Solvothermal Synthesis of Size-Controlled Monodispersed Superparamagnetic Iron Oxide Nanoparticles

Abstract

Superparamagnetic iron oxide nanoparticles are of great interest in magnetic targeted drug delivery due to their unique properties. In this paper, size-controlled superparamagnetic iron oxide nanoparticles were synthesized in an ethylene glycol/diethylene glycol (EG/DEG) binary solvent system via a facile solvothermal method. X-ray diffraction (XRD), a scanning electron microscope (SEM), and a vibrating sample magnetometer (VSM) were used to confirm that the prepared samples were superparamagnetic ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanospheres. When the $V_{\mathrm{EG}}$/$V_{\mathrm{DEG}}$ was varied from 100/0 to 80/20, 60/40, and 40/60, the average diameters of the resulting ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanospheres were approximately 700, 500, 300, and 100 nm, respectively. In addition, the saturation magnetization ($M_{\mathrm{s}}$) of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles with a size of 100, 300, 500, and 700 nm was 72.14, 75.94, 80.28, and 85.41 emu/g, and the corresponding remanent magnetization ($M_{\mathrm{r}}$) was 3.34, 3.97, 3.26, and 4.28 emu/g, respectively. The relevant formation mechanisms of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles are proposed at the end. These superparamagnetic ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles with high saturation magnetization may have use as targeted drug carriers.

1. Introduction

Delivering a drug accurately and safely to its target site remains the yardstick for the design of drug delivery systems. Targeted drug delivery has attracted a significant amount of attention due to the unique advantage of precise control over a drug’s release [1]. In particular, magnetic drug targeting is currently recognized as one of the most promising approaches to drug delivery [2,3,4]. A pharmaceutical drug is loaded onto the surface of the magnetic nanoparticles, which are released at the target site with an external localized magnetic field gradient, thereby achieving an accurate and targeted dose [5].

During the process of delivering magnetic drug-loaded nanoparticles, the magnetic force that is exerted on the particles plays a crucial role and is strongly dependent on the size of the particle [6]. Furthermore, the magnetic force is proportional to $d^3$, where d is the diameter of the particle [7]. In addition, to minimize the aggregation that is caused by the magnetic attractive forces, magnetic nanoparticles must have dependable superparamagnetic properties. As a result, superparamagnetic nanoparticles become magnetic in the presence of the external magnetic field, but revert to a nonmagnetic state that allows them to be excreted when the external magnetic field is removed [8]. Therefore, the size and superparamagnetism of magnetic nanoparticles are predominantly important to controlling the transport of a targeted drug.

Superparamagnetic iron oxide (${\mathrm{Fe}}_3{\mathrm{O}}_4$) nanoparticles are frequently used as the drug carrier because of their low toxicity [9]. Among the reported synthetic methods, including ball-milling [10], co-precipitation [11,12], thermal decomposition [13,14], and microemulsion templating [15], the solvothermal method has been proven to be feasible for the synthesis of magnetic nanoparticles with a controllable morphology and microstructure [16,17,18,19,20]. A considerable amount of effort has been devoted to the size-controlled synthesis of magnetic nanoparticles, mainly focusing on changing the reaction time, temperature, surfactants, and the initial concentration of reagents [20,21,22,23,24,25]. However, despite these advances, the synthesis of size-controllable magnetic nanoparticles based on changing the solvent deserves further research.

In this study, size-tunable superparamagnetic ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles were synthesized via a facile solvothermal method based on a binary solvent system with ethylene glycol (EG) and diethylene glycol (DEG). To obtain superparamagnetic nanoparticles with a high saturation magnetization, polyvinyl pyrrolidone (PVP) and sodium citrate (${\mathrm{Na}}_3\mathrm{C}\mathrm{i}\mathrm{t}$) were used together as structure guide agents. The ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles have nearly monodispersed sizes that are tunable in the range of 60–800 nm by varying the volume ratio of EG/DEG. The reaction mechanism of the solvothermal system is discussed. These superparamagnetic ferrite nanoparticles may be candidate targeted drug carriers.

2. Materials and Methods

2.1. Materials

Iron (ш) chloride (${\mathrm{FeCl}}_3·{6\mathrm{H}}_2\mathrm{O}$), sodium acetate (NaAc), K30 polyvinyl pyrrolidone (PVP), sodium citrate (${\mathrm{Na}}_3{\mathrm{C}}_6{\mathrm{H}}_5{\mathrm{O}}_7·{2\mathrm{H}}_2{\mathrm{O}, \mathrm{Na}}_3\mathrm{C}\mathrm{i}\mathrm{t}$), ethylene glycol (EG), and diethylene glycol (DEG) were purchased from Aladdin, Shanghai, China. All reagents were of analytical purity and used without further purification.

