Efficient Peroral Delivery of Insulin via Vitamin B12 Modified Trimethyl Chitosan Nanoparticles

Abstract

ABSTRACT-PURPOSE:We investigated the effect of vitamin B12 (VB12) modification on the insulin absorption from trimethyl chitosan(TMC) nanoparticles (NPs) under the influence of mucus. METHODS: TMC and TMC-VB12 were synthesized and insulin loaded TMC/TMC-VB12 nanoparticles were prepared and characterized. Modified and unmodified nanoparticles were studied with Caco-2/HT29-MTX cell model and ligated rat ileum loop. RESULTS: Compared with unmodified NPs, VB12 modified NPs showed significantly higher drug internalization in Caco-2/HT29-MTX cell model. The internalization mechanism via VB12 mediation included caveolae and clathrin-mediated endocytosis pathway. Meanwhile, an increased transportation of drugs was observed for VB12 modified NPs, possibly due to the ligand-receptor interaction via an intrinsic factor-dependent fashion. Although the uptake and transport of VB12 modified NPs could be partially influenced by mucus, they still showed higher drug permeation through Caco-2/HT29-MTX co-cultured cells than unmodified NPs in the presence or absence of mucus. Moreover, in situ study in ligated rat ileum loop demonstrated that VB12 modified nanoparticles could reduce the residual insulin in intestinal lumen (0.59 times) and increase their absorption in epithelial tissue (4.8 times) compared with the unmodified ones. CONCLUSION: VB12 modified trimethyl chitosan nanoparticle is a promising carrier for peroral delivery of insulin.

Enhancement of scutellarin oral delivery efficacy by vitamin B12-modified amphiphilic chitosan derivatives to treat type II diabetes induced-retinopathy

“…Francis et al [ 27 ] reported that oral absorption and delivery efficiency of polymeric micelles were substantially enhanced by linkage to VB12 and that the process is initiated by the complexation of VB12 with IF. Ke et al [ 28 ] showed that VB12 modified nanoparticles significantly improved the drug internalization and the transport efficacy through cell monolayer. According to these findings, we designed and synthesized the Chit-DC-VB12 nanoparticles, while the FTIR, 1 H NMR and UV–Vis analyses confirmed that the deoxycholic acid residues and vitamin B12 residues were conjugated with the chitosan chains and their DS values were 3 and 0.3%, respectively.…”

“…Upon reaching the small intestine, this complex binds to IF receptors located in the luminal surface of the intestine, facilitating the transport across intestinal epithelium by receptor-mediated endocytosis. In previous works [ 28 ], after modified by VB12, nanoparticles showed significantly higher drug internalization in cell model than unmodified nanoparticles, and an increased transportation of insulin. However, no such report is available where this concept has been used for oral delivery of scutellarin.…”

Oral drug delivery with nanoparticles into the gastrointestinal mucosa

“…However, a membrane filter simply covered by the mucus layer can generate a comparison of the penetration of compounds without the existence of an epithelial barrier and can be used to evaluate the diffusion of different substances through the mucus layer [26–29]. A study used the Caco‐2/HT29‐MTX coculture cell model to evaluate the transcellular permeation of nanoparticles by virtue of not only the presence of the mucus layer but also a TEER value that was close to that of the intestinal epithelium [30]. The results indicated the ability of tight junctions to open epithelial cells, which plays a key role in the paracellular route of drug transport.…”

Lyophilisation Improves Bioactivity and Stability of Insulin-Loaded Polymeric-Oligonucleotide Nanoparticles for Diabetes Treatment

“…Lyophilised nanoparticles can be absorbed by different mechanisms including endocytotic pathway and paracellular pathway in the GI tract (15,49,(72)(73)(74)(75)(76). In terms of endocytic pathway, as ligand conjugation was not manipulated in the developed nanoparticles, the nanoparticles can only be adsorbed to the GI cells by unspecific electrostatic forces (adsorptive endocytosis), but not active targeting to GI receptors (receptor-mediated endocytosis).…”