Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia

Lisa Godfrey, Antonio Iannitelli, Natalie L. Garrett, Julian Moger, Ian Imbert, Tamara King, Frank Porreca, Ramesh Soundararajan, Aikaterini Lalatsa, Andreas G. Schätzlein, Ijeoma F. Uchegbu

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The delivery of peptide drugs to the brain is challenging, principally due to the blood brain barrier and the low metabolic stability of peptides. Exclusive delivery to the brain with no peripheral exposure has hitherto not been demonstrated with brain quantification data. Here we show that polymer nanoparticles encapsulating leucine5-enkephalin hydrochloride (LENK) are able to transport LENK exclusively to the brain via the intranasal route, with no peripheral exposure and nanoparticle localisation is observed within the brain parenchyma. Animals dosed with LENK nanoparticles (NM0127) showed a strong anti-nociceptive response in multiple assays of evoked and on going pain whereas animals dosed intranasally with LENK alone were unresponsive. Animals did not develop tolerance to the anti-hyperalgesic activity of NM0127 and NM0127 was active in morphine tolerant animals. A microparticulate formulation of clustered nanoparticles was prepared to satisfy regulatory requirements for nasal dosage forms and the polymer nanoparticles alone were found to be biocompatible, via the nasal route, on chronic dosing.

Original languageEnglish (US)
Pages (from-to)135-144
Number of pages10
JournalJournal of Controlled Release
Volume270
DOIs
StatePublished - Jan 28 2018

Keywords

  • Analgesia
  • Brain delivery
  • Chitosan amphiphiles
  • Delta opioid receptor
  • Intranasal
  • Leucine-enkephalin
  • Microparticles
  • Nanoparticles

ASJC Scopus subject areas

  • Pharmaceutical Science

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  • Cite this

    Godfrey, L., Iannitelli, A., Garrett, N. L., Moger, J., Imbert, I., King, T., Porreca, F., Soundararajan, R., Lalatsa, A., Schätzlein, A. G., & Uchegbu, I. F. (2018). Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia. Journal of Controlled Release, 270, 135-144. https://doi.org/10.1016/j.jconrel.2017.11.041