Research Article | Open Access
R. Asmatulu, A. Fakhari, H. L. Wamocha, H. Y. Chu, Y. Y. Chen, M. M. Eltabey, H. H. Hamdeh, J. C. Ho, "Drug-Carrying Magnetic Nanocomposite Particles for Potential Drug Delivery Systems", Journal of Nanotechnology, vol. 2009, Article ID 238536, 6 pages, 2009. https://doi.org/10.1155/2009/238536
Drug-Carrying Magnetic Nanocomposite Particles for Potential Drug Delivery Systems
Drug-carrying magnetic nanocomposite spheres were synthesized using magnetite nanoparticles and poly (D,L-lactide-co-glycolide) (PLGA) for the purpose of magnetic targeted drug delivery. Magnetic nanoparticles (13 nm on average) of magnetite were prepared by a chemical coprecipitation of ferric and ferrous chloride salts in the presence of a strong basic solution (ammonium hydroxide). An oil-in-oil emulsion/solvent evaporation technique was conducted at 7000 rpm and 1.5–2 hours agitation for the synthesis of nanocomposite spheres. Specifically, PLGA and drug were first dissolved in acetonitrile (oily phase I) and combined with magnetic nanoparticles, then added dropwise into viscous paraffin oil combined with Span 80 (oily phase II). With different contents (0%, 10%, 20%, and 25%) of magnetite, the nanocomposite spheres were evaluated in terms of particle size, morphology, and magnetic properties by using dynamic laser light scattering (DLLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and a superconducting quantum interference device (SQUID). The results indicate that nanocomposite spheres (200 nm to 1.1 m in diameter) are superparamagnetic above the blocking temperature near 40 K and their magnetization saturates above 5 000 Oe at room temperature.
Recently, researchers have been trying to develop targeted therapeutic systems by using external forces, including magnetic fields, ultrasound, electric fields, temperature, light, and mechanical forces to concentrate drugs within tumors [1–4]. In these systems, the drug is localized at a specific targeted area by externally generated forces, and then activated them . Of the type considered, magnetic particles carrying drug molecules are targeted to specific sides of the body by external magnetic fields. Shortly after concentration on targeted region, drug molecules are gradually released, thus improving the therapeutic efficiency of the drugs by lowering the collateral toxic site effects on the healthy cells or tissues [6–9]. Magnetic targeted system with fields generated between 100 and 2500 Oe seems more promising as the basis of a drug localization system due to their effectiveness, lower risk, cost, and practical use, as compared to other systems [10–12].
The three main mechanisms for releasing drug molecules from the polymeric magnetic spheres into a blood vessel or tissue are diffusion, degradation, and swelling followed by diffusion [13, 14]. Diffusion occurs when drug molecules dissolve in bodily fluids around or within the particles and migrate away from the particles. Degradation takes place when the polymer chains hydrolyze into lower molecular weight species, effectively releasing drug molecules that were trapped by the polymer chains. Swelling-controlled release systems are initially dry. When they are placed in the body, they swell to increase inside pressure and porosity, enabling the drug molecules to diffuse from the swollen network. The release of active drug molecules can also be varied over a certain period based on external and internal parameters [11–13]. Figure 1 shows the diffusion, degradation, and swelling release mechanisms of drug-carrying magnetic spheres.
Poly (D,L-lactide-co-glycolide) (PLGA), approved by the Food and Drug Administration (FDA) for drug delivery purposes [15–18], is used as a host material because of its biodegradability. In the present research, this polymer was embedded with magnetic nanoparticles (MNPs) and a drug via the oil-in-oil emulsion/solvent evaporation technique [19–22]. MNP concentrations in PLGA were varied in the range of 0% to 25%. After the fabrication step, biodegradable nanocomposite spheres were characterized to determine the size distribution, morphology, and magnetic properties using dynamic laser light scattering (DLLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and a superconducting quantum interference device (SQUID).
Unless otherwise specified, all chemicals utilized without further purification or modification in our experiment were reagent grades and purchased from Sigma-Aldrich.
2.2.1. Magnetic Nanoparticle Synthesis
Magnetic nanoparticles were prepared using 50 mL of 2 M HCl and 55 mL of 5 M ammonium hydroxide (NH4OH) solutions in a 100 mL beaker. In separate beakers, 2 g of ferric chloride (FeCl3·6H2O) was dissolved in 40 mL of 2 M HCl and 1.25 g of ferrous chloride (FeCl2·4H2O) in 10 mL of 2 M HCl. The two solutions were combined and stirred vigorously at 1200 rpm. Then, 55 mL of 5 M ammonium hydroxide was added in 5 minutes at room temperature. The magnetite nanoparticles with a diameter of 12.7 nm were then collected using an Nd magnet and dried in an oven overnight. Figure 2 shows the size distribution of the magnetic nanoparticles obtained using TEM images. ImageJ software was used in the calculations of size distribution.
2.2.2. Magnetic Nanocomposite Spheres Synthesis
In this step, two dissimilar oil phases were prepared. During the first oil phase, 1.25% w/v of PLGA (wt 40 000–75 000) was added to 5 mL of the solvent (acetonitrile), which was placed in a conical flask with a stopper. The mixture was kept on a hotplate for 20 to 30 minutes to dissolve completely PLGA in acetonitrile using a small magnetic bar. The magnetic bar was removed before known amounts of magnetite nanoparticles and the drug were added to the same solution. Afterwards, the flask was placed in a sonicator for about 10 minutes (or until the MNPs and drug molecules were completely dispersed).
