Abstract
The potential of poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) to overcome the intestinal barrier that limits oral liraglutide delivery was evaluated. Liraglutide-loaded PLGA NPs were prepared by the double emulsion solvent evaporation method. In vitro release kinetics and enzymatic degradation studies were conducted, mimicking the gastrointestinal environment. The permeability of liraglutide solution, liraglutide-loaded PLGA NPs, and liraglutide in the presence of the absorption enhancer PN159 peptide was tested on the Caco-2 cell model. Liraglutide release from PLGA NPs showed a biphasic release pattern with a burst effect of less than 15%. The PLGA nanosystem protected the encapsulated liraglutide from the conditions simulating the gastric environment. The permeability of liraglutide encapsulated in PLGA NPs was 1.5-fold higher (24 × 10−6 cm/s) across Caco-2 cells as compared to liraglutide solution. PLGA NPs were as effective at elevating liraglutide penetration as the tight junction-opening PN159 peptide. No morphological changes were seen in the intercellular junctions of Caco-2 cells after treatment with liraglutide-PLGA NPs, confirming the lack of a paracellular component in the transport mechanism. PLGA NPs, by protecting liraglutide from enzyme degradation and enhancing its permeability across intestinal epithelium, hold great potential as carriers for oral GLP-1 analog delivery.
Highlights
The worldwide prevalence of type 2 diabetes mellitus (T2DM) has been increasing dramatically and has become a serious issue at an alarming rate
Oral delivery appears to be feasible for Lira due to the relatively large safety window of GLP1 analogs compared to insulin [9]
As there is no available literature regarding the intestinal permeability of Lira solution, we evaluated the permeability of Lira through the Caco-2 cell model
Summary
The worldwide prevalence of type 2 diabetes mellitus (T2DM) has been increasing dramatically and has become a serious issue at an alarming rate. Because the incretin effect has been proven to be severely reduced or lost in relatively lean type 2 diabetic patients, incretin-based therapy, especially glucagon-like peptide 1 (GLP-1) receptor agonists, is widely investigated for T2DM [1]. Our group has recently demonstrated, that a permeability enhancing 18-mer amphiphilic peptide, PN159, known as KLAL or MAP, has a dual action: by acting on claudin transmembrane tight junction proteins it opens the paracellular route in both epithelial and blood–brain barrier models [23] and at the same time it has cell permeabilizing and penetrating properties [24]. We investigated the potential of the optimized PLGA NPs in enhancing the permeability of encapsulated Lira through the Caco-2 cell model and compared it with the permeability enhancer PN159 peptide
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