREB-IRE1alpha/XBP1 pathway. Mol Ther Nucleic Acids. 2017;7:439–52.CrossRefGoogle Scholar
  38. 38.
    Anitua E, Pascual C, Antequera D, et al. Plasma rich in growth factors (PRGF-Endoret) reduces neuropathologic hallmarks and improves cognitive functions in an Alzheimer’s disease mouse model. Neurobiol Aging. 2014;35(7):1582–95.CrossRefGoogle Scholar
  39. 39.
    Gozes I, Bardea A, Reshef A, et al. Neuroprotective strategy for Alzheimer disease: intranasal administration of a fatty neuropeptide. Proc Natl Acad Sci U S A. 1996;93(1):427–32.CrossRefGoogle Scholar
  40. 40.
    Cheng YS, Chen ZT, Liao TY, et al. An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice. EMBO Mol Med. 2017;9(5):703–15.CrossRefGoogle Scholar
  41. 41.
    Rangasamy SB, Corbett GT, Roy A, et al. Intranasal delivery of NEMO-binding domain peptide prevents memory loss in a mouse model of Alzheimer’s disease. J Alzheimer’s Dis. 2015;47(2):385–402.CrossRefGoogle Scholar
  42. 42.
    Zheng X, Shao X, Zhang C, et al. Intranasal H102 peptide-loaded liposomes for brain delivery to treat Alzheimer’s disease. Pharm Res. 2015;32(12):3837–49.CrossRefGoogle Scholar
  43. 43.
    Jayachandra Babu R, Dayal PP, Pawar K, et al. Nose-to-brain transport of melatonin from polymer gel suspensions: a microdialysis study in rats. J Drug Target. 2011;19(9):731–40.CrossRefGoogle Scholar
  44. 44.
    Tschiffely AE, Schuh RA, Prokai-Tatrai K, et al. A comparative evaluation of treatments with 17beta-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer’s disease. Horm Behav. 2016;83:39–44.CrossRefGoogle Scholar
  45. 45.
    Al-Ghananeem AM, Traboulsi AA, Dittert LW, et al. Targeted brain delivery of 17 beta-estradiol via nasally administered water soluble prodrugs. AAPS PharmSciTech. 2002;3(1):E5.CrossRefGoogle Scholar
  46. 46.
    Wang X, Chi N, Tang X. Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting. Eur J Pharm Biopharm. 2008;70(3):735–40.CrossRefGoogle Scholar
  47. 47.
    Stutzmann GE, Irwin RW, Solinsky CM, et al. Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer’s disease. PLoS One. 2015;10(6):e0128313.CrossRefGoogle Scholar
  48. 48.
    Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000;6(8):916–9.CrossRefGoogle Scholar
  49. 49.
    Cattepoel S, Hanenberg M, Kulic L, et al. Chronic intranasal treatment with an anti-Abeta(30-42) scFv antibody ameliorates amyloid pathology in a transgenic mouse model of Alzheimer’s disease. PLoS One. 2011;6(4):e18296.CrossRefGoogle Scholar
  50. 50.
    Chauhan NB, Davis F, Xiao C. Wheat germ agglutinin enhanced cerebral uptake of anti-Abeta antibody after intranasal administration in 5XFAD mice. Vaccine. 2011;29(44):7631–7.CrossRefGoogle Scholar
  51. 51.
    Danielyan L, Beer-Hammer S, Stolzing A, et al. Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer’s and Parkinson’s disease. Cell Transplant. 2014;23(Suppl 1):S123–39.CrossRefGoogle Scholar
  52. 52.
    Harach T, Jammes F, Muller C, et al. Administrations of human adult ischemia-tolerant mesenchymal stem cells and factors reduce amyloid beta pathology in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2017;51:83–96.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Xinxin Wang
    • 1
  • Fangxia Guan
    • 1
    • 2
  1. 1.The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  2. 2.School of Life SciencesZhengzhou UniversityZhengzhouChina

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