Skip to main content

Advertisement

SpringerLink
Log in

Development of Imatinib Mesylate-Loaded Liposomes for Nose to Brain Delivery: In Vitro and In Vivo Evaluation

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Neurodegenerative diseases like Alzheimer’s disease require treatment where it is essential for drug to reach brain. Nose to brain delivery of drugs enables direct transport to brain bypassing blood brain barrier. Imatinib mesylate, an anti-cancer agent, was found to have potential anti-Alzheimer’s activity and thus repurposed for the same. However, the drug has severe side effects, poor brain bioavailability which may hinder effective treatment of Alzheimer’s disease. In the current work, imatinib mesylate-loaded liposomes were prepared with particle size below 150 nm with sustained drug release up to 96 h. The liposomal drug formulation was compared with plain drug solution for cytotoxicity on N2a cells and did not show any kind of toxicity at concentrations up to 25 μg/mL. The nanocarrier formulation was then evaluated for brain deposition by nose to brain administration in comparison with drug solution in rats. The liposomes effectively improved the brain deposition of drug in brain from formulation compared to pure drug solution as indicated by AUC from in vivo experiments. These results indicate that the nose to brain delivery of liposomal imatinib mesylate improved the drug deposition and residence time in brain compared to drug solution administered through oral and intranasal routes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2(1):3–14.

    Article  Google Scholar 

  2. De Rosa G, Salzano G, Caraglia M, Abbruzzese A. Nanotechnologies: a strategy to overcome blood-brain barrier. Curr Drug Metab. 2012;13(1):61–9.

    Article  Google Scholar 

  3. Vyas TK, Shahiwala A, Marathe S, Misra A. Intranasal drug delivery for brain targeting. Curr Drug Deliv. 2005;2(2):165–75.

    Article  CAS  Google Scholar 

  4. Illum L. Is nose-to-brain transport of drugs in man a reality? J Pharm Pharmacol. 2004;56(1):3–17.

    Article  CAS  Google Scholar 

  5. Mittal D, Ali A, Md S, Baboota S, Sahni JK, Ali J. Insights into direct nose to brain delivery: current status and future perspective. Drug Deliv. 2014;21(2):75–86.

    Article  CAS  Google Scholar 

  6. Bangham A, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol. 1965;13(1):238–IN27.

    Article  CAS  Google Scholar 

  7. Zheng X, Shao X, Zhang C, Tan Y, Liu Q, Wan X, et al. Intranasal H102 peptide-loaded liposomes for brain delivery to treat Alzheimer’s disease. Pharm Res. 2015;32(12):3837–49.

    Article  CAS  Google Scholar 

  8. Yang Z-Z, Zhang Y-Q, Wang Z-Z, Wu K, Lou J-N, Qi X-R. Enhanced brain distribution and pharmacodynamics of rivastigmine by liposomes following intranasal administration. Int J Pharm. 2013;452(1–2):344–54.

    Article  CAS  Google Scholar 

  9. Muntimadugu E, Dhommati R, Jain A, Challa VGS, Shaheen M, Khan W. Intranasal delivery of nanoparticle encapsulated tarenflurbil: a potential brain targeting strategy for Alzheimer’s disease. Eur J Pharm Sci. 2016;92:224–34.

    Article  CAS  Google Scholar 

  10. Samudre S, Tekade A, Thorve K, Jamodkar A, Parashar G, Chaudhari N. Xanthan gum coated mucoadhesive liposomes for efficient nose to brain delivery of curcumin. Drug Deliv Lett. 2015;5(3):201–7.

    Article  CAS  Google Scholar 

  11. Association As. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 2016;12(4):459–509.

    Article  Google Scholar 

  12. Prince MJ. World Alzheimer Report 2015: the global impact of dementia: an analysis of prevalence, incidence, cost and trends. Alzheimer’s Disease International; 2015 [cited 2020 29 June]; Available from: https://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf.

  13. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348(14):1356–64.

