The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery
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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.
| Original language | English |
|---|---|
| Journal | Acta Pharmaceutica Sinica B |
| Volume | 12 |
| Issue number | 3 |
| Pages (from-to) | 1460-1472 |
| ISSN | 2211-3835 |
| DOIs | |
| Publication status | Published - 2022 |
Bibliographical note
Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
- Diabetes, Endocytosis, Expression level, Intracellular trafficking, Ligand-modified nanoparticles, Oral insulin delivery, Proton-coupled folate transporter, Transporter
Research areas
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