Nanostructure-loaded mesoporous silica for controlled release of coumarin derivatives: A novel testing of the hyperthermia effect

Abstract

The synthesis of three types of mesoporous materials is reported: pure mesoporous silica (MCM-41), a nanocomposite of mesoporous silica with hydroxyapatite (MCM-41-HA) and mesoporous silica/gold nanorods nanocomposite (MCM-41-GNRs). The mesoporous materials were characterized by X-ray diffraction, N₂ adsorption isotherms, FTIR spectroscopy, transmission electron microscopy, and scanning electron microscopy. The samples were loaded with coumarin thiourea derivatives (I–IV) having functional groups of varying sizes and the in vitro release assays were monitored, and the release behavior was investigated as a function of soaking time in simulated body fluid. Two release stages were obtained in MCM-41, MCM-41-HA and MCM-41-GNRs loaded samples with the early release stages accounting for about 30% of loaded derivatives. These early release stages are characterized by Higuchi rate constant values nearly twice the values associated with the second release stages. The influence of substituent size on the release rate constants was explained in terms of sorption sites and hydrogen bonding with silanol groups on silicates. The release of coumarin derivatives loaded on MCM-41, MCM-41-HA and MCM-41-GNRs occurs over remarkably long time of the order of about 260 h with faster release rates in loaded MCM-41 and MCM-41-GNRs samples compared with MCM-41-HA ones. The role of hyperthermia effect in enhancing release rates was investigated by subjecting loaded MCM-41-GNRs to near infrared (NIR) radiation at 800 nm. This would be of significance in targeted drug release using hyperthermia effect. Unlike hydroxyl apatite, loading MCM-41 with gold nanorods does not affect the release kinetics. Only when these samples are irradiated with NIR photons, does the release occur with enhanced rates. This property could be valuable in selected targeting of drugs.

Introduction

The administration of drugs by a drug delivery system provides advantages over conventional drug therapies because the drug is delivered locally rather than systemically. This minimizes harmful side effects [1]. The entire drug dose needed for a desired period is administered at one time and released in a controlled manner. Other potential advantages include drug targeting, improved compliance and comfort [2]. Numerous systems have been studied for controlled drug delivery, such as biodegradable polymers [3], hydroxyapatite (HA) [4], [5], [6], calcium phosphate cement [7], [8], [9], xerogels [10], [11], hydrogels [12], [13] mesoporous silica [14] and others.

Mesoporous materials show ordered arrangements of channels and cavities of different geometries built up from SiO₂ units [15]. These materials exhibit variable pore size (2–50 nm), high surface areas (ca. 1000 m²/g), high pore volume (ca. 1 cm³/g) and homogeneous nanostructures which can be tailored by varying the synthesis procedure [16]. The pore walls have high surface density of silanol groups (SiOH) that could be reactive toward appropriate guest molecules [17].

Siliceous mesoporous materials have the advantage of being biocompatible and degradable in aqueous solutions, and thus problems related to the removal of the material after use can be avoided.

Since 2001, when MCM-41 was purposed for the first time as controlled delivery system [18], much research efforts have been devoted to tailor the chemical properties of mesoporous carriers at the nanometer scale to achieve a better control over loading and release of molecules. The mesoporous carrier is selected according to the features of the guest molecule and the targeted application. Therefore, different guest molecules have been successfully confined into mesoporous silicas. Some of these molecules are drugs [18], [19], [20], [21], [22], [23], [24], [25]. Other guest molecules consisted of biologically active species, such as proteins, e.g. bovine serum albumin (BSA) [26] and certain amino acids [27]. The textural properties (i.e., pore diameter, surface area and pore volume) of mesoporous materials are key factors that govern molecules adsorption and release [28]. Moreover, functionalization of silica walls using different organic groups has been revealed as the main strategy to modulate molecule loading and release.

Nanoparticles derived from gold provide an attractive system for diagnostic and therapeutic applications owing to their ease of preparation, ready bioconjugation, good biocompatibility, and unique optical properties [29], [30], [31].

In particular, gold nanorods (GNRs) are important metal nanomaterial with distinctive shape-dependent optical properties. Especially, they possess two distinct plasmon bands, one associated with the transverse mode and the other with the longitudinal modes. These properties suggest several advantages of GNRs for the applications not only in biological sensing [32] and imaging [33] but more importantly, they are potential candidates for localized photothermal therapy because they mediate strong plasmon-induced surface heat flux upon absorption of near infrared light [34], [35], [36], [37].

Although most of the synthetic methods used for the preparation of metal nanorods suffered from limitations, either in the amount of material [38] or in the yield of nanorods, when compared to nanospheres [39], Nikoobakht and El-Sayed recently reported a variation of the so-called seed-mediated method [40] that affords the synthesis of relatively large amounts of nanorods with very little contamination by nanospheres and variable aspect ratio.

Coumarin derivatives possess a wide range of applications as anticoagulants [41], antitumor [42], photosensitizers [43], anti-HIV [44], antimicrobial [45] and anti inflammatory agents [46]. Coumarin derivatives have been liked to other molecules in gene expression studies [47] as well as in salmonella detection [48]. Coumarin derivatives are also currently used as fluorogenic dyes in proteomics [49].

In the present communication, we report the application of mesoporous silicate, mesoporous silicate coating gold nanorods and mesoporous silicates loaded by apatite nanostructures as carriers for coumarin thiourea derivatives (I–IV) linked to functional groups of varying sizes in an effort to correlate group size and release rate constants. The advantage of using mesoporous silicates as carriers of the present coumarin derivatives is the remarkably long time-scale of release (Scheme 1).

Loading mesoporous silicates with gold nanorods offers a novel method of enhanced release based on hyperthermia effect. Plasmon-resonant gold nanorods are highly effective at transducing NIR light into heat leading to localized hyperthermia. Hyperthermia is currently under consideration as a noninvasive approach to cancer therapy, in which biological tissues are exposed to higher than normal temperatures to promote the selective destruction of abnormal cells [37]. Our present approach offers a dual action in which hyperthermia effect can produce severe blebbing in cell membranes, and render them permeable to chemical agents. The other simultaneous effect is the enhanced release of drugs loaded on mesoporous silicates. The biosafety of metallic gold is well known, and they have been used in vivo since the 1950s and recently the noncytotoxicity of gold nanoparticles in human cells has been studied in detail by Wyatt et al. [50].