The second oil phase was prepared by adding 1% v/v of Span 80 as a surfactant to 40 mL of a heavy liquid (paraffin). This mixture was then placed under an overhead mixer operated at 7000 rpm with a specially designed high-shear impeller (Figure 3(a)). Note that the shape and size of the impeller is critically important to achieve smaller-size nanocomposite spheres. Approximately 3 mL of the first phase was then added to the second phase using a burette. The mixer was allowed to run for one hour and 30 minutes to evaporate acetonitrile and form nanocomposite spheres in the heavy oil at the high-shear speed. Nanocomposite spheres were collected by centrifugation at 17 000 rpm for 30 minutes at 10°C and washed four times with n-hexane to completely remove the heavy paraffin liquid. Figure 3(b) shows the schematic illustration of magnetic nanocomposite sphere fabrication. Finally, particles were filtered using a 200 nm filter media under a 25 inHg vacuum and dried prior to the SQUID (Quantum Design), DLLS (Malvern Instrument), SEM (Leo1550), and TEM (Joel 2010, 200 kV) analyses.
3. Results and Discussion
Four samples with different MNP and drug contents were prepared to determine the size distribution by DLLS. Table 1 gives the formulation of nanocomposite samples and their size distributions. As the MNP concentration increases from 0% to 25%, the nanocomposite sphere size increases gradually, as well. This may be due to the viscosity changes, lesser shear forces acting on the spheres, and/or agglomeration of the nanoparticles in the first oil phase.
The samples prepared at each concentration were characterized using SEM. Figure 4 shows the SEM images of samples 2 and 3 containing 10% and 20% of magnetite nanoparticles in PLGA, respectively. The nanocomposite spheres are mostly rounded shapes and have a diameter between 200 nm and 1.1 m, which confirms DLLS test results, as indicated in Table 1. The variation of sphere size and shape in each concentration contributes to the changes in process parameters, viscosity, and heat generated during fabrication .
In addition to DLLS and SEM analysis, TEM images (Figure 5) reveal the distribution of magnetic nanoparticles in the drug-carrying nanocomposite spheres. These nanoparticles are randomly oriented in the nanocomposite structure; however, in some areas, the magnetic nanoparticles tend to form clusters, which may be due to the large surface/volume ratio and intermolecular interactions, such as electrostatic, hydrophobic, and van der Waals interactions . Additionally, at high magnification, a crystal lattice is visible in a single magnetite particle, suggesting a single-domain and fully crystalline state.
Magnetic properties of biodegradable nanocomposite spheres were characterized using the SQUID technique. For each sample the magnetization at 300 K was measured over a range of applied fields between 10 000 and 10 000 Oe. The data (Figure 6(a)) show that, near 5 000 Oe, the magnetization reaches a saturation value roughly proportional to the magnetite content (10, 20, or 25%) in the three samples as expected [11, 23]. In addition to magnetic inclusion, sample 3 also contains 20% of nonmagnetic drug molecules.
Figure 6(b) shows the typical temperature dependence of magnetization for the nanocomposites. The sample 3 was first cooled to the liquid helium temperature near 4 K before a 1 000-Oe field was applied, and then the sample was heated up in steps to 300 K for magnetization measurements. As the temperature increases, the magnetization of nanocomposite spheres initially increases to reach a peak at 40 K, beyond which it decreases a paramagnetic-type behavior. This reflects the superparamagnetic characteristics of the nanoparticles, while 40 K is generally referred to as the blocking temperature [24–26]. Additionally, it is obvious that the merger of the zero field cooled (ZFC) and field cooled (FC) curves starts at about 125 K, and there is a plateau region in ZFC curve. In an earlier study  on Dextran-coated magnetite of similar size distribution, a similar blocking temperature was observed but with the two curves merge at a much lower temperature, and the ZFC lacks the features observed in our sample. The magnetite particles of the above mentioned study were evenly dispersed in water based ferrofluid. In contrast, the magnetic particles in our study were randomly separated inside the polymeric nanocomposite spheres. This leads to a distribution of the dipolar interactions among the particles. Knowing that the dipolar interaction energies of these particles are of the same order of their anisotropy energy barriers , these energies have significantly contributed to the observed features of the ZFC curve. As a result, the way of mixing the magnetite particles and drug inside the nanocomposite spheres may affect the efficiency of their magnetic delivery system.
This study deals with the synthesis of drug-carrying magnetic nanocomposite spheres by an oil-in-oil emulsion/solvent evaporation technique. The effect of magnetic particles (13 nm) on the size and morphology of the product was determined by DLLS and SEM, which yield a spherical size ranging from 200 nm to 1.1 m. TEM images further revealed magnetite nanoparticles are mostly clustered and randomly distributed in the PLGA matrix. Meanwhile, SQUID data confirmed that the nanocomposite spheres behave as superparamagnetic nanomaterials. Overall, this study may be useful for targeted drug delivery application in the future.
The authors gratefully acknowledge Wichita State University for supporting this work.
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