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Abstract

Uniform and nearly monodisperse superparamagnetic Fe₃O₄/Poly(methyl methacrylate) (core)/SiO₂ (shell) nanoparticles with raspberry-like morphology and high saturation magnetization were prepared in three different steps. At first, a facile, one-shot procedure to synthesize hydrophobic Fe₃O₄ nanoparticles through a modified co-precipitation method was implemented. Based on the hydrophobic interactions, these nanoparticles were used directly in a mini-emulsion polymerization resulting in encapsulation with PMMA. Then, for the covering with a silica shell, the surfaces of the Fe₃O₄/PMMA nanospheres were hydrolyzed in alkaline media and became hydrophilic through hydrolyzation. In the last step shell deposition of the Fe₃O₄/PMMA nanospheres through a modified Stober method was implemented. The surface morphology was investigated by scanning electron microscopy (SEM) and the core-shell structure and the prepared products’ diameters were measured by transmission electron microscopy (TEM); the size of the magnetic nanospheres was approximately 83 nm. Vibrating sample magnetometry (VSM) showed high magnetic saturation and superparamagnetic characteristics of the particles. Thermogravimetric analysis (TGA) was used as a supplementary test and, based on the mass loss at high temperature (600°C), the magnetic (Fe₃O₄) and non-magnetic content (PMMA) of the Fe₃O₄/PMMA nanospheres was measured as 81 and 19%, respectively. The narrow polydispersity of the nanospheres, measured by dynamic light scattering (DLS), was approximately 0.101. In every preparation step, the synthesized products were characterized by Fourier transform infrared (FTIR) spectroscopy. Our study focused on designing two-layered magnetic nanoparticles with drug delivery potential using two-layer encapsulation based on the hydrophobic and hydrophilic surface characteristics of the PMMA core and silica shells, respectively.

Keywords

superparamagnetic composite nanospheres mini-emulsion polymerization modified Stober method two-layered magnetic nanoparticles raspberry-like morphology

Introduction

Recent developments in the field of biotechnology have introduced inorganic and organic nanocomposites owing to their intriguing properties.^1–6 Among a wide range of nanocomposites, magnetic polymer composite nanospheres have profound merits in many biomedicine applications because they can be easily collected under a magnetic field. The promising applications of these MNPs (magnetic nanoparticles) involve drug delivery,^1,2 magnetic resonance imaging (MRI),³ hyperthermia,³ nucleic acid detection,⁴ enzyme immobilization,⁵ magnetically assistance site-specific drug delivery,⁶ and water treatment.⁷ Magnetic polymer particles in the field of biomedicine should possess some exclusivity, such as a narrow nano-sized distribution, high and uniform magnetic content, and high saturation magnetization (M_S),⁸ no sedimentation,⁹ and nontoxicity.¹⁰ In the use of MNPs in cancer treatment, there are three specific properties of concern:

1. The size of the NPs

2. A high surface area

3. A functionalized surface in order to enhance targeting cancer drugs.¹¹

The naked MNPs aggregate due to their magnetic dipolar attractions; therefore, they need to be encapsulated for biomolecule immobilization with high stability^12–14 but remain magnetic. As surface engineering of the MNPs is a particular issue for encapsulation with polymers, as we showed previously, they should possess a compatible surface with the polymer shell which emphasizes the need for surface modification of the MNPs.¹⁵

Diverse approaches have been applied for the preparation of magnetic/polymer composite particles. To our knowledge, Guesdom and Avrameas first synthesized magnetic polymer spheres, using acrylamide and agarose in the presence of iron oxide NPs.¹⁶ Encapsulation of MNPs can be conducted by various polymerization methods, such as emulsion polymerization, soapless emulsion polymerization, inverse emulsion polymerization, inverse microemulsion polymerization, seed precipitation polymerization, and so on. All these approaches produce various shapes (nanoflowers, nanospheres, nanorods, nanocubes, etc.) in three kinds of nanoparticles¹¹: P/M (polymer particle core/magnetic nanoparticles shell),¹⁷ P/M/P (polymer particle core/magnetic shell/polymer shell),¹⁸ and MP (magnetic core/polymer shell¹⁹ or magnetic NPs dispersed in a polymer matrix²⁰). Recent studies have demonstrated the usefulness of suspension polymerization to synthesize core-shell NPs; Chen et al., for instance, applied suspension polymerization to synthesize PMMA/Fe₃O₄ microspheres.²¹ Still, their produced microspheres suffered from irregular morphology, rough surface, and weak uniformity due to the addition of the Fe₃O₄. Other studies have been implemented to investigate the mini-emulsion approach for nanoscale particles. Yan et al. prepared Fe₃O₄/polystyrene composite particles via mini-emulsion polymerization,²² but the polydispersity of the MNPs increased with the addition of more Fe₃O₄ nanoparticles which had been modified with oleic acid. Ma et al. conducted a new mini-emulsion polymerization approach to synthesize Fe₃O₄ NMPs encapsulated with poly(methyl methacrylate-acrylic acid).²³ In their research, NMPs with good hydrophilicity and high saturation magnetization were synthesized. Mahdavian et al. prepared Fe₃O₄-poly(butyl acrylate-styrene) via initiator free mini-emulsion polymerization; in their research, the Fe₃O₄ NMPs was located in the core and poly(butyl acrylate-styrene) encapsulated the magnetic core²⁴ and the core-shells were obtained under ultrasonic irradiation. The nanospheres were uniform, but the saturation magnetism was reduced sharply due to various factors, such as the addition of OA as a surface modifier, ultrasonic use (which can oxidize the Fe₃O₄ to $γ$ -Fe₂O₃) and the presence of oxidizing H₂O₂ and polymer in the shell of the core-shell nanospheres. In another research project, magnetic nanospheres (Fe₃O₄/ $γ$ -Fe₂O₃) with polystyrene shells were prepared with a soap-free emulsion polymerization method,²⁵ the nanospheres were uniform, but the saturation magnetization was very low.

