Preparation and Thermal Decomposition Kinetics of a New Type of a Magnetic Targeting Drug Carrier.

We have designed a new magnetic targeting drug carrier Fe3O4-PVA with a core of triiron tetroxide (Fe3O4) and a shell made of polyvinyl alcohol (PVA) to improve the hydrophilicity of Fe3O4. With adriamycin hydrochloride as a model drug, this study goes on to measure the drug carrier performance of Fe3O4-PVA. In addition, the thermal stability and enthalpy of thermal decomposition of Fe3O4-PVA were measured using a differential scanning calorimeter with a non-isothermal decomposition method. The kinetics of thermal decomposition of Fe3O4-PVA were also investigated. Over the course of this study, it was determined that the resulting drug carrier Fe3O4-PVA exhibited high drug loading levels and excellent release levels.

Introduction

In recent years, a new carrier in the form of magnetic nanoparticles has seen rapid development. This new carrier is made up of nanoscale particles, which generally consist of a magnetic core derived from metal oxides, such as iron and cobalt, and features a shell layer that is wrapped around this magnetic core.[1−3] The most common cores are primarily made of Fe3O4, which is both inexpensive and also capable of being magnetically targeted, allowing for directional movement. Thus, it can be used for positioning and separation.[4,5] Polymers generally make up the most common shell layers, on which biologically active groups coupled to this layer can bind to a variety of biological molecules, such as proteins, nucleic acids, antigens, and antibodies. This binding then functionalizes them. As a result, magnetic nanoparticles have unique physico-chemical properties.[6−8]

There is a wide range of applications for magnetic nanoparticles within the biomedical field. In terms of magnetic targeted drug delivery systems, magnetic nanoparticles are mainly applied to tumor hyperthermia, magnetic targeted drug delivery, and magnetic resonance imaging.[9−13] For example, Mhlanga et al. prepared Fe3O4 nanoparticles by co-precipitation, which was followed by the preparation of PLA/DOX/Fe3O4 core-shell nanoparticles via a solvent evaporation (oil-in-water) technique. Oleic acid was used to coat the core Fe3O4 nanoparticle, thus improving their hydrophobicity and biocompatibility for drug delivery.[14] Delavari et al. have developed a nanothermal system that utilizes alpha-lactalbumin, with Fe3O4 nanoparticles acting as a magnetic resonance imaging (MRI) contrast agent for medical imaging and adriamycin as a therapeutic agent.[15]

PVA is known for its good water solubility, film forming, adhesion, emulsification, and excellent resistance to oil and solvent resistance. It is also non-toxic and odorless, non-irritating to the skin, elastic, possesses good biological adaptability, and will not cause allergic reactions on the skin. All these properties account for why it has found such wide use in pharmaceutical carriers.[16−22] One example of applying PVA to drug delivery is a functional polyvinyl alcohol/VB2/TiO2 nanofiber produced by Lou et al. through an electrostatic spinning process. The prepared VB2-loaded polyvinyl alcohol (PVA) nets can release 60% of the VB2 within 168 h.[23] A second example of applications for polyvinyl alcohol can be seen in the work of Kuddushi et al. Using PVA, they designed a stimulus-responsive, self-healing, adhesive, and injectable polymer hydrogel. The product responds to both intracellular biological stimuli (e.g., acidic pH and the temperature of cancer cells) and changes morphology by altering the shape and size of the gelling agent within the hydrogel matrix and effectively releases encapsulated adriamycin (DOX) at the tumor site.[24]

A new magnetic target drug carrier, Fe3O4-PVA, was designed with Fe3O4 as the core and PVA as the shell structure. The synthesis process is shown in Figure . The application of PVA allows for the improved hydrophilicity of Fe3O4. The way in which the macromolecular carbon chain structure of PVA swells and dissolves equips the drug carrier with a slow-release property. Adriamycin hydrochloride (DOX·HCl) was selected as a model drug to measure the drug carrier properties of Fe3O4-PVA. In addition, in order to offer the possibility of industrialization of magnetic drug carriers, by using a differential scanning calorimeter (DSC) with a non-isothermal decomposition method, we measured Fe3O4-PVA’s thermal stability and enthalpy of thermal decomposition and the thermal decomposition kinetic equation of the final Fe3O4-PVA.

