A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain.
Title | A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Lalatsa A, Lee V, Malkinson JP, Zloh M, Schätzlein AG, Uchegbu IF |
Journal | Mol Pharm |
Volume | 9 |
Issue | 6 |
Pagination | 1665-80 |
Date Published | 2012 Jun 4 |
ISSN | 1543-8392 |
Keywords | Administration, 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. |
DOI | 10.1021/mp300009u |
Alternate Journal | Mol. Pharm. |
PubMed ID | 22574705 |
Grant List | / / Wellcome Trust / United Kingdom |