Wang Jie, Zhang Zilong, Zhang Zhuan, Zou Zhiwen, Zhuo Yan, Liu Chang, Nie Di, Gan Yong, Yu Miaorong
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
ACS Nano. 2024 Dec 31;18(52):35310-35324. doi: 10.1021/acsnano.4c11453. Epub 2024 Dec 16.
The development of effective oral drug delivery systems for targeted gut-to-liver transport remains a significant challenge due to the multiple biological barriers including the harsh gastrointestinal tract (GIT) environment and the complex protein corona (PC) formation. In this study, we developed ligand-modified nanoparticles (NPs) that enable gut-to-liver drug delivery by crossing the GIT and attenuating PC formation. Specifically, mesoporous silica nanoparticles (MSNs) were functionalized with peptides targeting the neonatal Fc receptor (FcRn), capitalizing on FcRn expression in the small intestine and liver for targeted drug delivery. We showed that MSNs decorated with a small cyclic FcRn binding peptide (MSNs-FcBP) obtained enhanced diffusion in intestinal mucus and superior transportation across the intestine compared to unmodified MSNs and MSNs decorated with a large IgG Fc fragment (MSNs-Fc), which correlated with diminished protein adsorption and weaker interaction with mucin. After entering the blood circulation, reduced serum PC formation by MSNs-FcBP reduces the proteolytic and phagocytic propensity of the reticuloendothelial system, ultimately ameliorating accumulation in hepatocytes. Pharmacokinetic and pharmacodynamic studies in diabetic mice revealed that MSNs-FcBP effectively transported the therapeutic agent exenatide across the intestinal epithelium, leading to a significant hypoglycemic response and improved glucose tolerance. This study underscores the critical role of ligand selection in limiting protein corona formation, thereby significantly enhancing gut-to-liver drug delivery by increasing mucus permeation and minimizing serum-protein interactions. The effective delivery of exenatide in diabetic mice illustrates the potential of this strategy to optimize oral drug bioavailability and therapeutic efficacy.
由于存在包括恶劣的胃肠道（GIT）环境和复杂的蛋白质冠层（PC）形成在内的多种生物屏障，开发用于靶向肠道到肝脏转运的有效口服给药系统仍然是一项重大挑战。在本研究中，我们开发了配体修饰的纳米颗粒（NPs），其能够通过穿越胃肠道并减弱PC形成来实现肠道到肝脏的药物递送。具体而言，介孔二氧化硅纳米颗粒（MSNs）用靶向新生儿Fc受体（FcRn）的肽进行功能化，利用FcRn在小肠和肝脏中的表达进行靶向药物递送。我们表明，与未修饰的MSNs和用大的IgG Fc片段修饰的MSNs（MSNs-Fc）相比，用小的环状FcRn结合肽修饰的MSNs（MSNs-FcBP）在肠道黏液中获得了增强的扩散能力和跨越肠道的卓越转运能力，这与减少的蛋白质吸附以及与黏蛋白的较弱相互作用相关。进入血液循环后，MSNs-FcBP减少血清PC形成，降低了网状内皮系统的蛋白水解和吞噬倾向，最终改善了在肝细胞中的蓄积。糖尿病小鼠的药代动力学和药效学研究表明，MSNs-FcBP有效地将治疗剂艾塞那肽转运穿过肠上皮，导致显著的降血糖反应并改善了葡萄糖耐量。本研究强调了配体选择在限制蛋白质冠层形成中的关键作用，从而通过增加黏液渗透和最小化血清-蛋白质相互作用显著增强了肠道到肝脏的药物递送。艾塞那肽在糖尿病小鼠中的有效递送说明了该策略在优化口服药物生物利用度和治疗效果方面的潜力。