Figure 1

Synthetic route of Fe3O4-PVA.

Results and Discussion

Characterization

Figure a shows the IR spectra of PVA and Fe3O4-PVA, where the b curve is the IR spectrum of PVA. The telescopic vibration peak seen at 3422 cm–1 is caused by −OH. The curve at 3432 cm–1 is the telescopic vibration caused by −OH on the carbon chain of Fe3O4-PVA, whereas 1084 cm–1 is the telescopic vibration caused by the Fe–O–C bond. The presence of Fe–O–C bonds in the IR spectra demonstrates the successful synthesis of a new magnetic targeting drug carrier with a hydrophilic shell-land of PVA with Fe3O4 as its core. Figure b displays the XRD spectra of Fe3O4 and Fe3O4-PVA compared to the Fe3O4 standard card (JCPDS card no. 72-2303).[21] Peaks at 2θ = 30.1, 35.5, 43.3, 57.3, and 62.7° are assigned to the characteristic peaks of Fe3O4, thus proving the successful formation of Fe3O4 nanoparticles in the PVA matrix.

Figure 2

(a) IR spectra of PVA and Fe3O4-PVA. (b) XRD spectra of Fe3O4 and Fe3O4-PVA. (c) SEM image of Fe3O4. (d) SEM image of Fe3O4-PVA. (e) EDS image of Fe3O4. (f) EDS image of Fe3O4-PVA.

Figure c is an SEM image of the Fe3O4 nanoparticles. From this figure, it can be determined that the Fe3O4 particles are uniformly dispersed in size. Figure d is the SEM image of Fe3O4-PVA. The spheres in this image are Fe3O4. PVA can be seen dispersed around Fe3O4. This indicates a successful synthesis that resulted in a Fe3O4 core and PVA hydrophilic shell layer for a new magnetic target drug carrier. Figure e shows the EDS image of Fe3O4 nanoparticles, and the ratio was calculated at Fe/O = 1.095:1.664. Figure f shows the EDS image of Fe3O4-PVA nanoparticles that had a ratio of Fe/O/C = 1.437:0.650:0.732.

Drug Loading and Drug Release Analysis

The loading and release of any given drug serve as a metric for a drug carrier’s drug transport properties and are key parameters for practical applications. Thus, we chose adriamycin hydrochloride (DOX·HCl) as a model drug to study the loading and release characteristics of the magnetic target drug carrier Fe3O4-PVA. The loading procedure was carried out by immersing dried Fe3O4-PVA in a DOX·HCl solution for 48 h. As shown in Figure a, Fe3O4-PVA can reach a loading of 84% for DOX·HCl within 48 h. This loading level was largely possible due to the carbon skeleton chains of PVA that can adsorb DOX molecules through strong interactions, such as van der Waals interactions and hydrogen bonding. Furthermore, the adsorbed DOX can be dispersed between the pores of Fe3O4-PVA. A final 87% drug loading was achieved.

Figure 3

(a) Loading of Fe3O4-PVA on DOX·HCl at pH 4.7, 37 °C. (b) Release of Fe3O4-PVA on DOX·HCl at pH 4.7, 37 °C.

As shown in Figure b the DOX·HCl release curve of Fe3O4-PVA within a 48 h period shows that the drug carrier releases DOX·HCl from the surface of the rapid drug carrier in less than 10 h. Eventually, 84% of the DOX·HCl is released within 48 h as the PVA carbon backbone chain slowly swells and dissolves.

Isothermal Thermodynamic Analysis of Fe3O4-PVA

Thermal Stability of Fe3O4-PVA

The thermal decomposition curves of Fe3O4-PVA under non-isothermal conditions are shown in Figure and the thermal decomposition data are shown inTable . Decomposition starts at 180 °C and peaks at 222 °C. Due to the reactive nature of the hydroxyl groups (−OH) contained in the molecular structure of PVA, the −OH decomposes due to thermal instability when the temperature is steadily increased to a certain level. As can be seen from the diagram, when the temperature reaches 180 °C, a thermal release peak occurs and the hydroxyl groups are thermally decomposed into reactive radicals. When the temperature rises to 222 °C, the hydroxyl groups break off in large numbers, the heat breaks off at a peak, and the rate of decomposition is the fastest. As the temperature continues to rise, the DSC curve shows that the heat break value begins to fall and the hydroxyl groups in the product gradually decompose completely. High temperatures in excess of 222 °C result in the complete decomposition of Fe3O4-PVA.