    Article  CAS  Google Scholar 

  14. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6.

    Article  CAS  Google Scholar 

  15. Maccioni RB, Farías G, Morales I, Navarrete L. The revitalized tau hypothesis on Alzheimer’s disease. Arch Med Res. 2010;41(3):226–31.

    Article  CAS  Google Scholar 

  16. Savage DG, Antman KH. Imatinib mesylate—a new oral targeted therapy. N Engl J Med. 2002;346(9):683–93.

    Article  CAS  Google Scholar 

  17. Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, et al. Gleevec inhibits β-amyloid production but not Notch cleavage. Proc Natl Acad Sci. 2003;100(21):12444–9.

    Article  CAS  Google Scholar 

  18. Netzer WJ, Bettayeb K, Sinha SC, Flajolet M, Greengard P, Bustos V. Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage. Proc Natl Acad Sci. 2017;114(6):1389–94.

    Article  CAS  Google Scholar 

  19. Sun W, Netzer WJ, Sinha A, Gindinova K, Chang E, Sinha SC. Development of Gleevec analogues for reducing production of β-amyloid peptides through shifting β-cleavage of amyloid precursor proteins. J Med Chem. 2019;62(6):3122–34.

    Article  CAS  Google Scholar 

  20. Senior K. Gleevec does not cross blood–brain barrier. Lancet Oncol. 2003;4(4):198.

    Article  Google Scholar 

  21. Wolff NC, Richardson JA, Egorin M, Ilaria RL. The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia. Blood. 2003;101(12):5010–3.

    Article  CAS  Google Scholar 

  22. Leis JF, Stepan DE, Curtin PT, Ford JM, Peng B, Schubach S, et al. Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma. 2004;45(4):695–8.

    Article  CAS  Google Scholar 

  23. Hada N, Netzer WJ, Belhassan F, Wennogle LP, Gizurarson S. Nose-to-brain transport of imatinib mesylate: a pharmacokinetic evaluation. Eur J Pharm Sci. 2017;102:46–54.

    Article  CAS  Google Scholar 

  24. Hasin F, Islam M, Ahmad M, Rahib M, Hasan M. Validation of assay method for the estimation of imatinib mesylate in tablet dosage form by HPLC. Eur J Biomed Pharm Sci. 2017;4(7):74–81.

  25. Bharate SS, Bharate SB, Bajaj AN. Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. J Excip Food Chem. 2016;1(3):1131.

    Google Scholar 

  26. Kommineni N, Mahira S, Domb AJ, Khan W. Cabazitaxel-loaded nanocarriers for cancer therapy with reduced side effects. Pharmaceutics. 2019;11(3):141.

    Article  CAS  Google Scholar 

  27. Jaafar-Maalej C, Diab R, Andrieu V, Elaissari A, Fessi H. Ethanol injection method for hydrophilic and lipophilic drug-loaded liposome preparation. J Liposome Res. 2010;20(3):228–43.

    Article  CAS  Google Scholar 

  28. Briuglia M-L, Rotella C, McFarlane A, Lamprou DA. Influence of cholesterol on liposome stability and on in vitro drug release. Drug Deliv Transl Res. 2015;5(3):231–42.

    Article  CAS  Google Scholar 

  29. Abraham SA, Waterhouse DN, Mayer LD, Cullis PR, Madden TD, Bally MB. The liposomal formulation of doxorubicin. Methods Enzymol: Elsevier. 2005; 391:71–97.

  30. Haran G, Cohen R, Bar LK, Barenholz Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. BBA Biomembranes. 1993;1151(2):201–15.

    Article  CAS  Google Scholar 

  31. Hwang S, Maitani Y, Qi X-R, Takayama K, Nagai T. Remote loading of diclofenac, insulin and fluorescein isothiocyanate labeled insulin into liposomes by pH and acetate gradient methods. Int J Pharm. 1999;179(1):85–95.