2.2. Synthesis of Nanoparticles

The monodispersed superparamagnetic iron oxide nanoparticles were synthesized by the solvothermal method. In a typical synthesis, 13 g ${\mathrm{FeCl}}_3·{6\mathrm{H}}_2\mathrm{O}$ was dissolved in 350 mL of ethylene glycol and diethylene glycol. Subsequently, 2 g NaAc, 2 g polyvinyl pyrrolidone (PVP), and sodium citrate (${\mathrm{Na}}_3\mathrm{C}\mathrm{i}\mathrm{t}$) were added to the solution’s ultrasonic processing. After an hour, the solution was sealed in a 400 mL Teflon-lined stainless-steel autoclave. The autoclave was heated to 210 °C for 12 h, and then cooled to room temperature naturally. The black products were collected by magnetic decantation and centrifugation, followed by repeated washing with deionized water and ethanol. The final products were dried in a vacuum oven at 50 °C for 12 h.

2.3. Characterization

A scanning electron microscope (SEM, JSM-7500F, Japan) and a transmission electron microscope (TEM, JEM 1200EX, Japan) were used to examine the structure of the samples. Phase analyses of the products were performed by X-ray diffraction (XRD, Bruker AXSD8 Advance, Germany) with Cu target radiation. The magnetic properties of the particles were measured at room temperature (298 K) using a vibrating sample magnetometer (VSM, Lake Shore7410, USA).

3. Results and Discussion

3.1. Structure and Morphology Analyses

Figure 1 shows the powder XRD patterns of the samples obtained with different ratios of $V_{\mathrm{EG}}$/$V_{\mathrm{DEG}}$. According to the patterns, all peaks of the four samples match well with those of standard ${\mathrm{Fe}}_3{\mathrm{O}}_4$ XRD diffraction (JCPDS Card No. 19-0629). Additionally, the intensity and full width at half maximum (FWHM) of the characteristic diffraction peaks are almost identical for the four samples. Table 1 shows the average crystal sizes of the ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles calculated using the Scherrer equation, and the measurements of the FWHM of the (311) peaks. It is known that the superparamagnetic limit for magnetite is ~20 nm [26,27,28]. Hence, the as-prepared ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles may have satisfactory superparamagnetism, because the grain size of the samples is close to 20 nm (23.62 nm, 25.25 nm, 25.65 nm, 27.86 nm, respectively).

Figure 1. X-ray diffraction patterns of the ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles synthesized by using different ratios of $V_{\mathrm{EG}}$/$V_{\mathrm{DEG}}$: (a) 40/60, (b) 60/40, (c) 80/20, and (d) 100/0.

Table 1. Grain size of the samples calculated for the strongest peak (311).

Sample	EG/DEG	Grain Size (nm)
a	40/60	23.62
b	60/40	25.25
c	80/20	25.65
d	100/0	27.86

To confirm the morphology of the samples, we recorded SEM images of the ${\mathrm{Fe}}_3{\mathrm{O}}_4$ monodispersed nanoparticles, which are shown in Figure 2. The mean diameter of the ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles increased with the increasing ratio of $V_{\mathrm{EG}}$/$V_{\mathrm{DEG}}$ during the solvothermal reaction. When the $V_{\mathrm{EG}}$/$V_{\mathrm{DEG}}$ was varied from 100/0 to 80/20, 60/40, and 40/60, the average diameters of the resulting ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanospheres were approximately 700, 500, 300, and 100 nm, respectively. Additionally, it can be confirmed from the TEM image of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles shown in Figure 3 that the as-prepared ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanospheres are clusters of numerous superfine particles.

Figure 2. Scanning electron microscope (SEM) images and particle size distribution histograms of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles synthesized by using different ratios of $V_{\mathrm{EG}}$/$V_{\mathrm{DEG}}$: (a), (b) 40/60; (c), (d) 60/40; (e), (f) 80/20, and (g), (h) 100/0.

Figure 3. A transmission electron microscope (TEM) image of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles.

3.2. Magnetic Properties

The room-temperature hysteresis loop of the ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles was measured using a vibrating sample magnetometer (VSM). The magnetization curves of the samples are shown in Figure 4, and the magnetic parameters are listed in Table 2. All ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticle samples show excellent superparamagnetic properties with really narrow hysteresis loops. From Table 2, the remanent magnetization ($M_{\mathrm{r}}$) of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles with a size of 100, 300, 500, and 700 nm was 3.34, 3.97, 3.26, and 4.28 emu/g, respectively. The saturation magnetization ($M_{\mathrm{s}}$) of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles with a size of 100, 300, 500, and 700 nm was 72.14, 75.94, 80.28, and 85.41 emu/g, respectively. In this work, it was further found that the saturation magnetization ($M_{\mathrm{s}}$) and the remanent magnetization ($M_{\mathrm{r}}$) can be mildly affected by the size of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles.

