Abstract

High proteolytic degradation and poor absorption through epithelial barriers are major challenges to successful oral delivery of therapeutics. Nanoparticle platforms can enhance drug stability and extend the residence time in gastrointestinal (GI) tract. However, drug delivery systems are often inactivated in acidic environment of stomach or suffer poor absorption from intestinal cells due to the mucus layer. To overcome these issues we developed a drug delivery system constituted by a protein construct made by a Rotavirus capsid protein (VP6) and the small ubiquitin‐like modifier SUMO. This chimeric construct allows specificity towards intestinal cells, the Rotavirus natural target, combined by an enhanced stability given by the eukaryotic protein transporter SUMO. Furthermore SUMO can act as a molecular switch that facilitates import/export of its ligand to the nucleus, the hypersensitive subcellular site target of many cell killing therapies. In this paper we show that SUMO‐VP6 constructs self‐assembly into stable nanocarriers. SUMO‐VP6 nanocarriers display ideal features for drug delivery: a small size and high monodispersity, a high stability in different pH conditions and a high uptake in the nuclear and cytoplasmic compartment of intestinal cells. These features make SUMO‐VP6 nanocarriers a promising novel system for oral delivery of poorly soluble drugs.

Highlights

  • In the field of drug delivery there is a continuous effort for optimization of pharmaceutical formulation to obtain a maximal accumulation in the targeted tissue [1, 2]

  • Drug delivery systems are often inactivated in acidic environment of stomach or suffer poor absorption from intestinal cells due to the mucus layer

  • To overcome these issues we developed a drug delivery system constituted by a protein construct made by a Rotavirus capsid protein (VP6) and the small ubiquitin-like modifier Small Ubiquitin Like Modifier (SUMO)

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Summary

Introduction

In the field of drug delivery there is a continuous effort for optimization of pharmaceutical formulation to obtain a maximal accumulation in the targeted tissue [1, 2]. Despite the advantage of the high absorptivity of intestinal epithelium, oral formulations face several problems, such as (i) poor stability in the gastric environment, (ii) low solubility and/or bioavailability, and (iii) low penetration in the mucus barrier, which prevents drug absorption [3]. To overcome these limitations and design a carrier with high specificity towards intestinal cells combined to stability in GI environment, we produced a construct made of VP6 protein fused with the Small Ubiquitin Like Modifier (SUMO). SUMO is ubiquitously expressed in eukaryotic cells where it is reversibly conjugated to specific targets to modulate

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