Abstract
Ingestion is the preferred way for drug administration. However, many drugs have poor oral bioavailability, warranting the use of injections. Extracellular vesicles (EVs) from cow milk have shown potential utility in improving oral drug bioavailability. However, EVs produced by intestinal epithelial cells have not been investigated for this application. We compared the capacity of cow milk EVs and intestinal epithelial cell-derived counterparts to enhance oral drug bioavailability. EVs were isolated, fluorescently labelled, and loaded with curcumin (CUR) as a model poorly absorbable drug. These were then characterised before testing in an intestinal model (Caco-2). Epithelial cell-derived EVs showed notably higher cell uptake compared to cow milk EVs. Cell uptake was significantly higher in differentiated compared to undifferentiated cells for both types of EVs. While both milk- and cell-derived EVs improved the cell uptake and intestinal permeability of CUR (confirming oral drug bioavailability enhancement potential), epithelial cell EVs demonstrated a superior effect.
Highlights
The oral route is the preferred method of drug administration [1,2,3,4]
Dulbecco’s Modified Eagle’s Medium (DMEM) with 4.5 g/L glucose, L-glutamine, sodium pyruvate and sodium bicarbonate, Hank’s Balanced Salt Solution (HBSS) modified with sodium bicarbonate, non-essential amino acids (NEAA), antibiotic/antimycotic solution and foetal bovine serum (FBS, non-USA origin), Curcumin (CUR), Triton X-100 and QuantiProTM Bicinchoninic acid (BCA) Assay Kit were purchased from Sigma-Aldrich (Poole, UK)
Exosome isolation kit from other body fluids and exosome isolation kit form cell culture were purchased from Thermo Fisher Scientific (Loughborough, UK), ExoGlowTM-Protein Extracellular vesicles (EVs) Labeling Kit (Red) and exosome-depleted FBS were purchased from System Biosciences (Palo Alto, CA, USA)
Summary
The oral route is the preferred method of drug administration [1,2,3,4]. many drugs, including poorly water-soluble small drug molecules and macromolecular biologics (peptides, therapeutic proteins and nucleic acid-based therapies), have low oral bioavailability. Drug nanocarrier systems utilised to improve oral drug bioavailability can be designed to target epithelial biological transport pathways [7,9,10,11] While some of these systems have shown potential in vitro and in animal studies, current understanding of orally-administered nanomedicine behaviours and biotransformation within the complex environment of the gastrointestinal tract (including interaction with gut biofluid and mucus, as well as potential toxicity) is lacking. The present study for the first time compared the intestinal translocation (and oral drug delivery potential) of cow milk EVs with that of epithelial cell derived EVs. EV were initially isolated and characterised, prior to fluorescent labelling (to enable quantitation) and encapsulation, of curcumin (CUR) as a model of a poorly absorbed drug. The study sheds further light into the potential utility of EVs, including those from edible sources, as natural systems for improving oral drug delivery
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