Skip to main content

Advertisement

SpringerLink
Log in

Analgesic Efficacy and Safety of DALDA Peptide Analog Delivery to the Brain Using Oil-in-Water Nanoemulsion Formulation

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

The main objective of this study was to develop and evaluate therapeutic efficacy and safety following systemic delivery of a peptide analgesic into the CNS using an oil-in-water nanoemulsion system.

Methods

We have formulated a safe and effective, omega-3 rich polyunsaturated fatty acid containing oil-in-water nanoemulsion formulation, for encapsulating and delivering chemically-modified DALDA, a potent mu-opioid peptide analogue, to the CNS. One of the challenges with CNS delivery is the lack of a non-invasive bioanalytical technique to confirm CNS uptake and therapeutic efficacy. Using blood oxygen-level dependent (BOLD) functional magenetic resonance imaging (fMRI), we provide quantitative evidence of nanoemulsion-based delivery and analgesic activity of DALDA analogue in capsaicin-induced awake rat model of pain.

Results

Nanoemulsion formulation effectively encapsulated the modified analgesic peptide and demonstrated efficacy in the capsaicin- pain induced functional magnetic resonance imaging model in rodents. Preliminary safety evaluations show that the nanoemulsion system was well tolerated and did not cause any acute negative effects.

Conclusions

Overall, these results show tremendous opportunity for the development of modified peptide analgesic-encapsulated nanoemulsion formulations for CNS delivery and therapeutic efficacy.

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

Similar content being viewed by others

REFERENCES

  1. Prokai L. Peptide drug delivery into the central nervous system. Prog Drug Res. 1998;51:95–131.

    Article  PubMed  CAS  Google Scholar 

  2. Wolburg H, Lippoldt A. Tight junctions of the blood-brain barrier: development, composition and regulation. Vasc Pharmacol. 2002;38:323–37.

    Article  CAS  Google Scholar 

  3. Shah L, Yadav S, Amiji M. Nanotechnology for CNS delivery of bio-therapeutic agents. Drug Deliv Transl Res. 2013;10:957–72. 3.

    Google Scholar 

  4. Aldrich JV, McLaughlin JP. Opioid peptides: potential for drug development. Drug Discov Today Technol. 2012;9:e23–31.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Pasero C. Introduction. In: Pasero C, McCaffery M, editors. Pain assessment and pharmacologic management. St. Louis: Mosby Inc, Elsevier Inc.; 2011. p. 1–12.

    Google Scholar 

  6. Schiller PW, Nguyen TM, Berezowska I, Dupuis S, Weltrowska G, Chung NN, et al. Synthesis and in vitro opioid activity profiles of DALDA analogues. Eur J Med Chem. 2000;35:895–901.

    Article  PubMed  CAS  Google Scholar 

  7. Farooqui AA. n-3 fatty acid-derived lipid mediators in the brain: new weapons against oxidative stress and inflammation. Curr Med Chem. 2012;19:532–43.

    Article  PubMed  CAS  Google Scholar 

  8. Farooqui AA. Recent development on the neurochemistry of docosanoids. In: Farooqui AA, editor. Lipid mediators and their metabolism in the brain. New York: Springer Science+Business Media, LLC; 2011. p. 49.

    Chapter  Google Scholar 

  9. Hamilton JA, Brunaldi K. A model for fatty acid transport into the brain. J Mol Neurosci. 2007;33:12–7.

    Article  PubMed  CAS  Google Scholar 

  10. Sarker DK. Engineering of nanoemulsions for drug delivery. Curr Drug Deliv. 2005;2:297–310.

    Article  PubMed  CAS  Google Scholar 

  11. Ganta S, Deshpande D, Korde A, Amiji M. A review of multifunctional nanoemulsion systems to overcome oral and CNS drug delivery barriers. Mol Membr Biol. 2010;27:260–73.

    Article  PubMed  CAS  Google Scholar 

  12. Vyas TK, Shahiwala A, Amiji MM. Improved oral bioavailability and brain transport of Saquinavir upon administration in novel nanoemulsion formulations. Int J Pharm. 2008;347:93–101.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Tiwari SB, Amiji MM. A review of nanocarrier-based CNS delivery systems. Curr Drug Deliv. 2006;3:219–32.

    Article  PubMed  CAS  Google Scholar 

  14. Le B. Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci. 2003;4:469–80.

    Article  Google Scholar 

  15. Ferris CF, Febo M, Luo F, Schmidt K, Brevard M, Harder JA, et al. Functional magnetic resonance imaging in conscious animals: a new tool in behavioural neuroscience research. J Neuroendocrinol. 2006;18:307–18.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Borsook D, Becerra L, Hargreaves R. Biomarkers for chronic pain and analgesia. Part 1: the need, reality, challenges, and solutions. Discov Med. 2011;11:197–207.

