UCL School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK., WC1N 1AX.
Mol Pharm. 2012 Jun 4;9(6):1764-74. doi: 10.1021/mp300068j. Epub 2012 May 21.
The clinical development of therapeutic peptides has been restricted to peptides for non-CNS diseases and parenteral dosage forms due to the poor permeation of peptides across the gastrointestinal mucosa and the blood-brain barrier. Quaternary ammonium palmitoyl glycol chitosan (GCPQ) nanoparticles facilitate the brain delivery of orally administered peptides such as leucine(5)-enkephalin, and here we examine the mechanism of GCPQ facilitated oral peptide absorption and brain delivery. By analyzing the oral biodistribution of radiolabeled GCPQ nanoparticles, the oral biodistribution of the model peptide leucine(5)-enkephalin and coherent anti-Stokes Raman scattering microscopy tissue images after an oral dose of deuterated GCPQ nanoparticles, we have established a number of facts. Although 85-90% of orally administered GCPQ nanoparticles are not absorbed from the gastrointestinal tract, a peak level of 2-3% of the oral GCPQ dose is detected in the blood 30 min after dosing, and these GCPQ particles appear to transport the peptides to the blood. Additionally, although peptide loaded nanoparticles from low (6 kDa) and high (50 kDa) molecular weight GCPQ are taken up by enterocytes, polymer particles with a polymer molecular weight greater than 6 kDa are required to facilitate peptide delivery to the brain after oral administration. By examining our current and previous data, we conclude that GCPQ particles facilitate oral peptide absorption by protecting the peptide from gastrointestinal degradation, adhering to the mucus to increase the drug gut residence time and transporting GCPQ associated peptide across the enterocytes and to the systemic circulation, enabling the GCPQ stabilized peptide to be transported to the brain. Orally administered GCPQ particles are also circulated from the gastrointestinal tract to the liver and onward to the gall bladder, presumably for final transport back to the gastrointestinal tract.
治疗性肽的临床开发一直受到限制，只能用于非中枢神经系统疾病和肠外剂型，这是因为肽在胃肠道黏膜和血脑屏障中的通透性较差。季铵化棕榈酰基乙二醇壳聚糖（GCPQ）纳米颗粒促进了经口给予的肽如亮氨酸（5）-脑啡肽递送至脑部，在此我们研究了 GCPQ 促进口服肽吸收和递送至脑部的机制。通过分析放射性标记的 GCPQ 纳米颗粒的口服生物分布、模型肽亮氨酸（5）-脑啡肽的口服生物分布以及口服氘化 GCPQ 纳米颗粒后的相干反斯托克斯拉曼散射显微镜组织图像，我们确定了以下事实。尽管 85-90%的口服 GCPQ 纳米颗粒未被胃肠道吸收，但在给药后 30 分钟，血液中可检测到 2-3%的口服 GCPQ 剂量，这些 GCPQ 颗粒似乎将肽转运至血液中。此外，尽管低（6 kDa）和高（50 kDa）分子量 GCPQ 负载的纳米颗粒可被肠细胞摄取，但聚合物颗粒的分子量大于 6 kDa 是促进肽递送至口服后脑部所必需的。通过检查我们当前和以前的数据，我们得出结论，GCPQ 颗粒通过保护肽免受胃肠道降解、黏附在黏液上以增加药物在肠道中的停留时间以及将 GCPQ 相关肽转运穿过肠细胞并进入体循环，从而促进口服肽的吸收。口服给予的 GCPQ 颗粒也从胃肠道循环到肝脏，然后再到胆囊，推测最终将返回胃肠道。
