A facile synthetic strategy for Mg–Al layered double hydroxide material as nanocarrier for methotrexate

Abstract

Mg–Al layered double hydroxide nanopowders were synthesised by a facile coprecipitation technique at different pH conditions. LDH nanoparticles of higher aspect ratio with an average particle size of 26 nm were obtained at pH 9 whereas a pH of 11.3 resulted in LDH nanoparticles of average size 50 nm with lower aspect ratio and narrower size distribution. LDH–MTX organo–inorganic nanohybrid was produced with an average particle size of 53 nm after intercalation of MTX into the interlayer space of LDH, as evident from the shift of (0 0 3) peak in X-ray diffraction. This was corroborated by the transmission electron micrograph, which showed an increase in average interlayer spacing from 8.00 Å in pristine LDH to 21.4 Å in LDH–MTX nanohybrid. Thermogravimetric analyses showed ∼33.2 wt% MTX loading in the LDH structure. The MTX release profile from Mg–Al LDH–MTX nanohybrid in phosphate buffer saline at pH 7.4 follows Ritger–Peppas kinetics model which demonstrates that the release kinetics is diffusion controlled. An attempt has been made to explain the above observations based on the effect of electrical double layer repulsions on the growth of LDH nuclei, primarily considering significance of the particle morphology in drug delivery application.

Introduction

Numerous efforts have been made in recent times to develop novel drug carrier for transport, storage and release, which exhibit numerous advantages over the conventional forms of dosage, such as enhanced bioavailability, greater efficacy and safety, controlled and prolonged release time, and predictable therapeutic response [1]. So far, a large number of materials have been employed as various drug delivery systems, such as biodegradable polymers, hydroxyapatite, xerogels, hydrogels [1], guar gum nanoparticles [2], fluoride hollow structures [3], superparamagnetic nanoparticles [4], [5], functionalized mesoporous materials [6], [7], [8] and layered double hydroxides (LDHs) [9]. LDHs are considered to be the new generation materials, comprising two dimensional layered structure similar to that of mineral brucite, Mg(OH)₂ [10]. LDHs have many other properties which make them attractive for real applications; these include nanomedicine [10], [11], catalyst supports [11], [12], agriculture, pharmaceuticals, and detergent manufacturing [13]. Mg–Al layered double hydroxide (LDH) is a good reservoir for different kind of drugs in their anionic form [14], [15], [16], [17] and is of particular interest in the field of cellular delivery of drug and biomolecules. LDH nanoparticles are reported to be easily endocytosed inside the cellular compartments based on their size and morphology [18], [19]. Intensive investigations in the area of targeted drug delivery to combat with cancer disease has prompted the use of LDHs [20], that have a cationic framework formed by the isomorphous substitution of M²⁺ (where M is Mg, Ca, Zn Fe, Cu, Mn, etc.) ions, with M³⁺ (where M is Al, Fe, Cr, Co, etc.) ions in the structure of M²⁺(OH)₂ [11]. The incorporated drugs inside the LDH nanocarriers would possess higher resistance to enzymatic degradation, do not easily desorb away in the blood circulation and thus can be targeted to specific cells and tissues.

The shape or morphology of nanocarrier plays an important role in drug transport to specific cells or tissues and subsequent endocytosis inside the cellular compartments. Interaction of spherical particles with cells of animals has been studied extensively [21], [22], but the effects of shape have received little attention. Depending on the requirements, the shape of nanocarrier can be tailored and transport to specific targets can be made faster or slower [23], [24]. The size of nanoparticles used in a drug delivery system should be optimum to prevent their rapid release into blood capillaries but small enough to escape capture by fixed macrophages that are lodged in the reticuloendothelial system, such as the liver and spleen and reach tumor tissues [25], [26]. There is substantial progress in preparation, application and perspectives of LDHs with different morphologies. Kuang et al. have summarized the progress in fabrication of range of LDH morphologies from spherical, one-dimensional (1-D) belt/fiber to 2-D films [27]. Further, they have mentioned that LDH nanopowders synthesized by conventional coprecipitation technique showed preferential growth of the a–b plane to form hexagonal platelet morphology. Lu et al. have correlated the relationship between particle morphology and hydrothermal treatment conditions, e.g. time, temperature and concentration [28]. To the best of our knowledge, no attempt has been made to elaborate the effect of precipitating pH conditions on the formation of LDH nanocrystals of different morphology.

In view of the above, this communication reports a simple but useful method to prepare stable homogeneous LDH suspensions with controllable morphology by pH variation of the precursor solution at 25 °C. The particles have a narrow size distribution in nanoscale. MTX, an anticancer drug is intercalated into the LDH framework by anion exchange technique. The Mg–Al LDH and LDH–MTX composites were characterized using powder X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR) and particle size analysis. The extent of intercalation is studied by thermogravimetric analyses (TG). The drug release kinetics was diffusion controlled as evidenced from the best fit into the Ritger–Peppas model.