A facile synthetic strategy for Mg–Al layered double hydroxide material as nanocarrier for methotrexate
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.
Section snippets
Synthetic methods
All the chemicals used were of analytical grade. Magnesium nitrate hexahydrate Mg(NO3)2·6H2O (99%), aluminium nitrate nonahydrate Al(NO3)3·9H2O (99%) and sodium hydroxide NaOH (pellets) were purchased from Merck, India. Methotrexate (MTX) was procured from Sun Laboratory (Bangalore, India). Ultrapure decarbonated water (Millipore, specific resistivity 18 MΩ, decarbonated in XL grade nitrogen atmosphere) was used in all the experiments.
Two sets of Mg–Al LDHs were synthesized chemically by
Results and discussion
The powder X-ray diffraction patterns of LDH9, LDH11 and LDH–MTX are shown in Fig. 1. Almost all characteristic diffraction peaks of a hexagonal Mg–Al LDH matching with the JCPDS pattern (JCPDS File No. 35-0964) were observed, with rhombocentered lattice. The peaks corresponding to the higher order reflections are indexed. For the present study, we considered (0 0 6) reflection for single profile analysis to calculate crystallite size (DXRD) and lattice strain (ɛ) of the LDH samples because (0 0 3)
Conclusions
A pH dependent variation in morphology of Mg–Al LDH nanopowder and its plausible explanation has been discussed in this study. Presence of surface charge at precipitation pH 9 resulted in LDH with lower particle size in 10–100 nm range in LDH9 whereas isotropic growth at pH close to its isoelectric point produced larger particles in 25–290 nm range in LDH11. Estimated lattice strain from XRD in LDH9 is 1.29% more than the same in LDH11. This observation was supported by the EDS analysis which
Acknowledgements
The authors are grateful to the Director, Central Glass and Ceramic Research Institute, Kolkata, India for providing the permission to carry on the above work. Thanks are due to all other support staffs of CGCRI, Kolkata who made this work possible. Authors thank IIT, Kharagpur for low angle X-ray diffraction studies. We are indeed indebted to the CSIR Network Program NWP 0035 for all the kind support and the financial assistance for undertaking this work.
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2022, ParticuologyCitation Excerpt :The category of anions with different size and charge greatly affects the interlayer spacing (Rives, 2001). The interlayer anions can be exchanged with others depending on their affinity for the positively charged hydroxide layer, therefore many therapeutic molecules such as anticancer drugs, including immunosuppressant (Gunawan & Xu, 2008), 5-fluorouracil (5-FU) (Choi, Oh, & Choy, 2008; Pan, Zhang, Fan, Chen, & Duan, 2011; Wang, Wang, Gao, & Xu, 2005), and methotrexate (MTX) (Chakraborty et al., 2012; Li, Gu, Gu, Liu, & Xu, 2016; Ray, Mishra, Mandal, Sa, & Chakraborty, 2015), indocyanine green (ICG) (Wang et al., 2021; Wei, Kuthati, Kankala, & Lee, 2015), proteins and enzymes (Nakayama, Wada, & Tsuhako, 2004; Szerlauth, Muráth, & Szilagyi, 2020; Zhang et al., 2017), and nucleic acids (Ladewig, Niebert, Xu, Gray, & Lu, 2010; Yu et al., 2020) can be loaded into the interlayer and physically protected by the hydroxide layer. These loaded species can be released via anion exchange and/or pH-sensitive dissolution (Ladewig et al., 2010; Yu et al., 2020).
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