A Prodrug Nanoparticle Approach for the Oral Delivery of a Hydrophilic Peptide, Leucine5-enkephalin, to the Brain

被引:59
作者
Lalatsa, Aikaterini [1 ]
Lee, Vivian [1 ]
Malkinson, John P. [1 ]
Zloh, Mire [1 ]
Schaetzlein, Andreas G. [1 ]
Uchegbu, Ijeoma F. [1 ]
机构
[1] Univ London, UCL Sch Pharm, London WC1N 1AX, England
基金
英国工程与自然科学研究理事会; 英国惠康基金;
关键词
chitosan amphiphiles; quaternary ammonium palmitoyl glycol chitosan; GCPQ blood-brain barrier; peptides; oral; leucine(5)-enkephalin; LEU-ENKEPHALIN; LEUCINE-ENKEPHALIN; OPIOID-PEPTIDES; BARRIER; BIOAVAILABILITY; ABSORPTION; DALARGIN; INSULIN; EPIDEMIOLOGY; TRANSPORTERS;
D O I
10.1021/mp300009u
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
100103 [病原生物学]; 100218 [急诊医学];
摘要
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.
引用
收藏
页码:1665 / 1680
页数:16
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