Enhanced oral delivery of docetaxel using thiolated chitosan nanoparticles: preparation, in vitro and in vivo studies.

Shahrooz Saremi,Fatemeh Atyabi,Abbas Kebriaeezadeh,Seyed Nasser Ostad,Rassoul Dinarvand

doi:10.1155/2013/150478

Shahrooz Saremi, Fatemeh Atyabi + Show 3 more

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https://doi.org/10.1155/2013/150478

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Abstract

The aim of this study was to evaluate a nanoparticulate system with mucoadhesion properties composed of a core of polymethyl methacrylate surrounded by a shell of thiolated chitosan (Ch-GSH-pMMA) for enhancing oral bioavailability of docetaxel (DTX), an anticancer drug. DTX-loaded nanoparticles were prepared by emulsion polymerization method using cerium ammonium nitrate as an initiator. Physicochemical properties of the nanoparticles such as particle size, size distribution, morphology, drug loading, and entrapment efficiency were characterized. The pharmacokinetic study was carried out in vivo using wistar rats. The half-life of DTX-loaded NPs was about 9 times longer than oral DTX used as positive control. The oral bioavailability of DTX was increased to 68.9% for DTX-loaded nanoparticles compared to 6.5% for positive control. The nanoparticles showed stronger effect on the reduction of the transepithelial electrical resistance (TEER) of Caco-2 cell monolayer by opening the tight junctions. According to apparent permeability coefficient (P app) results, the DTX-loaded NPs showed more specific permeation across the Caco-2 cell monolayer in comparison to the DTX. In conclusion, the nanoparticles prepared in this study showed promising results for the development of an oral drug delivery system for anticancer drugs.

Highlights

In recent years, many works have been focused on the development of oral chemotherapy systems
The main reasons for the poor oral bioavailability of DTX are related to low solubility of DTX in water, its high affinity to the multidrug efflux pump Pglycoprotein (P-gp), and hepatic first pass metabolism [8, 9]
In this study we investigated the capacity of prepared thiolated nanoparticles based on thiolated chitosan to improve the oral bioavailability of DTX as a model anticancer drug with poor oral absorption

Summary

Introduction

Many works have been focused on the development of oral chemotherapy systems. DTX like other taxans has a poor oral absorption from gastrointestinal (GI) tract [7] and the only dosage form of DTX in the market is an injection dosage form (Taxotere). The main reasons for the poor oral bioavailability of DTX are related to low solubility of DTX in water, its high affinity to the multidrug efflux pump Pglycoprotein (P-gp), and hepatic first pass metabolism [8, 9]. Due to the poor solubility of DTX in water, it has been formulated as a solution using high amount of Tween 80 in ethanol (50 : 50 v/v). Various methods have been suggested to overcome these problems such as applying a P-gp/P450 inhibitor such as cyclosporine A [11, 12], formulated as liposomes [13, 14], emulsions [15, 16], polymeric nanoparticles [17,18,19,20,21], and conjugation of DTX with water soluble polymers [22, 23]

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