Pharmaceutical Research

, Volume 32, Issue 12, pp 3837–3849 | Cite as

Intranasal H102 Peptide-Loaded Liposomes for Brain Delivery to Treat Alzheimer’s Disease

  • Xiaoyao Zheng
  • Xiayan Shao
  • Chi Zhang
  • Yuanzhen Tan
  • Qingfeng Liu
  • Xu Wan
  • Qizhi ZhangEmail author
  • Shumei Xu
  • Xinguo Jiang
Research Paper



H102, a novel β-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer’s disease (AD).


The H102 liposomes were prepared using a modified thin film hydration method, and their transport characteristics were tested on Calu-3 cell monolayers. The pharmacokinetics in rats’ blood and brains were also investigated. Behavioral experiments were performed to evaluate the improvements on AD rats’ spatial memory impairment. The neuroprotective effects were tested by detecting acetylcholinesterase (AchE), choline acetyltransferase (ChAT) and insulin degrading enzyme (IDE) activity and conducting histological assays. The safety was evaluated on rats’ nasal mucosa and cilia.


The liposomes prepared could penetrate Calu-3 cell monolayers consistently. After intranasal administration, H102 could be effectively delivered to the brain, and the AUC of H102 liposomes in the hippocampus was 2.92-fold larger than that of solution group. H102 liposomes could excellently ameliorate spatial memory impairment of AD model rats, increase the activities of ChAT and IDE and inhibit plaque deposition, even in a lower dosage compared with H102 intranasal solution. H102 nasal formulations showed no toxicity on nasal mucosa.


The H102-loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment.


H102 peptide Liposome Intranasal administration Brain delivery Alzheimer’s disease (AD) 





Alzheimer’s disease

β-amyloid protein


Blood–brain barrier


Circular dichroism


Choline acetyltransferase


Central nervous system






Egg phosphatidylcholine




Insulin degrading enzyme


Olfactory bulb


Poly ethylene glycol


Transendothelial electrical resistance



This work was supported by grants from the National Science and Technology Major Project 2009ZX09103-029 and The Open Project Program of Key Lab of Smart Drug Delivery (Fudan University), Ministry of Education, China.

Supplementary material

11095_2015_1744_MOESM1_ESM.docx (14 kb)
Table S1 (DOCX 13 kb)
11095_2015_1744_MOESM2_ESM.docx (15 kb)
Table S2 (DOCX 15 kb)
11095_2015_1744_MOESM3_ESM.docx (15 kb)
Table S3 (DOCX 14 kb)
11095_2015_1744_MOESM4_ESM.docx (102 kb)
Fig. S1 (DOCX 101 kb)


