Magnetite-based nanobioplatform for site delivering Croton cajucara Benth essential oil
Graphical abstract
Introduction
In recent years, nanoscience has developed steeply since it was recognized that nanostructured materials show unique and modulated properties, depending for instance on size, shape, and surface coating [1], [2]. Iron oxide nanoparticles (NPs) comprise a wide class of nanomaterials, which are of great interest for biological and medical applications credited to their superior biocompatibility, biodegradation and safe excretion routes while within living systems [3], [4]. Among magnetic NPs magnetite (Fe3O4) has raised huge interest and found many applications in biology and medicine, as for example in cell manipulation and contrast agent for magnetic resonance imaging [5], [6]. Structurally, bulk magnetite shows an inverse spinel structure, in which oxygen atoms form a face centered cubic lattice and iron ions (Fe2+ and Fe3+) occupy tetrahedral and octahedral sites. Within magnetite's crystal structure electron transferring from ferrous to ferric ion has been reported at room temperature, i.e. above the Verwey transition ∼125 K. As far as biological and medical applications are concerned, after synthesizing pristine magnetite nanoparticles (MNPs) surface coating should be the next step to follow in order to incorporate functionality, site specificity, and enhanced biocompatibility. Moreover, surface coating also promotes colloidal stability via electrostatic and/or steric interactions, preventing suspended single units in liquid media to aggregate themselves into larger clusters driven by attractive interactions such as magnetic dipole-dipole and Van der Walls and leading to decreased effective magnetization and deleterious biological response [7].
Surface coating MNPs can be realized using organic moieties, such as fatty acids with long tail, in which case the polar carboxyl group complexes the MNP's surface while the hydrophobic tail provides steric repulsion [8]. Additionally, it is possible to carry out surface coating with multiple layers of surfactants, in which case the inner surface layer can be further dressed with a second and third one, the outer layer being for instance a specific drug [9]. In this way, the first coating layer may offers both stable dispersion for the MNP in a suitable solvent and favorable anchoring environment for the next layer, which are meant to provide special features to the end nanomaterial, such as bioactive characteristics [10]. Moreover, MNPs can be manipulated by applying external magnetic field gradients with the interest of moving and fixing the surface-functionalized MNPs in a specific biological site, where a particular bioactive molecule is engineered to be delivered, thus facilitating the direct and effective interaction between the target site and the bioactive molecule [11]. This approach minimizes risks of biological side effects related to excessive dose level exposition. Besides, in the case of non-interacting superparamagnetic MNPs reversible dispersion while in suspension in liquid media would be quickly achieved as one removes the external magnetic field gradient, thus favoring routes of excretion out from the living host [12].
Indeed, engineering nanomaterials' surface is an essential step for successful biological and medical applications. In this way, several compounds have been tested, such as dextran, chitosan, dimercaptosuccinic acid (DMSA), and polyethylene glycol (PEG) [[13], [14], [15]]. Other compound commonly used to provide colloidal stability is the oleic acid (OA) [16], which can be used as an anchor agent for a second layer with bioactive features. In this regard, a very interesting substance is the essential oil (EO) obtained from the Croton cajucara Benth leaves, a common plant from the Brazilian Amazon region and successfully used for infusion in popular medicine against gastrointestinal and liver disorders, diabetes, and for reducing higher levels of cholesterol [[17], [18], [19]].
Although, the antiulcerogenic activity of the EO has been extensively studied for the treatment of gastric ulcers, the exact mechanism is not clear yet (HIRUMA-LIMA et al., 2002). It is known that the ulcerative process is complex, and there are many factors involved. It is known that the arising of ulcers is a consequence of an imbalance between mucosal gastro protective factors (mucus secretion, bicarbonate production, etc.) and the components that can cause injury (acid secretions, pepsin, etc.) [20]. Himura-Lima et al. [18], reported that the EO extracted from Croton cajucara Benth shows the ability to increase the prostaglandins (PGE2) release from mucus cells of the stomach tissue, which favors the gastro protective effect in the case of lesions due to ulcers. Additionally, an increase in the release of PGE2, inhibit the physiological responses that would be caused by the production of histamines (among them the most important is the gastric acid secretion by the parietal cells) [21].
