Pharmaceutical Research

, Volume 33, Issue 7, pp 1682–1695 | Cite as

A Comparative Study of Orally Delivered PBCA and ApoE Coupled BSA Nanoparticles for Brain Targeting of Sumatriptan Succinate in Therapeutic Management of Migraine

Research Paper



The present investigation aimed at brain targeting of sumatriptan succinate (SS) for its optimal therapeutic effect in migraine through nanoparticulate drug delivery system using poly (butyl cyanoacrylate) (PBCA) and bovine serum albumin linked with apolipoprotein E3 (BSA-ApoE).


The study involved formulation optimization of PBCA nanoparticles (NPs) using central composite design for achieving minimum particle size, maximum entrapment efficiency along with sustained drug release. SS incorporated in BSA-ApoE NPs (S-AA-NP) were prepared by desolvation technique and compared with SS loaded polysorbate 80 coated optimized PBCA NPs (FPopt) in terms of their brain uptake potential, upon oral administration in male Wistar rats. The NPs were characterized by FTIR, thermal, powder XRD and TEM analysis.


The in vivo studies of FPopt and S-AA-NP on male Wistar rats demonstrated a fairly high brain/plasma drug ratio of 9.45 and 12.67 respectively 2 h post oral drug administration. The behavioural studies on male Swiss albino mice affirmed the enhanced anti-migraine potential of S-AA-NP than FPopt (P < 0.001).


The results of this work, therefore, indicate that BSA-ApoE NPs are significantly better than polysorbate 80 coated PBCA NPs for brain targeting of SS (P < 0.05) and also offer an improved therapeutic strategy for migraine management.


apolipoprotein brain targeting BSA PBCA sumatriptan succinate 



Dummy Apolipoprotein E coupled bovine serum albumin nanoparticles (without drug)


Apolipoprotein E


Blood Brain Barrier


Bovine Serum Albumin


Bovine Serum Albumin covalently linked with Apolipoprotein E


Differential Scanning Calorimetry


Sumatriptan succinate loaded polysorbate 80 coated chitosan solid lipid nanoparticles


Sumatriptan succinate loaded polysorbate 80 coated optimized Poly (butyl cyanoacrylate) nanoparticles


Fourier-Transform Infrared Spectroscopy


High-Performance Liquid Chromatography








Poly (butyl cyanoacrylate) (PBCA)


Powder X-Ray Diffraction


Sumatriptan succinate loaded apolipoprotein E coupled BSA nanoparticles


Solid lipid nanoparticles


Sumatriptan Succinate


Transmission Electron Microscopy


Thermogravimetric analysis



The authors acknowledge the Coordinator, DST FIST, Department of Pharmaceutical Sciences (GJU S&T, Hisar) and SAIF, Panjab University (Chandigarh) for providing particle size analysis and TEM analysis facility respectively. The authors are thankful to Department of Science & Technology, New Delhi for providing DST-INSPIRE fellowship as financial assistance. The contribution of Dr. Tikva Vogel in providing the gift sample of ApoE is gratefully acknowledged. The authors also wish to thank Dr. A.K. Mohanty, (Animal Biotechnology Centre, National Dairy Research Institute, Karnal, India) for kindly helping in the thiolation of apolipoprotein E. The authors report no conflict of interest and are solely responsible for the content and writing of the paper.