Figure 4

Thermal decomposition curve of Fe3O4-PVA.

Table 1

Thermal Decomposition Temperature and a Peak Temperature of Fe3O4-PVA

compound	decomposition temperature(°C)	peak temperature (°C)
Fe3O4-PVA	180	222

Kinetic Analysis of Isothermal Thermal Decomposition of Fe3O4-PVA

The decomposition rate constant (Kd) of the reaction product Fe3O4-PVA during thermal decomposition serves as an important parameter for measuring the reaction rate, which can be obtained by varying the reactant concentration (c) with time (t). The amount of Fe3O4-PVA change (ΔC) can be determined by calculating the decomposition rate constant (Kd). Furthermore, in calculating the relative data, information such as the half-life (t1/2) of the reactants can be obtained.

The activation energy and its rate of thermal decomposition are determined by using the isothermal decomposition mode. From the isothermal decomposition data, Kd can be calculated from the ΔH of the decomposition, which is a first-order reaction and is expressed as[25]

In the DSC isothermal decomposition mode,[26] the reactant concentration variation is unknown. Enthalpy was used for conversion calculations:

Combining decomposition 5 (eq ) with decomposition 4 (eq ) yields the new equation (eq ) as follows:

Half-life (t1/2) and reaction activation energy (ΔE) were determined using the DSC isothermal decomposition model.[27] As seen in Figure , the decomposition rate is the fastest at the initial stage of the isothermal reaction, where the heat release increases rapidly. The release of heat tends to be stable after this initial rapid increase. Fe3O4-PVA decomposed for 5, 10, and 20 min at different temperatures, and the corresponding ΔH is shown in Table .[28]

Figure 5

Thermal decomposition curves of Fe3O4-PVA prepared at different temperatures.

Table 2

DSC Data of Isothermal Thermal Decomposition Kinetics of Fe3O4-PVA Prepared at Different Temperatures

preparation temperature (°C)	ΔH0	ΔH5 (5 min)	ΔH10 (10 min)	ΔH20 (20 min)
50	292.9 J/g	34.0 J/g	79.0 J/g	199.3 J/g
60	308.9 J/g	35.9 J/g	80.9 J/g	200.4 J/g
70	384.8 J/g	37.4 J/g	91.1 J/g	206.0 J/g
80	412.4 J/g	37.6 J/g	99.2 J/g	213.2 J/g
90	412.8 J/g	37.9 J/g	100.8/g	233.2 J/g

Table shows the relationship between the change in the Fe3O4-PVA concentration (ΔC) and the change in energy in thermal decomposition (ΔH) from the final obtained eq .

Table 3

Thermal Decomposition Rate Constants of Fe3O4-PVA Prepared at Different Temperatures

preparation temperature (°C)	ΔKd5 (5 min)	ΔKd10 (10 min)	ΔKd20 (20 min)	average Kd
50	0.411 × 10–3	0.524 × 10–3	0.951 × 10–3	0.629 × 10–3
60	0.412 × 10–3	0.506 × 10–3	0.872 × 10–3	0.597 × 10–3
70	0.341 × 10–3	0.450 × 10–3	0.639 × 10–3	0.477 × 10–3
80	0.319 × 10–3	0.459 × 10–3	0.695 × 10–3	0.491 × 10–3
90	0.321 × 10–3	0.467 × 10–3	0.694 × 10–3	0.494 × 10–3

The Arrhenius (eq ) is as follows:

According to eq , 1/T is the horizontal coordinate, and ln Kd is the vertical coordinate used to draw the diagram. It can be seen from Figure that these points present a discrete trend. In addition, the Arrhenius empirical equation is also a one-time function, thus the points on the diagram are processed by a linear regression. The resulting equation represents the equation for the isothermal thermal decomposition of Fe3O4-PVA.[29]

Figure 6

Arrhenius equation curves for Fe3O4-PVA prepared at different temperatures.

