The upregulated intestinal folate transporters direct the uptake of ligand-modified nanoparticles for enhanced oral insulin delivery.
10.1016/j.apsb.2021.07.024
- Author:
Jingyi LI
1
;
Yaqi ZHANG
2
;
Miaorong YU
2
;
Aohua WANG
2
;
Yu QIU
2
;
Weiwei FAN
2
;
Lars HOVGAARD
3
;
Mingshi YANG
4
;
Yiming LI
1
;
Rui WANG
1
;
Xiuying LI
5
;
Yong GAN
2
Author Information
1. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3. Oral Formulation Development, Novo Nordisk A/S, Maalov 2760, Denmark.
4. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
5. University of Texas at Dallas, Richardson, TX 75080, USA.
- Publication Type:Journal Article
- Keywords:
Diabetes;
Endocytosis;
Expression level;
Intracellular trafficking;
Ligand-modified nanoparticles;
Oral insulin delivery;
Proton-coupled folate transporter;
Transporter
- From:
Acta Pharmaceutica Sinica B
2022;12(3):1460-1472
- CountryChina
- Language:English
-
Abstract:
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.
