Synthesis of CSK-DEX-PLGA Nanoparticles for the Oral Delivery of Exenatide to Improve Its Mucus Penetration and Intestinal Absorption

Abstract

The oral absorption of exenatide, a drug for type 2 diabetes treatment, can be improved by using nanoparticles (NPs) for its delivery. To improve the mucus penetration and intestinal absorption of exenatide, we designed a block copolymer, CSKSSDYQC-dextran-poly­(lactic-co-glycolic acid) (CSK-DEX-PLGA), and used it for the preparation of exenatide-loaded NPs. The functionalized exenatide-loaded NPs composed of CSK-DEX-PLGA were able to target intestinal epithelial cells and reduce the mucus-blocking effect of the intestine. Moreover, the CSK modification of DEX-PLGA was found to significantly promote the absorption efficiency of NPs in the small intestine based on in vitro ligation of the intestinal rings and an examination of different intestinal absorption sites. Compared to DEX-PLGA-NPs (DPs), the absorption of CSK-DEX-PLGA-NPs (CDPs) was increased in the villi, allowing the drug to act on gobletlike Caco-2 cells through clathrin-, caveolin-, and gap-mediated endocytosis. Furthermore, the enhanced transport ability of CDPs was observed in a study on Caco-2/HT-29-MTX cocultured cells. CDPs exhibited a prolonged hypoglycemic response with a relative bioavailability of 9.2% in diabetic rats after oral administration. In conclusion, CDPs can target small intestinal goblet cells and have a beneficial effect on the oral administration of macromolecular peptides as a nanometer-sized carrier.

<p>Evaluation of Intestinal Absorption Mechanism and Pharmacokinetics of Curcumin-Loaded Galactosylated Albumin Nanoparticles</p>

“…The absorption mechanism of the NPs has not been reported, which may be an ideal material for oral drug delivery. In addition, other nanocarriers were internalized into Caco-2 cells by multiple endocytosis mechanisms,31 which reminds us that these nanocarriers may be also considered to improve the intestine absorption by oral administration 32–34…”

Delivery of Nanoparticles across the Intestinal Epithelium via the Transferrin Transport Pathway

“…We utilised fluorescently-labelled model polystyrene NP systems and achieved ligand (Tf) presentation on NP via physical adsorption. This produced Tf-NP of approximately 180 nm (Figure 2), which fall within the optimal size range for intestinal epithelial transport [6,20,27,28]. Furthermore, it was previously shown that following presentation as coating on the surface of NP via physical adsorption, Tf retains the ability to target and interact with TfR [29].…”

Nanomedicine strategies to target coronavirus

“…For instance, nanocarriers modified with the goblet cell-targeted peptide (CSKSSDYQC (CSK)), have demonstrated enhanced mucus penetrating characteristics, reduced mucus clearance as well as specific uptake into goblet cells. Studies demonstrate the CSK peptide enhanced nanocarrier uptake in the oral mucosa for the delivery of insulin or exenatide for the treatment of diabetes [ [178] , [179] , [180] , [181] ], as well as enhanced uptake of gemcitabine in intestinal goblet cells for the treatment of breast cancer after oral administration [ 182 ]. The combination of nanocarriers loaded with drug candidates focusing on the treatment of CoVs combined with such surface peptides could form a promising strategy for the nasal delivery towards CoV-infected epithelial cells.…”