A Prodrug Nanoparticle Approach for the Oral Delivery of a Hydrophilic Peptide, Leucine(5)-enkephalin, to the Brain

作者：Lalatsa Aikaterini; Lee Vivian; Malkinson John P; Zloh Mire; Schaetzlein Andreas G; Uchegbu Ijeoma F^*

来源：Molecular Pharmaceutics, 2012, 9(6): 1665-1680.

DOI：10.1021/mp300009u

• chitosan amphiphiles
• quaternary ammonium palmitoyl glycol chitosan
• GCPQ blood-brain barrier
• peptides
• oral
• leucine(5)-enkephalin

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.

• 出版日期2012-6