    Article  CAS  Google Scholar 

  32. Pecora R. Dynamic light scattering measurement of nanometer particles in liquids. J Nanopart Res. 2000;2(2):123–31.

    Article  CAS  Google Scholar 

  33. Kaszuba M, Corbett J, Watson FM, Jones A. High-concentration zeta potential measurements using light-scattering techniques. Philos Trans R Soc A. 2010;368(1927):4439–51.

    Article  CAS  Google Scholar 

  34. Bibi S, Kaur R, Henriksen-Lacey M, McNeil SE, Wilkhu J, Lattmann E, et al. Microscopy imaging of liposomes: from coverslips to environmental SEM. Int J Pharm. 2011;417(1–2):138–50.

    Article  CAS  Google Scholar 

  35. Doppalapudi S, Mahira S, Khan W. Development and in vitro assessment of psoralen and resveratrol co-loaded ultradeformable liposomes for the treatment of vitiligo. J Photochem Photobiol B. 2017;174:44–57.

    Article  CAS  Google Scholar 

  36. Govender T, Stolnik S, Garnett MC, Illum L, Davis SS. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J Control Release. 1999;57(2):171–85.

    Article  CAS  Google Scholar 

  37. Shaikh HK, Kshirsagar R, Patil S. Mathematical models for drug release characterization: a review. World J Pharm Pharm Sci. 2015;4(4):324–38.

    CAS  Google Scholar 

  38. Aydin E, Türkez H, Geyikoğlu F. Antioxidative, anticancer and genotoxic properties of α-pinene on N2a neuroblastoma cells. Biologia. 2013;68(5):1004–9.

    Article  CAS  Google Scholar 

  39. Hussain I, Fabrègue J, Anderes L, Ousson S, Borlat F, Eligert V, et al. The role of γ-secretase activating protein (GSAP) and imatinib in the regulation of γ-secretase activity and amyloid-β generation. J Biol Chem. 2013;288(4):2521–31.

    Article  CAS  Google Scholar 

  40. Seju U, Kumar A, Sawant K. Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery: in vitro and in vivo studies. Acta Biomater. 2011;7(12):4169–76.

    Article  CAS  Google Scholar 

  41. Gabrielsson J., Weiner D. (2012) Non-compartmental Analysis. In: Reisfeld B., Mayeno A. (eds) Computational Toxicology. Methods in Molecular Biology (Methods and Protocols), vol 929. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-050-2_16.

  42. Kozlovskaya L, Abou-Kaoud M, Stepensky D. Quantitative analysis of drug delivery to the brain via nasal route. J Control Release. 2014;189:133–40.

    Article  CAS  Google Scholar 

  43. Claessens M, Van Oort B, Leermakers F, Hoekstra F, Stuart MC. Charged lipid vesicles: effects of salts on bending rigidity, stability, and size. Biophys J. 2004;87(6):3882–93.

    Article  CAS  Google Scholar 

  44. Shaker S, Gardouh AR, Ghorab MM. Factors affecting liposomes particle size prepared by ethanol injection method. Res Pharm Sci. 2017;12(5):346–52.

    Article  Google Scholar 

Download references

Funding

The authors would like to acknowledge the Director, NIPER-Hyderabad, for timely encouragement and funding for the project.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India

    Raju Saka, Naveen Chella & Wahid Khan

  2. Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education & Research (NIPER), Guwahati, 781101, India

    Naveen Chella

  3. NATCO Pharma Ltd., Industrial Estate, Sanath Nagar, Hyderabad, 500018, India

    Wahid Khan

Authors
  1. Raju Saka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naveen Chella
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wahid Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Naveen Chella or Wahid Khan.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saka, R., Chella, N. & Khan, W. Development of Imatinib Mesylate-Loaded Liposomes for Nose to Brain Delivery: In Vitro and In Vivo Evaluation. AAPS PharmSciTech 22, 192 (2021). https://doi.org/10.1208/s12249-021-02072-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-021-02072-0

KEY WORDS

Search

Navigation