  1. 1.
    Lipton RB, Silberstein SD, Stewart WF. An update on the epidemiology of migraine. Headache. 1994;34:319–28.CrossRefPubMedGoogle Scholar
  2. 2.
    Shapiro RE, Goadsby PJ. The long drought: the dearth of public funding for headache research. Cephalalgia. 2007;27:991–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Girotra P, Singh SK, Saini D. Disentangling the intricacies of migraine: a review. CNS Neurol Disord Drug Targets. 2014;13:776–91.CrossRefPubMedGoogle Scholar
  4. 4.
    Ferrari MD, Saxena PR. Clinical effects and mechanism of action of sumatriptan in migraine. Clin Neurol Neurosurg. 1992;94:73–7.CrossRefGoogle Scholar
  5. 5.
    Goadsby PJ, Edvinsson L. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90. Headache. 1994;34:394–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Edvinsson L, Tfelt-Hansen P. The blood brain barrier in migraine treatment. Cephalalgia. 2008;24:1245–58.CrossRefGoogle Scholar
  7. 7.
    Nagpal K, Singh SK, Mishra DN. Drug targeting to brain: a systematic approach to study the factors, parameters and approaches for prediction of permeability of drugs across BBB. Expert Opin Drug Deliv. 2013;10:927–55.CrossRefPubMedGoogle Scholar
  8. 8.
    Alonso MJ, Csaba NS. Nanostructured biomaterials for overcoming biological barriers. RSC Publishing; 2012.Google Scholar
  9. 9.
    Gao S, Xu Y, Asghar S, Chen M, Zou L, Eltayeb S, et al. Poly butylcyanoacrylate nanocarriers as promising targeted drug delivery systems. J Drug Target. 2015;4:1–16.Google Scholar
  10. 10.
    Joshi SA, Chavhan SS, Sawant KK. Rivastigmine-loaded PLGA and PBCA nanoparticles: reparation, optimization, characterization, in vitro and pharmacodynamic studies. Eur J Pharm Biopharm. 2010;76:189–99.CrossRefPubMedGoogle Scholar
  11. 11.
    Kreuter J. Drug delivery to the central nervous system by polymeric nanoparticles: what do we know? Adv Drug Deliv Rev. 2014;71:2–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Kreuter J. Nanoparticulate systems for brain delivery of drugs. Adv Drug Deliv Rev. 2001;47:65–81.CrossRefPubMedGoogle Scholar
  13. 13.
    Kreuter J, Shamenkov D, Petrov V, Ramge P, Cychutek K, Koch-Brandt C, et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood–brain barrier. J Drug Target. 2002;10:317–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Ramge P, Unger RE, Oltrogge JB, Zenker D, Begley D, Kreuter J, et al. Polysorbate 80-coating enhances uptake of polybutylcyano-acrylate (PBCA)- nanoparticles by human, bovine and murine primary brain capillary endothelial cells. Eur J Neurosci. 2000;12:1931–40.CrossRefPubMedGoogle Scholar
  15. 15.
    Alyautdin R, Gothier D, Petrov V, Kharkevich D, Kreuter J. Analgesic activity of the hexapeptide dalargin adsorbed on the surface of polysorbate 80-coated poly (butyl cyanoacrylate) nanoparticles. Eur J Pharm Biopharm. 1995;41:44–8.Google Scholar
  16. 16.
    Yu Z, Yu M, Zhang Z, Hong G, Xiong Q. Bovine serum albumin nanoparticles as controlled release carrier for local drug delivery to the inner ear. Nanoscale Res Lett. 2014;9:1–7.CrossRefGoogle Scholar
  17. 17.
    Michaelis K, Hoffmann MM, Dreis S, Herbert E, Alyautdin RN, Michaelis M, et al. Covalent linkage of Apolipoprotein E to albumin nanoparticles strongly enhances drug transport into the brain. J Pharmacol Exp Ther. 2006;317:1246–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Hoffmann M, Scharnagl H, Panagiotou E, Banghard W, Wieland H, Marz W. Diminished LDL receptor and high heparin binding of apolipoprotein E2 Sendai associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 2001;12:524–30.PubMedGoogle Scholar
  19. 19.
    Ribalta J, Vallve JC, Girona J, Masana L. Apolipoprotein and apolipoprotein receptor genes, blood lipids and disease. Curr Opin Clin Nutr Metab Care. 2003;6:177–87.CrossRefPubMedGoogle Scholar
  20. 20.
    Wu LS. Product testing with consumers for research guidance. ASTM Int. 1989;1035:48–50.Google Scholar
  21. 21.
