Original articles
Jingyi Li, Yaqi Zhang, Miaorong Yu, Aohua Wang, Yu Qiu, Weiwei Fan, Lars Hovgaard, Mingshi Yang, Yiming Li, Rui Wang, Xiuying Li, Yong Gan. The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1460-1472

The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery
Jingyi Lia,b, Yaqi Zhangb,c, Miaorong Yub, Aohua Wangb,c, Yu Qiub,c, Weiwei Fanb, Lars Hovgaardd, Mingshi Yange, Yiming Lia, Rui Wanga, Xiuying Lif, Yong Ganb,c,g
a. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;
b. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
c. University of Chinese Academy of Sciences, Beijing 100049, China;
d. Oral Formulation Development, Novo Nordisk A/S, Maalov 2760, Denmark;
e. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark;
f. University of Texas at Dallas, Richardson, TX 75080, USA;
g. NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, National Institutes for Food and Drug Control, Beijing 100050, China
Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores. In this study, we demonstrate that the upregulated intestinal transporter (PCFT), which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats, mediates the uptake of the folic acid-grafted nanoparticles (FNP). Specifically, the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway, Golgi-targeting pathway and basolateral exocytosis, featuring a high oral insulin bioavailability of 14.4% in the diabetic rats. Conversely, in cells with relatively low PCFT expression, the positive surface charge contributes to the cellular uptake of FNP, and FNP are mainly degraded in the lysosomes. Overall, we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway. This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.
Key words:    Ligand-modified nanoparticles    Transporter    Proton-coupled folate transporter    Expression level    Endocytosis    Intracellular trafficking    Diabetes    Oral insulin delivery   
Received: 2021-05-17     Revised: 2021-07-10
DOI: 10.1016/j.apsb.2021.07.024
Funds: The authors thank the financial support from the National Natural Science Foundation of China (NSFC, No. 81773651, 82025032, and 81803445, China), NN-CAS foundation, National Key R&D Program of China (No. 2020YFE0201700, China), and Major International Joint Research Project of Chinese Academy of Sciences (No. 153631KYSB20190020, China). We would like to thank Dr. Ulrik Lytt Rahbek from Novo Nordisk A/S, Denmark, for helpful discussion about folate receptors and transporters. We also thank the National Center for Protein Science Shanghai for two-photon intravital imaging of experimental rats.
Corresponding author: Rui Wang,E-mai:wr@shutcm.edu.cn;Xiuying Li,E-mai:Xiuying.Li@utdallas.edu;Yong Gan,E-mai:ygan@simm.ac.cn     Email:wr@shutcm.edu.cn;Xiuying.Li@utdallas.edu;ygan@simm.ac.cn
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Jingyi Li
Yaqi Zhang
Miaorong Yu
Aohua Wang
Yu Qiu
Weiwei Fan
Lars Hovgaard
Mingshi Yang
Yiming Li
Rui Wang
Xiuying Li
Yong Gan

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