In the obtained equation, the intercept[30] represents the logarithm value ln Ad of the prefactor in the Arrhenius empirical formula. The slope stands for the negative ratio of the decomposition activation energy to the gas molar constant –Ed/R in the Arrhenius empirical formula. Therefore, the decomposition reaction’s activation energy is Ed = 269.511 kJ/mol, and the pre-exponential factor is Ad = 3.314 × 10–4. The thermal decomposition kinetic eq of the final Fe3O4-PVA is as follows:

Conclusions

We have successfully prepared Fe3O4-PVA, which is a new hydrophilic magnetic targeting drug with a core-shell structure. In addition, the isothermal pyrolysis kinetics of Fe3O4-PVA was analyzed. The thermal decomposition kinetic equation of the final Fe3O4-PVA is ln Kd = −269.511/RT + ln(3.314 × 10–4). By loading 87% DOX·HCl, this study demonstrated the excellent drug loading capacity of Fe3O4-PVA. The successful test suggests that Fe3O4-PVA can be developed into an effective carrier for targeted drugs. Furthermore, due to the low cost of magnetic carrier materials, our research findings have practical applications as there is a high feasibility for the industrial production of magnetically targeted drug materials. These factors create tremendous opportunities for making full use of magnetic carrier materials in magnetic drug carriers and other applications.

Experimental Section

Materials

Polyvinyl alcohol (PVA) (Mw = 89,000) was purchased from Aladdin (Shanghai, China). Materials including ferric chloride(II) tetrahydrate (FeCl2·4H2O), ferric chloride(III) hexahydrate (FeCl3·6H2O), and ammonia solution (25 wt %) were purchased from Sinopharm Chemical Reagents Co.

Synthesis of Magnetic (Fe3O4) Nanoparticles

Magnetic (Fe3O4) nanoparticles were prepared via ultrasonic precipitation. First, the ratio FeCl3·6H2O/FeCl2·4H2O = 3:2 was dispersed into 200 mL of distilled water. Over the course of an hour, the whole system was sonicated. Then, 30 mL of ammonia (NH3) was added to the solution and stirred at 65 °C for 5 h. Nitrogen was used to protect the entire reaction system. Finally, the product was rinsed repeatedly with water and then freeze dried.

Synthesis of Fe3O4-PVA

The appropriate amount of PVA was dissolved in 100 mL of distilled water with the aid of a mechanical stirrer. Fe3O4 was sonicated for 1 h and added to the PVA solution with the appropriate amount of ammonia solution added for the proper adjustment of the pH. The whole system was reacted at several temperatures (50, 60, 70, 80, and 90 °C) for 5 h under nitrogen protection. The resulting black precipitate was then washed with distilled water until the whole system reached neutral pH.

An IRAffinity-1 spectrometer was used to capture the Fourier transform infrared (FTIR) spectra. X-ray powder diffraction (XRD) spectra were taken on a Holland PANalytical X-Pert PRO X-ray diffractometer with CuKα radiation. A JSM-6380 LV microscope was used in order to record scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) images. Differential scanning calorimetry (DSC) was performed on an NETZSCH STA 449C analyzer with a nitrogen flow rate of 5 °C min–1.

Drug Loading

The supernatant was collected after a predetermined time interval for analysis via a UV spectrophotometer as a means of studying the drug loading capacity of Fe3O4-PVA. The Fe3O4-PVA loading was calculated by the following eq :

Mat is the mass of the drug nanocarrier at t, Ma0 is the mass of the drug fed initially.

Drug Release from Fe3O4-PVA

A UV–vis spectrophotometer was used to observe the change in concentration over a 48 h period. The drug-loaded Fe3O4-PVA was placed into a dialysis bag in PBS at 37 °C pH 7.2. In order to assess the release process of the drug, an oscillograph set to a certain vibration frequency was used to simulate the environment of the body. At specific time intervals, the supernatant was collected for analysis by a UV spectrophotometer. Each experiment was repeated three times following eq :

Pyrolysis Kinetics

Samples between 5 and 10 mg were added to a crucible and protected with a high-purity N2 atmosphere. The thermal stability and pyrolysis kinetics of the product were determined using a DSC 204-F1 (NETZSCH, Germany) at a heating rate of 50–300 °C, 5 °C min–1. Through isothermal thermodynamic methods, the relationship between heat flow and time at a constant temperature was ascertained. Equations for thermal decomposition kinetics were determined by an analysis of the thermal stability, decomposition constant (Kd) and activation energy (Ea) of Fe3O4-PVA.