Journal
ACTA PHARMACEUTICA SINICA B
Volume 12, Issue 3, Pages 1460-1472Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.07.024
Keywords
Ligand-modified nanoparticles; Transporter; Proton-coupled folate transporter; Expression level; Endocytosis; Intracellular trafficking; Diabetes; Oral insulin delivery
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Funding
- National Natural Science Foundation of China (NSFC), China [81773651, 82025032, 81803445]
- NN-CAS foundation
- National Key R&D Program of China, China [2020YFE0201700]
- Major International Joint Research Project of Chinese Academy of Sciences, China [153631KYSB20190020]
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This study demonstrates that the upregulated intestinal transporter PCFT facilitates the uptake and intracellular trafficking of ligand-modified nanoparticles. In cells with low expression of PCFT, nanoparticles are predominantly degraded in lysosomes.
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. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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