A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain.

TitleA prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain.
Publication TypeJournal Article
Year of Publication2012
AuthorsLalatsa A, Lee V, Malkinson JP, Zloh M, Schätzlein AG, Uchegbu IF
JournalMol Pharm
Volume9
Issue6
Pagination1665-80
Date Published2012 Jun 4
ISSN1543-8392
KeywordsAdministration, Oral, Animals, Blood-Brain Barrier, Brain, Enkephalins, Hydrophobic and Hydrophilic Interactions, Magnetic Resonance Spectroscopy, Male, Mass Spectrometry, Mice, Nanoparticles, Peptides, Prodrugs, Rats, Rats, Wistar
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.

DOI10.1021/mp300009u
Alternate JournalMol. Pharm.
PubMed ID22574705
Grant List / / Wellcome Trust / United Kingdom