Besides, previous studies have demonstrated that the linalool-rich EO extracted from Croton cajucara Benth is extremely efficient for treating tegumentary Leishmania amazonensis [19]. Due to the chemical structure of the main component (linalool) of the EO extracted from the Croton cajucara Benth leaves it can be used as a second layer on top of for instance oleic acid (OA) pre-coated MNPs. More advantageously, the EO-coated MNPs can be dispersed in excess of EO carrier to produce a very stable magnetic fluid sample. Finally, magnetite-based core-shell nanostructures can be fabricated using the above-mentioned scheme in order to take advantage of the magnetic properties of the core plus the medicinal properties of the shell. This material platform could be successfully used as a vector in medical applications, such as in association with magnetohyperthermia, as it will be emphasized later on in this report. Additionaly, innovative applications that combine both diagnostic and therapeutic elements in biomedicine (theranostics), can be obtained using MNPs which can be used to deliver a remediation agent to target sites using magnetohyperthermia while the diagnostic capability of monitoring the biodistribution of the particles can be obtained using magnetic resonance images (MRI) [22], [23].
In this study, we report on the synthesis and characterization of spherically shaped MNPs with average diameter of ∼10 nm and very low diameter polydispersity index (around 0.16). More interesting, the employed synthesis route used a single step (one-pot approach) for fabrication of OA-coated MNPs, thus protecting the core phase to be quickly oxidized into ferric oxide phases. Two samples were fabricated and characterized, namely OA-coated MNPs (sample M1) and MNPs coated with a first layer of OA plus a second layer of EO (sample M2). The structural, morphological, optical, thermal and magnetic properties of the core-shell structure before and after the second coating (EO-coating) is herein reported. The magnetic results indicated that the additional coating layer improves the magnetic properties of the double layer coated (OA + EO) MNPs, which are important to control the reversible dispersion while in suspension in a liquid media. We anticipate that sample M2 is a very good candidate for site delivering the outer moiety (EO) for a therapeutic purposes against, for instance, gastrointenstinal ulcers. The detachment of EO moiety can be remotely activated by AC magnetic field using the magnetohyperthermia (MHT) effect due to the low temperature of EO release. Moreover, due to the well know biocompatibility of OA-coated MNPs [24] the material platform provided by sample M2 is ready to be tested using in vitro as well as in vivo assays. Meanwhile, the EO outer covering layer of the MNPs can be used for the therapeutic action, the magnetic core can also be explored for diagnostic purposes via magnetic resonance image.
Section snippets
Nanoparticle fabrication
The synthesis of OA-coated MNPs was carried out using a variation of the protocol reported elsewhere [25]. In short, ferric acetylacetonate (2 mmol), 1,2-hexadecanodiol (10 mmol), benzyl ether (20 mL), oleic acid (6 mmol) and oleylamine (6 mmol) were placed in a three-neck round-bottom flask under argon flow. Thereafter, the system was mixed homogeneously with a magnetic stirrer while increasing the temperature up to 220 °C, meanwhile maintaining the stirring for 2 h. Next, the temperature was
Results and discussion
As reported in the literature [25], [30] thermal decomposition of ferric acetate in presence of benzyl ether and oleic acid provides one-pot synthesis route for fabrication of MNPs surface-coated with OA (sample M1). In this case, OA also provides size control during the synthesis process while dressing the growing MNPs. Moreover, the OA carboxylate group is assumed to attach onto the MNP's surface while the OA hydrocarbon tail faces outwards and provides steric repulsion in non-polar liquid
Conclusions
Monodispersed core magnetite nanoparticles with average diameter ∼10 nm were successfully synthesized and surface-coated with oleic acid (sample M1) and oleic acid plus essential oil (sample M2). Both samples were characterized using a variety of experimental techniques (XRD, TEM, FTIR, TGA, MM), confirming successful single-coating layer (sample M1) and double-coating layer (sample M2). The data assessed from TGA showed a reduction of oleic acid (OA) content in sample M2 (67.5%) while compared
Acknowledgments
Authors want to thank CAPES, CNPq and FAP/DF for financial support. Special thanks to Dr. E. Mendes from Institute of Geoscience of the University of Brasilia for the X-ray diffraction experiments and Dr. M. J. A. Sales from Institute of Chemistry of the University of Brasilia for the TGA measurements.
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