Abstract
To improve the oral efficiency of exenatide, we prepared polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) NPs modified with Fc (NPs-Fc) for exenatide oral delivery. Exenatide was encapsulated into the NPs by the w/o/w emulsion-solvent evaporation method. The particle size of the NPs-Fc was approximately 30 nm larger than that of the unmodified NPs with polydispersity indices in a narrow range (PDIs; PDI < 0.3) as detected by DLS, and the highest encapsulation efficiency of exenatide in the NPs was greater than 80%. Fc-conjugated NPs permeated Caco-2 cells faster and to a greater extent compared to unmodified NPs, as verified by CLSM and flow cytometry. Hypoglycemic effect studies demonstrated that oral administration of exenatide-loaded PEG-PLGA NPs modified by an Fc group extended the hypoglycemic effects compared with s.c. injection of the exenatide solution. Fluorescence-labeled NPs were used to investigate the effects of Fc targeting, and the results demonstrated that the NPs-Fc stayed in the gastrointestinal tract for a longer time in comparison with the unmodified NPs, as shown by the whole-body fluorescence images and fluorescence images of the dissected organs detected by in vivo imaging in live mice. Therefore, Fc-targeted nano-delivery systems show great promise for oral peptide/protein drug delivery.
Highlights
Exenatide, a 39-amino-acid peptide with a molecular weight of 4186 Da and isoelectric point of pH 4.86, is similar to glucagon like peptide-1 (GLP-1) in terms of glucoregulatory actions and is used for type 2 diabetes therapy[1]
This PEG shell is capable of alleviating the aforementioned barriers, as free PEG chains perform as a protein repellent for protecting the nanoparticles from enzymatic attack in the gastrointestinal tract (GIT); on the other hand, the PEG chains can penetrate the GIT’s mucosal layer, which enhance the cellular uptake of the nanocarriers[10]
The efficacy of oral Fc-modified exenatide-loaded PEG-PLGA NPs was studied to provide a non-invasive route for diabetes treatment as an alternative to frequent injections
Summary
A 39-amino-acid peptide with a molecular weight of 4186 Da and isoelectric point of pH 4.86, is similar to glucagon like peptide-1 (GLP-1) in terms of glucoregulatory actions and is used for type 2 diabetes therapy[1]. Exenatide administration is limited to parenteral routes, resulting in low patient compliance. One of the major challenges is the development of a patient-friendly delivery of proteins/ peptides in the pharmaceutical field. Oral delivery of proteins/peptides is still challenging mainly because of the instability of these molecules in the gastrointestinal tract, their considerably low permeation efficiency through the intestinal epithelium, and their rapid indigestive degradation[5,6]. System might be improved by the hydrophilic character of PEG9 This PEG shell is capable of alleviating the aforementioned barriers, as free PEG chains perform as a protein repellent for protecting the nanoparticles from enzymatic attack in the gastrointestinal tract (GIT); on the other hand, the PEG chains can penetrate the GIT’s mucosal layer, which enhance the cellular uptake of the nanocarriers[10]. It is necessary to apply a new strategy to overcome these barriers
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