  1. 1.
    Bolukbasi HF, Hatip-Al-Khatib I. Effects of beta-sheet breaker peptides on altered responses of thoracic aorta in rats’ Alzheimer’s disease model induced by intraamygdaloid Aβ40. Life Sci. 2013;92(3):228–36.CrossRefGoogle Scholar
  2. 2.
    Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 2007;3(3):186–91.CrossRefPubMedGoogle Scholar
  3. 3.
    Kurz A, Perneczky R. Novel insights for the treatment of Alzheimer’s disease. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35(2):373–9.CrossRefGoogle Scholar
  4. 4.
    Liu Y, Hua Q, Lei H, Li P. Effect of Tong Luo Jiu Nao on Aβ-degrading enzymes in AD rat brains. J Ethnopharmacol. 2011;137(2):1035–46.CrossRefPubMedGoogle Scholar
  5. 5.
    Chacon MA, Barria MI, Soto C, Inestrosa NC. β-sheet breaker peptide prevents Aβ-induced spatial memory impairments with partial reduction of amyloid deposits. Mol Psychiatry. 2004;9(10):953–61.CrossRefPubMedGoogle Scholar
  6. 6.
    Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416(6880):535–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Bruinsma IB, Karawajczyk A, Schaftenaar G, de Waal RM, Verbeek MM, van Delft FL. A rational design to create hybrid β-sheet breaker peptides to inhibit aggregation and toxicity of amyloid-β. Med Chem Commun. 2011;2(1):60–4.CrossRefGoogle Scholar
  8. 8.
    Lin LX, Bo XY, Tan YZ, Sun FX, Song M, Zhao J, et al. Feasibility of β-sheet breaker peptide-H102 treatment for Alzheimer’s disease based on β-amyloid hypothesis. PLoS One. 2014;9(11), e112052.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Soto C, Kindy MS, Baumann M, Frangione B. Inhibition of Alzheimer’s amyloidosis by peptides that prevent β-sheet conformation. Biochem Biophys Res Commun. 1996;226(3):672–80.CrossRefPubMedGoogle Scholar
  10. 10.
    Benedict C, Hallschmid M, Schultes B, Born J, Kern W. Intranasal insulin to improve memory function in humans. Neuroendocrinology. 2007;86(2):136–42.CrossRefPubMedGoogle Scholar
  11. 11.
    Vaka SR, Sammeta SM, Day LB, Murthy SN. Delivery of nerve growth factor to brain via intranasal administration and enhancement of brain uptake. J Pharm Sci. 2009;98(10):3640–6.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Ma YP, Ma MM, Cheng SM, et al. Intranasal bFGF-induced progenitor cell proliferation and neuroprotection after transient focal cerebral ischemia. Neurosci Lett. 2008;437(2):93–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Feng C, Zhang C, Shao X, et al. Enhancement of nose-to-brain delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of beta-amyloid and ibotenic acid into the bilateral hippocampus. Int J Pharm. 2012;423(2):226–34.CrossRefPubMedGoogle Scholar
  14. 14.
    Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000;11(1):1–18.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang C, Zheng X, Wan X, et al. The potential use of H102 peptide-loaded dual-functional nanoparticles in the treatment of Alzheimer’s disease. J Control Release. 2014;192:317–24.CrossRefPubMedGoogle Scholar
  16. 16.
    Cao S, Ren X, Zhang Q, et al. In situ gel based on gellan gum as new carrier for nasal administration of mometasone furoate. Int J Pharm. 2009;365(1):109–15.CrossRefPubMedGoogle Scholar
  17. 17.
    Yuan J. Estimation of variance for AUC in animal studies. J Pharm Sci. 1993;82(7):761–3.CrossRefPubMedGoogle Scholar
  18. 18.
    Takeda S, Sato N, Niisato K, et al. Validation of Aβ1-40 administration into mouse cerebroventricles as an animal model for Alzheimer disease. Brain Res. 2009;1280:137–47.CrossRefPubMedGoogle Scholar
  19. 19.
    Jiang XG, Cui JB, Fang XL, Wei Y, Xi NZ. Toxicity of drugs on nasal mucocilia and the method of its evaluation. Yao Xue Xue Bao. 1995;30(11):848–53.PubMedGoogle Scholar
  20. 20.
    Kumaraswamy P, Sethuramanand S, Krishnan UM. Development of a dual nanocarrier system as a potential stratagem against amyloid-induced toxicity. Expert Opin Drug Deliv. 2014;11(8):1131–47.CrossRefPubMedGoogle Scholar
  21. 21.
    Driton V, Ruth E, Angeles H, Luca C, Martin G, Lisbeth I, et al. Tight junction modulation by chitosan nanoparticles: comparison with chitosan solution. Int J Pharm. 2010;400(1–2):183–93.Google Scholar
  22. 22.
    Zheng C, Guo Q, Wu Z, Sun L, Zhang Z, Li C, et al. Amphiphilic glycopolymer nanoparticles as vehicles for nasal delivery of peptides and proteins. Eur J Pharm Sci. 2013;49(4):474–82.CrossRefPubMedGoogle Scholar
  23. 23.