    PubMed  Google Scholar 

  17. Shah L, Gattacceca F, Amiji MM. CNS delivery and pharmacokinetic evaluations of DALDA analgesic peptide analog administered in nano-sized oil-in-water emulsion formulation. Pharm Res 2013. doi:10.1007/s11095-013-1252-8

  18. Malisza KL, Docherty JC. Capsaicin as a source for painful stimulation in functional MRI. J Magn Reson Imaging. 2001;14:341–7.

    Article  PubMed  CAS  Google Scholar 

  19. McCleskey EW, Gold MS. Ion channels of nociception. Annu Rev Physiol. 1999;61:835–56.

    Article  PubMed  CAS  Google Scholar 

  20. Mogil JS. Animal models of pain: progress and challenges. Nat Rev Neurosci. 2009;10:283–94.

    Article  PubMed  CAS  Google Scholar 

  21. Bie B, Brown DL, Naguib M. Synaptic plasticity and pain aversion. Eur J Pharmacol. 2011;667:26–31.

    Article  PubMed  CAS  Google Scholar 

  22. Ferris CF, Smerkers B, Kulkarni P, Caffrey M, Afacan O, Toddes S, et al. Functional magnetic resonance imaging in awake animals. Rev Neurosci. 2011;22:665–74.

    Article  PubMed  Google Scholar 

  23. Ferris CF, Stolberg T, Kulkarni P, Murugavel M, Blanchard R, Blanchard DC, et al. Imaging the neural circuitry and chemical control of aggressive motivation. BMC Neurosci. 2008;9:111.

    Article  PubMed  PubMed Central  Google Scholar 

  24. King JA, Garelick TS, Brevard ME, Chen W, Messenger TL, Duong TQ, et al. Procedure for minimizing stress for fMRI studies in conscious rats. J Neurosci Methods. 2005;148:154–60.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Limdi JK, Hyde GM. Evaluation of abnormal liver function tests. Postgrad Med J. 2003;79:307–12.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Gutkowska J, Mukaddam-Daher S, Jankowski M, Schiller PW. The cardiovascular and renal effects of the potent and highly selective mu opioid agonist [Dmt1]DALDA. J Cardiovasc Pharmacol. 2004;44:651–8.

    Article  PubMed  CAS  Google Scholar 

  27. Raboisson P, Dallel R, Clavelou P, Sessle BJ, Woda A. Effects of subcutaneous formalin on the activity of trigeminal brain stem nociceptive neurones in the rat. J Neurophysiol. 1995;73:496–505.

    PubMed  CAS  Google Scholar 

  28. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9:463–84.

    Article  PubMed  Google Scholar 

  29. Ganta S, Devalapally H, Amiji M. Curcumin enhances oral bioavailability and anti-tumor therapeutic efficacy of paclitaxel upon administration in nanoemulsion formulation. J Pharm Sci. 2010;99:4630–41.

    Article  PubMed  CAS  Google Scholar 

  30. Sundermann B, Maul C. Opioid peptides. In: Buschmann H, Christoph T, Friderichs E, Maul C, Sundermann B, editors. Analgesics: From chemistry and pharmacology to clinical application. Weinheim: Wiley; 2002. p. 127.

    Google Scholar 

  31. Gauriau C, Bernard JF. Pain pathways and parabrachial circuits in the rat. Exp Physiol. 2002;87:251–8.

    Article  PubMed  Google Scholar 

  32. Kupers R, Kehlet H. Brain imaging of clinical pain states: a critical review and strategies for future studies. Lancet Neurol. 2006;5:1033–44.

    Article  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

This study was partially supported by a grant (R21-NS066984) from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. We would like to thank Dr. Jing Xu for her assistance with transmission electron microscopy. Dr. Jerry Lyon at the Tufts University’s Veterinary School is deeply appreciated for his assistance with the tissue histology and analysis. We also appreciate the intellectual feedback from Dr. Anand Subramony of Novartis Institutes for Biomedical Research Inc. to this work.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, 02115, USA

    Lipa Shah & Mansoor M. Amiji

  2. Center for Translational Imaging, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, 02115, USA

    Praveen Kulkarni & Craig Ferris

Authors
  1. Lipa Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Praveen Kulkarni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Craig Ferris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mansoor M. Amiji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mansoor M. Amiji.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shah, L., Kulkarni, P., Ferris, C. et al. Analgesic Efficacy and Safety of DALDA Peptide Analog Delivery to the Brain Using Oil-in-Water Nanoemulsion Formulation. Pharm Res 31, 2724–2734 (2014). https://doi.org/10.1007/s11095-014-1370-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1370-y

KEY WORDS

Search

Navigation