Jia Fuya, Fan Xiaoxing, Wu Licheng, Wang Yating, Zhang Jisen, Zhou Zhou, Li Lian, Wen Jingyuan, Huang Yuan
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Grafton, Auckland 1023, New Zealand.
Asian J Pharm Sci. 2025 Jun;20(3):101019. doi: 10.1016/j.ajps.2025.101019. Epub 2025 Jan 10.
Solid lipid nanoparticles (SLN) could enhance the oral bioavailability of loaded protein and peptide drugs through lymphatic transport. Natural oligopeptides regulate nearly all vital processes and serve as a nitrogen source for nourishment. They are mainly transported by oligopeptide transporter-1 (PepT-1) which are primarily expressed in the intestine with the characteristics of high-capacity and low energy consumption. Our preliminary research discovered the transmembrane transport of SLN could be improved by stimulating the oligopeptide absorption pathway. This implied the potential of combining the advantages of SLN with oligopeptide transporter mediated transportation. Herein, two kinds of dipeptide modified SLN were designed with insulin and glucagon like peptide-1 (GLP-1) analogue exenatide as model drugs. These drugs loaded SLN showed enhanced oral bioavailability and hypoglycemic effect in both type I diabetic C57BL/6 mice and type II diabetic KKAy mice. Compared with un-modified SLN, dipeptide-modified SLN could be internalized by intestinal epithelial cells via PepT-1-mediated endocytosis with higher uptake. Interestingly, after internalization, more SLN could access the systemic circulation via lymphatic transport pathway, highlighting the potential to combine the oligopeptide-absorption route with SLN for oral drug delivery.
固体脂质纳米粒（SLN）可通过淋巴转运提高所载蛋白质和肽类药物的口服生物利用度。天然寡肽调节几乎所有重要生理过程，并作为营养的氮源。它们主要由主要在肠道表达的寡肽转运体-1（PepT-1）转运，具有高容量和低能耗的特点。我们的初步研究发现，刺激寡肽吸收途径可改善SLN的跨膜转运。这意味着将SLN的优势与寡肽转运体介导的转运相结合的潜力。在此，以胰岛素和胰高血糖素样肽-1（GLP-1）类似物艾塞那肽为模型药物，设计了两种二肽修饰的SLN。这些载药的SLN在I型糖尿病C57BL/6小鼠和II型糖尿病KKAy小鼠中均表现出增强的口服生物利用度和降血糖作用。与未修饰的SLN相比，二肽修饰的SLN可通过PepT-1介导的内吞作用被肠上皮细胞内化，摄取量更高。有趣的是，内化后，更多的SLN可通过淋巴转运途径进入体循环，突出了将寡肽吸收途径与SLN相结合用于口服给药的潜力。