    Vllasaliu D, Casettari L, Fowler R, Exposito-Harris R, Garnett M, Illum L, et al. Absorption-promoting effects of chitosan in airway and intestinal cell lines: a comparative study. Int J Pharm. 2012;430(1):151–60.CrossRefPubMedGoogle Scholar
  24. 24.
    Illum L. Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems? J Pharm Sci. 2007;96(3):473–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Kean T, Thanou M. Biodegradation, biodistribution and toxicity of chitosan. Adv Drug Deliv Rev. 2010;62(1):3–11.CrossRefPubMedGoogle Scholar
  26. 26.
    Abhay U, Renee R, Wyatt N, Don L, Peter W. Microfluidic preparation of liposomes to determine particle size influence on cellular uptake mechanisms. Pharm Res. 2014;31(2):401–13.CrossRefGoogle Scholar
  27. 27.
    Lotjonen J, Wolz R, Koikkalainen J, Julkunen V, Thurfjell L, Lundqvist R, et al. Fast and robust extraction of hippocampus from MR images for diagnostics of Alzheimer’s disease. NeuroImage. 2011;56(1):185–96.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Liu Q, Shen Y, Chen J, Gao X, Feng C, Wang L, et al. Nose-to-brain transport pathways of wheat germ agglutinin conjugated PEG-PLA nanoparticles. Pharm Res. 2012;29(2):546–58.CrossRefPubMedGoogle Scholar
  29. 29.
    Dhuria SV, Hanson LR, Frey 2nd WH. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010;99(4):1654–73.PubMedGoogle Scholar
  30. 30.
    Liu QF, Shen YH, Chen J, Gao XL, Feng CC, Wang L, et al. Nose-to-brain transport pathways of wheat germ agglutinin conjugated PEG-PLA nanoparticles. Pharm Res. 2012;29(2):546–58.CrossRefPubMedGoogle Scholar
  31. 31.
    Carvajal FJ, Inestrosa NC. Interactions of AChE with Aβ aggregates in Alzheimer’s brain: therapeutic relevance of IDN 5706. Front Mol Neurosci. 2011;4:19.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S. Aβ-degrading enzymes in Alzheimer’s disease. Brain Pathol. 2008;18(2):240–52.CrossRefPubMedGoogle Scholar
  33. 33.
    Funalot B, Ouimet T, Claperon A, et al. Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer’s disease. Mol Psychiatry. 2004;9(12):1122–8. 1058.CrossRefPubMedGoogle Scholar
  34. 34.
    McGowan E, Eriksen J, Hutton M. A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet. 2006;22(5):281–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Chen F, David D, Ferrari A, Gotz J. Posttranslational modifications of tau-role in human tauopathies and modeling in transgenic animals. Curr Drug Targets. 2004;5(6):503–15.CrossRefPubMedGoogle Scholar
  36. 36.
    Johann M, Vanessa V, Laurent G, Tangui M. The γ-secretase inhibitor 2-[(1R)-1-[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl) amino]ethyl-5-fluorobenzenebutanoic acid (BMS-299897) alleviates Aβ1–42 seeding and short-term memory deficits in the Aβ25–35 mouse model of Alzheimer’s disease. Eur J Pharmacol. 2013;698(1–3):193–9.Google Scholar
  37. 37.
    Capurro V, Busquet P, Lopes J, Bertorelli R, Tarozzo G, Bolognesi M, et al. Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer’s disease. PLoS ONE. 2013;8(2), e56870.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Van DD, De Deyn PP. Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov. 2006;5(11):956–70.CrossRefGoogle Scholar
  39. 39.
    Nomura I, Takechi H, Kato N. Intraneuronally injected amyloid beta inhibits long-term potentiation in rat hippocampal slices. J Neurophysiol. 2012;107(9):2526–31.CrossRefPubMedGoogle Scholar
  40. 40.
    Lian T, Ho RJ. Trends and developments in liposome drug delivery systems. J Pharm Sci. 2001;90(6):667–80.CrossRefPubMedGoogle Scholar
  41. 41.
    Samad A, Sultana Y, Aqil M. Liposomal drug delivery systems: an update review. Curr Drug Deliv. 2007;4(4):297–305.CrossRefPubMedGoogle Scholar
  42. 42.
    Pujol I, Serracant A, Cano M, Ampudia RM, Rodriguez S, Sanchez A. Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes. PLoS ONE. 2015;10(6), e0127057.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Xiaoyao Zheng
    • 1
  • Xiayan Shao
    • 1
  • Chi Zhang
    • 1
  • Yuanzhen Tan
    • 2
  • Qingfeng Liu
    • 1
  • Xu Wan
    • 1
  • Qizhi Zhang
    • 1
    • 3
    Email author
  • Shumei Xu
    • 2
  • Xinguo Jiang
    • 1
  1. 1.Key Laboratory of Smart Drug DeliveryMinistry of Education (Fudan University)ShanghaiPeople’s Republic of China
  2. 2.Department of PhysiologyTianjin Medical UniversityTianjinPeople’s Republic of China
  3. 3.Department of Pharmaceutics, School of PharmacyFudan UniversityShanghaiPeople’s Republic of China

Personalised recommendations