Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia

Lisa Godfrey, Antonio Iannitelli, Julian Moger, Ian Imbert, Tamara King, Frank Porreca, Ramesh Soundararajan, Katerina Lalatsa, Andreas G Schatzlein, Ijeoma F Uchegbu

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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
Pages (from-to)135-144
JournalJournal of Controlled Release: Official Journal of the Controlled Release Society
Early online date27 Nov 2017
Publication statusPublished - 28 Jan 2018


  • Intranasal
  • Peptide
  • Brain delivery
  • Chitosan
  • RCUK
  • EP/ K502340/1


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