title: A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain.
abstract: The oral use of neuropeptides to treat brain disease is currently not possible because of a combination of poor oral absorption, short plasma half-lives and the blood-brain barrier. Here we demonstrate a strategy for neuropeptide brain delivery via the (a) oral and (b) intravenous routes. The strategy is exemplified by a palmitic ester prodrug of the model drug leucine(5)-enkephalin, encapsulated within chitosan amphiphile nanoparticles. Via the oral route the nanoparticle-prodrug formulation increased the brain drug levels by 67% and significantly increased leucine(5)-enkephalin's antinociceptive activity. The nanoparticles facilitate oral absorption and the prodrug prevents plasma degradation, enabling brain delivery. Via the intravenous route, the nanoparticle-prodrug increases the peptide brain levels by 50% and confers antinociceptive activity on leucine(5)-enkephalin. The nanoparticle-prodrug enables brain delivery by stabilizing the peptide in the plasma although the chitosan amphiphile particles are not transported across the blood-brain barrier per se, and are excreted in the urine.
authors.affiliation: UCL School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Lalatsa
authors.forename: Vivian
authors.initials: V
authors.lastname: Lee
authors.forename: John P
authors.initials: JP
authors.lastname: Malkinson
authors.forename: Mire
authors.initials: M
authors.lastname: Zloh
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Schätzlein
authors.forename: Ijeoma F
authors.initials: IF
authors.lastname: Uchegbu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004745:Enkephalins / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004745:Enkephalins; D010455:Peptides; D011355:Prodrugs