Abstract
BackgroundThere is a strong need for non-invasive and patient-friendly delivery systems of protein drugs for long-term therapy. However, oral delivery of protein drugs is a big challenge due to many barriers including instability in the gastrointestinal (GI) tract and low permeability. To overcome the absorption barriers in GI tract and improve the patient compliance, this study aimed to develop an M cell targeted-nanocomposite delivery system of protein drugs.ResultsAn aminoclay-protein core complex (AC-Ins) was prepared by using insulin as a model protein and then sequentially coated with Ulex europaeus agglutinin 1 (UEA-1) for M-cell targeting and the pH sensitive polymer, Eudragit® L100 (EUAC-Ins). All nanoparticles were obtained with a high entrapment efficiency (> 90%) and their structural characteristics were confirmed by Fourier transform-infrared spectroscopy, energy dispersive X-ray spectroscopy, and circular dichroism. Among the developed nanoparticles, EUAC-Ins effectively suppressed drug release at pH 1.2, while rapidly released drugs at pH 6.8 due to dissolution of the outer coating layer. The conformational stability of insulin entrapped in EUAC-Ins was well maintained in the presence of proteolytic enzymes. Compared to free insulin, EUAC-Ins increased the membrane transport of insulin by 4.4-fold in M cells. In parallel, oral administration of EUAC-Ins in mice enhanced insulin uptake by 4.1-fold in the intestinal Peyer’s patches and 2.6-fold in intestinal epithelium tissues with normal villi, compared to free insulin. Orally administered EUAC-Ins decreased significantly the blood glucose level in diabetic mice, while the effect of oral insulin solution was negligible.ConclusionAn M cell targeted-ternary nanocomposite system obtained by dual coating of the aminoclay-protein core complex with UEA-1 and a pH dependent polymer is promising as an effective oral protein delivery carrier.
Highlights
There is a strong need for non-invasive and patient-friendly delivery systems of protein drugs for longterm therapy
Previous research has demonstrated the effectiveness of Microfold cell (M cell) targeting by Ulex europaeus agglutinin 1 (UEA-1), a representative lectin that interacts with α-l-fucose residues on the apical surface of M cells [11, 18, 19]
The amount of UEA-1 coating on the nanoparticles was approximately 0.18 ± 0.01 mg/mg nanoparticles, which was determined as the difference between the lectin added initially and the lectin recovered in the solution after incubation with the nanoparticles [32, 33]
Summary
There is a strong need for non-invasive and patient-friendly delivery systems of protein drugs for longterm therapy. Oral delivery of protein drugs is a big challenge due to many barriers including instability in the gastrointestinal (GI) tract and low permeability. To overcome the absorption barriers in GI tract and improve the patient compliance, this study aimed to develop an M cell targeted-nanocomposite delivery system of protein drugs. Researchers have attempted to develop M cell targeted drug carriers using lectins that bind to carbohydrate residues on the surface of M cells [7, 17]. Dual surface coating using M cell-targeted ligand and pH-dependent polymers could enhance the oral bioavailability of proteins. In addition to surface coating, the effectiveness of core nanoparticles as drug carriers is important to improve the oral bioavailability of proteins
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