Figure 4. Magnetization hysteresis loops of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles synthesized by using different ratios of ${\mathrm{V}}_{\mathrm{EG}}$/${\mathrm{V}}_{\mathrm{DEG}}$: (a) 40/6, (b) 60/40, (c) 80/20, and (d) 100/0.

Table 2. Magnetic parameters of the prepared nanoparticles.

Sample	Saturation Magnetization (${\mathit{M}}_{\mathbf{s}}$) emu/g	Remanent Magnetization (${\mathit{M}}_{\mathbf{r}}$) emu/g
a	72.14	3.34
b	75.94	3.97
c	80.28	3.26
d	85.41	4.28

3.3. Formation Mechanism of Fe₃O₄ Nanoparticles with Tunable Sizes

As a typical solvothermal reaction, the formation process of magnetic nanoparticles includes two main steps: nucleation and ripening growth [29]. In this case, the ethylene glycol and diethylene glycol act as the solvent and reductant, respectively, the iron (ш) chloride as the iron source, and the sodium acetate (NaAC) provides the hydroxyl-ion and maintains the acid–base equilibrium of the reaction system. The PVP and ${\mathrm{Na}}_3\mathrm{C}\mathrm{i}\mathrm{t}$ are structure guide agents.

As we previously reported [30], during the reaction process, parts of the hydrolyzed ${\mathrm{Fe}}^{3+}$ ions reduce to $\mathrm{Fe}{\left(\mathrm{OH}\right)}_2$, and combine with the remaining $\mathrm{Fe}{\left(\mathrm{OH}\right)}_3$ to finally form ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles. As is shown in Figure 5a, the small-molecule citrate groups that have adhered on the magnetic nanocrystals act as both resistance and bridging agents, which prevent the further growth of nanocrystals and agglomerate the neighboring nanocrystals into nanoclusters with low remanent magnetization. As for the PVP long-chain molecules shown in Figure 5b, in the initial process, the macromolecule stabilizers mostly act as bridging agents to guide the neighboring nanocrystals to self-assemble into larger nanoparticles with high saturation magnetization. After the larger nanoparticles are fully covered by the PVP long-chain molecules, the PVP long-chain molecules act as space blocks and prevent the further growth of the nanoparticles. In order to obtain superparamagnetic nanoparticles with high saturation magnetization, the binary ${\mathrm{Na}}_3\mathrm{C}\mathrm{i}\mathrm{t}$/PVP is added into the reaction system as a structure guide agent.

Figure 5. Schematic illustration of the process of obtaining magnetite nanospheres: (a) structure guided by sodium citrate (${\mathrm{Na}}_3\mathrm{C}\mathrm{i}\mathrm{t})$ and (b) structure guided by polyvinyl pyrrolidone (PVP).

In addition, the EG/DEG binary solvent system also plays a key role in controlling the size of the ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles [31]. From the above-mentioned analysis, the formation of magnetic nanoparticles is closely related to the aggregation process. When pure EG is used, the precursor iron alkoxides transform into crystal nuclei and further agglomerate rapidly into large nanoparticles due to their high surface energy. When DEG is added to form a binary solvent with EG, the size of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles decreases as the $V_{\mathrm{EG}}$/$V_{\mathrm{DEG}}$ ratio decreases. DEG forms a more stable coordination iron alkoxide with Fe ions than EG, so the growth rate of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ grains will slow down, consequently decreasing the size. Furthermore, when EG/DEG coordinates with ${\mathrm{FeCl}}_3$ to form an iron alkoxide, HCl is a byproduct from the reaction. The accumulation of HCl will inhibit further iron alkoxide formation. When NaAc is introduced, it can react with HCl to reduce the concentration of ${\mathrm{H}}^{+}$, and allow the coordination reaction to be completed [32,33].

4. Conclusions

In summary, we have demonstrated a facile synthesis of size-controllable superparamagnetic ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles via a solvothermal method based on an ethylene glycol/diethylene glycol (EG/DEG) binary solvent system. When the $V_{\mathrm{EG}}$/$V_{\mathrm{DEG}}$ was varied from 100/0 to 80/20, 60/40, and 40/60, the average diameters of the resulting ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanospheres were approximately 700, 500, 300, and 100 nm, respectively. In addition, the saturation magnetization ($M_{\mathrm{s}}$) of ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles with a size of 100, 300, 500, and 700 nm was 72.14, 75.94, 80.28, and 85.41 emu/g, and the corresponding remanent magnetization ($M_{\mathrm{r}}$) was 3.34, 3.97, 3.26, and 4.28 emu/g, respectively. These superparamagnetic ${\mathrm{Fe}}_3{\mathrm{O}}_4$ nanoparticles with high saturation magnetization show outstanding potential as targeted drug carriers.