Contents lists available at ScienceDirectJournal of Controlled Releasejournal homepage: www.elsevier.com/locate/jconrelPromoting apical-to-basolateral unidirectional transport ofnanoformulations by manipulating the nutrient-absorption pathwayLei Wu a , Yuli Bai a , Lingling Wang a , Xi Liu a , Rui Zhou a , Lian Li a , Ruinan Wu a , Zhirong Zhang a ,Xi Zhu b, ? , Yuan Huang a, ? SupervisionFunding acquisitiona Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, SouthernRenmin Road, Chengdu 610041, PR Chinab Shanghai InnoStar Biotech Co., LTD. (National Shanghai Center for New Drug Safety Evaluation and Research), 199 Guoshoujing Road, Pudong New Area, Shanghai, PRChinaA R T I C L E I N F OKeywords:Apical-to-basolateral transcytosisReceptor “amplif i er”Mimicking nutrient-absorptionCombination regimenOrally delivered nanoplatformA B S T R A C TThe epithelium is a formidable barrier to the absorption of orally delivered nano-vehicles. Here, by exploring anutrient-absorption pathway, a self-amplif i ed nanoplatform was developed to promote apical-to-basolateraltranscytosis across the epithelium. The nanoplatform consisted of fructose-modif i ed polyethylene glycol coatednanoparticles (Fru-PEG NPs) and a sweetener, acesulfame potassium (AceK) in combination. Compared withregular PEGylated nanoparticles, the combination exhibited a 3.9-fold increase of absorption following oralgavage in mice and an 8.8-fold increase of transepithelial transport in vitro. When encapsulated with insulin, thecombination regimen elicited a stronger hypoglycemic ef f ect, 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 NPsunderwent internalization and basolateral exocytosis via a glucose transporter type 2 (GLUT2)-dependent pro-cess, which is an important fructose assimilation pathway. Notably, co-administered AceK could prime theepithelial cells with increased apical distribution of GLUT2, thus amplifying this unidirectional transcytosis ofnanoparticles. This work is the f i rst proof-of-concept study of manipulating and amplifying a nutrient-absorptionpathway to facilitate the unidirectional trans-epithelial transport of orally administered nano-delivery vehicles.1. IntroductionThe ef f i cient delivery of therapeutics across the intestinal mucosaremains a long-standing challenge in the development of nanoplatforms[1]. To deliver a payload into the blood circulation, nanoparticles (NPs)need to penetrate the mucus layer, enter the intestinal epithelium,undergo complex intracellular traf f i cking, and exit from the basolateralmembrane [2,3]. By actively targeting epithelial receptors, ligand-de-corated NPs have exhibited improved endocytosis. However, previousstudies have demonstrated that insuf f i cient basolateral exocytosis is thebottle-neck step for ef f i cient transepithelial transport [4,5]. Thereby, itis necessary to establish an ef f i cient apical-to-basolateral transport f l owby improving not only apical endocytosis for “inward” f l ux, but alsobasolateral exocytosis for “outward” f l ux.The gastrointestinal (GI) tract can ef f i ciently absorb nutrients fromthe lumen into the bloodstream [6]. We hypothesized that an oral drugdelivery system could be established by leveraging the nutrient-ab-sorption pathway to “work with biology.” Glucose transporters (GLUTs)in enterocytes are responsible for the complete absorption of sugars [7].Gao et al. proved that GLUTs facilitate the exocytosis of mannose-modif i ed NPs from endothelial cells into the brain parenchyma [8];however, only limited ef f i ciency was achieved in traversing the blood-brain barrier using a GLUT-mediated nanoplatform [9]. The full po-tential of targeting GLUTs to facilitate the basolateral exocytosis oforally delivery NPs has not yet been explored.Fructose, a common dietary carbohydrate, has a high GLUT-mediatedabsorption rate [10]. GLUTs on the apical membrane mediate the epi-thelial internalization of fructose; glucose transporter type 2 (GLUT2) onthe basolateral membrane facilitates the transport of fructose into thebloodstream, forming a highly ef f i cient “uniport” [7]. Although not re-sident on the apical side in default-mode, GLUT2 can be rapidly andtransiently recruited from the cytosol to the apical membrane at highsugar concentrations [11]. Artif i cial sweeteners with much lower con-centrations can also induce apical GLUT2 insertion [12]. Thereby, wesupposed that co-administration of sweeteners and fructose-modif i edNPs may further improve GLUT-mediated NP transcytosis.https://doi.org/10.1016/j.jconrel.2020.04.013Received 11 December 2019; Received in revised form 3 April 2020? Corresponding authors.E-mail addresses: zhuxisid@163.com (X. Zhu), huangyuan0@163.com (Y. Huang).Journal of Controlled Release 323 (2020) 151–160Available online 08 April 20200168-3659/ © 2020 Elsevier B.V. All rights reserved.T
