Controlled release of IFC-305 encapsulated in silica nanoparticles for liver cancer synthesized by sol–gel

Abstract

IFC-305 was encapsulated into nanostructured silica and functionalized with OH groups by the sol–gel process using tetraethoxysilane (TEOS), to be used for a drug delivery system for the treatment of liver cancer. Synthesis was carried out at different molar hydrolysis ratios: 4, 8, 16 and 24 mol of water and drug concentrations of 10, 20 and 30%. Characterization of IFC-silica reservoirs by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermal analysis (DTA-TGA), transmission electron microscopy (TEM), and N₂ adsorption–desorption isotherms (BET), confirms that IFC-305 was trapped and stabilized in the SiO₂–OH matrix. Drug release was determined by UV spectrophotometry over a period of 1000 h. Results showed that the morphology and specific surface area are controlled by the amount of loaded drug and water content for the different synthesized reservoir systems. However, the in vitro analysis of drug discharge showed that the rate of drug release was independent of the amount of hydrolyzed water, although it was affected by the quantity of drug loaded. The mechanism of drug release is a combination of dissolution and diffusion processes.

Introduction

Chronic liver diseases are a major health issue world-wide [1]. In Mexico, the mortality rate due to cirrhosis ranks among the highest in the world, being the third cause of death in the general population and the second in young adults in 2005 [2]; in that year, patients died due to liver cirrhosis and other chronic liver diseases at a rate of 25.9/100,000 inhabitants, and a steady rise in the number of cases is expected to occur in the following years [2], [3]. Cirrhosis is a chronic degenerative disease in which normal liver cells are damaged and are then replaced by scar tissue; therefore, it reduces the liver's ability to manufacture proteins and process hormones, nutrients, medications and the normal biochemical processes.

In recent years, application of nanotechnology for the treatment of human diseases holds great promise. In particular, the use of SiO₂ nanoparticles has been extended to biomedical and biotechnological fields, since it has a unique matrix that allows the incorporation of different types of molecules. It has been applied as biosensors and biomarkers [4], as well as for cellular imaging applications [5]. For controlled release applications, it has been shown that silica is able to store and gradually release therapeutically relevant drugs like antibiotics [6], [7], [8], or drugs for treating neurological diseases as such as dopamine, valproic acid and sodium phenytoin [9], [10], [11], [12]. Furthermore, silica nanoparticles have been used to enhance the biocompatibility of several drug delivery systems for cancer therapy and catalysis [8], [13], [14], [15].

Amorphous, sol–gel derived SiO₂ is known to be a biocompatible and bioresorbable material that has potential applications as implants or injectable matrices in the controlled delivery of biologically active agents in living tissues [16], [17]. The sol is produced through hydrolysis and polycondensation reaction [18] from an alkoxide precursor. Due to the mild processing conditions, high concentrations of many types of biologically active agent can be incorporated in the liquid (sol) and, afterwards, is embedded in the matrix (gel), which after condensation and drying becomes a porous solid material [5], [6], [7], [8], [9], [10], [11]. It is also well known that release is dependent on synthesis parameters such as the molar ratio of silica precursor to water, type of precursor and the concentration of bioactive drug [8], [12], [19], [20], [21].

A promising therapeutic alternative to treat liver cirrhosis disease is the use of a novel drug called IFC-305, a derivative of 6-aminoribofuranosil purine, which has been tested to revert cirrhosis and liver dysfunction in rats, however, it shows a very short half-life due to its rapid metabolism in the liver [22]. In this work, silica nanoparticles were synthesized to encapsulate IFC-305, and to provide a stable reservoir to target the delivery of the drug to the liver in order to improve the metabolic stability and to achieve the appropriate dosage, needed to result in an efficient treatment. The drug molecule and both empty and loaded reservoirs were characterized to understand the linking mechanism, to verify the IFC-305 stabilization and to analyze in vitro the drug release behavior, with variation in the amount of water and drug content.