Promoting apical-to-basolateral unidirectional transport of nanoformulations by manipulating the nutrient-absorption pathway

The epithelium is a formidable barrier to the absorption of orally delivered nano-vehicles. Here, by exploring a nutrient-absorption pathway, a self-amplified nanoplatform was developed to promote apical-to-basolateral transcytosis across the epithelium. The nanoplatform consisted of fructose-modified polyethylene glycol coated nanoparticles (Fru-PEG NPs) and a sweetener, acesulfame potassium (AceK) in combination. Compared with regular PEGylated nanoparticles, the combination exhibited a 3.9-fold increase of absorption following oral gavage in mice and an 8.8-fold increase of transepithelial transport in vitro. When encapsulated with insulin, the combination regimen elicited a stronger hypoglycemic effect, with a pharmacological bioavailability of 18.56%, which was 3.2-fold higher than that of PEG NPs. We demonstrated that a large proportion of Fru-PEG NPs underwent internalization and basolateral exocytosis via a glucose transporter type 2 (GLUT2)-dependent process, which is an important fructose assimilation pathway. Notably, co-administered AceK could prime the epithelial cells with increased apical distribution of GLUT2, thus amplifying this unidirectional transcytosis of nanoparticles. This work is the first proof-of-concept study of manipulating and amplifying a nutrient-absorption pathway to facilitate the unidirectional trans-epithelial transport of orally administered nano-delivery vehicles.