UCL School of Pharmacy, University of London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
Mol Pharm. 2012 Jun 4;9(6):1665-80. doi: 10.1021/mp300009u. Epub 2012 May 18.
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.
由于口服吸收差、血浆半衰期短和血脑屏障等多种因素的综合作用，目前无法通过口服给予神经肽来治疗脑部疾病。在这里，我们展示了一种通过（a）口服和（b）静脉途径将神经肽递送至大脑的策略。该策略以模型药物亮氨酸（5）-脑啡肽的棕榈酸酯前药为例，封装在壳聚糖两亲性纳米粒子内。通过口服途径，纳米粒前药制剂使脑内药物水平增加了 67%，并显著提高了亮氨酸（5）-脑啡肽的镇痛活性。纳米粒子促进了口服吸收，前药防止了血浆降解，从而实现了脑内递药。通过静脉途径，纳米粒前药使肽类在大脑中的水平增加了 50%，并赋予亮氨酸（5）-脑啡肽镇痛活性。尽管壳聚糖两亲性颗粒本身不能穿过血脑屏障，但纳米粒前药通过稳定血浆中的肽来实现脑内递药，并通过尿液排出。
