Zein-Based Nanoparticles as Oral Carriers for Insulin Delivery.

Cristian Reboredo,Juan M Irache,Bruno Sarmento,Cristina Martínez-Ohárriz,Carlos J González-Navarro,Ana Luisa Martínez-López

doi:10.3390/pharmaceutics14010039

Abstract

Zein, the major storage protein from corn, has a GRAS (Generally Regarded as Safe) status and may be easily transformed into nanoparticles, offering significant payloads for protein materials without affecting their stability. In this work, the capability of bare zein nanoparticles (mucoadhesive) and nanoparticles coated with poly(ethylene glycol) (mucus-permeating) was evaluated as oral carriers of insulin (I-NP and I-NP-PEG, respectively). Both nanocarriers displayed sizes of around 270 nm, insulin payloads close to 80 µg/mg and did not induce cytotoxic effects in Caco-2 and HT29-MTX cell lines. In Caenorhabditis elegans, where insulin decreases fat storage, I-NP-PEG induced a higher reduction in the fat content than I-NP and slightly lower than the control (Orlistat). In diabetic rats, nanoparticles induced a potent hypoglycemic effect and achieved an oral bioavailability of 4.2% for I-NP and 10.2% for I-NP-PEG. This superior effect observed for I-NP-PEG would be related to their capability to diffuse through the mucus layer and reach the surface of enterocytes (where insulin would be released), whereas the mucoadhesive I-NP would remain trapped in the mucus, far away from the absorptive epithelium. In summary, PEG-coated zein nanoparticles may be an interesting device for the effective delivery of proteins through the oral route.

Highlights

The oral route is the preferred way for drug administration due to its advantages for the patient and for the manufacturer
The encapsulation of insulin increased the mean size of the resulting nanoparticles and decreased the negative zeta potential
The design of nanoparticles with either mucoadhesive or mucus-permeating properties may be of interest to increase the residence time of the drug delivery system in close contact with the epithelium, improving the probabilities for insulin absorption and/or interaction with its receptor [17]

Summary

Introduction

The oral route is the preferred way for drug administration due to its advantages for the patient and for the manufacturer. The large majority of peptides and therapeutic proteins are formulated and administered as injections due to their very low bioavailability when orally administered (usually lower than 1%) [3]. The reason for this low availability is the presence of several obstacles that hamper their access to the absorptive epithelium. The chemical barrier comprises the varying pH conditions all along the gastrointestinal tract, shifting from highly acidic in the stomach (pH ≈ 1.2) to slightly basic in the colon (pH ≈ 7.5) Under these conditions, many proteins undergo a loss of their activity due to hydrolysis, deamination, or pHinduced oxidation processes [3,4]. The enzymatic barrier refers to the efficient degrading enzymes present in the lumen of the gastrointestinal tract and in the apical membrane

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