    Nagpal K, Singh SK, Mishra DN. Minocycline encapsulated chitosan nanoparticles for central antinociceptive activity. Int J Biol Macromol. 2015;72:131–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Girotra PH, Singh SK, Kumar P. Sumatriptan succinate loaded chitosan solid lipid nanoparticles for enhanced anti-migraine potential. Int J Biol Macromol. 2015;81:467–76.CrossRefGoogle Scholar
  23. 23.
    Weber C, Kreuter J, Langer K. Desolvation process and surface characteristics of HSA-nanoparticles. Int J Pharm. 2000;196:197–200.CrossRefPubMedGoogle Scholar
  24. 24.
    Langer K, Balthasar S, Vogel V, Dinauer N, Von Briesen H, Schubert D. Optimization of the preparation process for human serum albumin (HSA) nanoparticles. Int J Pharm. 2003;257:169–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Yu Z, Kastenmuller G, He Y, Belcredi P, Moller G, Prehn C, et al. Differences between human plasma and serum metabolite profiles. PLoS One. 2011;6:e21230.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Girotra PH, Singh SK, Kumar G. Reversed phase HPLC method development and validation for the quantification of sumatriptan succinate nanoparticles in rat plasma and brain homogenate. Inventi Impact: Biomed Anal. 2016;1:1–5.Google Scholar
  27. 27.
    Girotra P, Singh SK, Kumar G. Development of Zolmitriptan loaded PLGA/poloxamer nanoparticles using quality by design approach for migraine management. Int J Biol Macromol. 2016;85:92–101.CrossRefPubMedGoogle Scholar
  28. 28.
    Patila S, Sandberg A, Heckert E, Self W, Sea S. Protein adsorption and cellular uptake of cerium oxide nanoparticles as a function of zeta potential. Biomaterials. 2007;28:4600–7.CrossRefGoogle Scholar
  29. 29.
    Ritger PL, Peppas NA. A simple equation for description of solute release II: Fickian and anomalous release from swellable devices. J Control Release. 1987;5:37–42.CrossRefGoogle Scholar
  30. 30.
    Nagpal K, Singh SK, Mishra DN. Formulation, optimization, in vivo pharmacokinetic behavioural and biochemical estimations of minocycline loaded chitosan nanoparticles for enhanced brain uptake. Chem Pharm Bull. 2013;61:258–72.CrossRefPubMedGoogle Scholar
  31. 31.
    Alam S, Khan ZI, Mustafa G, Kumar M, Islam F, Bhatnagar A, et al. Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: a pharmacoscintigraphic study. Int J Nanomedicine. 2012;7:5705–18.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Culot M, Fabulas-da Costa A, Sevin E, Szorath E, Martinsson S, Renftel M, et al. A simple method for assessing free brain/free plasma ratios using an in vitro model of the blood brain barrier. PLoS ONE. 2013;8:e80634.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nikai T, Basbaum AI, Ahn AH. Profound reduction of somatic and visceral pain in mice by intrathecal administration of the anti-migraine drug, sumatriptan. Pain. 2008;139:533–40.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bartsch T, Knight YE, Goadsby PJ. Activation of 5-HT (1B/1D) receptor in the periaqueductal gray inhibits nociception. Ann Neurol. 2004;56:371–81.CrossRefPubMedGoogle Scholar
  35. 35.
    Digre KB, Brennan KC. Shedding light on photophobia. J Neuroophthalmol. 2012;32:68–81.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Okamoto K, Thompson R, Tashiro A, Chang Z, Bereiter DA. Bright light produces Fos-positive neurons in caudal trigeminal brainstem. Neuroscience. 2009;160:858–64.CrossRefPubMedGoogle Scholar
  37. 37.
    Kaube H, Hoskin KL, Goadsby PJ. Inhibition by sumatriptan of central trigeminal neurones only after blood–brain barrier disruption. Br J Pharmacol. 1993;109:788–92.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Vijayan L, Bansal D, Ray SB. Nimodipine down-regulates CGRP expression in the rat trigeminal nucleus caudalis. Indian J Exp Biol. 2012;50:320–4.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesG. J. University of Sci. & Tech.HisarIndia

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