By considering the drawbacks of the various polymerization methods, mini-emulsion polymerization is the most efficient way because, in this method, the magnetic nanoparticles in the mini-emulsion media locate in the monomer droplets, and the polymer chains can encapsulate the nanoparticles.²⁶ For the preparation of Fe₃O₄/PMMA composite nanospheres, there has been extensive research. Lan et al. prepared nearly monodispersed Fe₃O₄/PMMA composite nanospheres with an M_S content of about 39 (emu.g⁻¹).⁸ Another article by these authors used the same preparation method for superparamagnetic composite Fe₃O₄/PMMA nanospheres with 10–90 nm size for application in protein separation.²⁷ They synthesized another shape of these NPs with this approach; the superparamagnetic SiO₂/(PMMA/Fe₃O₄) particles were prepared with a modified mini-emulsion polymerization and then coated with a SiO₂ layer via electrostatic interaction,²⁸ resulting in the outer silica shell being periodically mesoporous. There are also some reports about implementing two-layer shells. Wang et al., for instance, prepared magnetic nanospheres (PMMA/Fe₃O₄) coated by a silica shell by the Stober process with separation and DNA enrichment applications.²⁹ He et al. reported the surface modification of Fe₃O₄ nanoparticles in the SiO₂/(PMMA/Fe₃O₄) core-shell nanostructures;⁹ but, after the surface modification, the magnetic saturation decreased notably, probably due to the thick shell, and the particles were not monodisperse in size. Another research report described the use of linolenic acid as a crosslinking agent for nucleic acid detection by the chemiluminescent method.³⁰ In this approach, the size distribution range was 250–500 nm, all with the same shape, and high specificity, and good sensitivity properties.

Herein we report the synthesis of superparamagnetic PMMA (as core)/SiO₂ (as shell) nanoparticles, which have attached Fe₃O₄ nanoparticles resulting in a raspberry-like morphology, by mini-emulsion polymerization and the Stober method. Before the mini-emulsion process, the Fe₃O₄ NPs were hydrophilic and needed to be modified. NPs which contain hydroxylated surfaces of metal ions (Fe₃O₄, Al₂O₃, and TiO₂) can be functionalized with carboxylic agents.^21,31,32 Besides hydroxyl groups, magnetic metal-based NPs with hydrophilic surfaces may also contain surface-metal ions. This surface can be functionalized with biofunctionalized ligands, where one functional group is metal-coordinating and can be grafted on the surface of the metals. Simultaneously, the remaining chain has a weaker affinity for metal coordination and remains free for further reactions.³³ Until now, many surface modifiers for Fe₃O₄ have been applied.²⁹ Oleic acid, for instance, can make Fe₃O₄ dispersible in nonpolar media and can control particle agglomeration. Here, we introduce a modified co-precipitation method to synthesize hydrophobic NPs of Fe₃O₄ directly. In this method, the aggregation of NPs in the core of the nanostructure can be prevented effectively by the carboxylic acid group hindrance of oleic acid. In earlier studies by Lee et al.,³⁰ an MMA’s polymerization process for encapsulation of Fe₃O₄ NMPs modified with OA produced many PMMA microspheres without magnetic NPs, and some of these modified NPs could agglomerate easily. For overcoming these consequences, we introduced OA during the Fe₃O₄ co-precipitation method. The next step was a mini-emulsion polymerization. The hydrophobic Fe₃O₄, MMA, and surfactants were sonicated and formed a mixed mini-emulsion with a homogeneous size dispersion of monomer droplets containing NMPs in water before the polymerization initiation. Modification with a polymer layer can preserve the colloidal stability through steric hindrance and increase the critical concentration of Fe₃O₄ MNPs during the next step.²⁹ The last step was silica coating with high drug delivery capacity.³⁴ Another benefit of this layer was the silane agents' reaction, which produced a stable dispersion in non-aqueous media. The silica coating was applied via the in-situ Stober method after hydrolysis of the nanospheres^35–38 and the final product had an excellent spherical shape with superb monodispersity.

Materials and methods

Materials

Ferric chloride (FeCl₃, 6H₂O, Merck Co., USA) and ferrous chloride (FeCl₂, 4H₂O, Merck Co., USA) were used as received. Methyl methacrylate (MMA, Sigma-Aldrich Co., Ltd., Germany) and sodium dodecyl sulfate (SDS), citric acid (CA), and tetraethoxysilane (TEOS) all from Merck Co. were all analytical grades. Oleic acid (OA, 90% Merck) was used without purification. In each step, doubly distilled and deoxygenated (DI) water was used.

Characterization

The hydrodynamic diameter and size distribution of both the Fe₃O₄ and (Fe₃O₄/PMMA)-SiO₂ MNPs were characterized by dynamic light scattering (DLS, model BI-200SM, Brookhaven Instrument Co., USA, with the wavelength of 657 nm). The Fourier transform infrared (FTIR) spectroscopy, by a spectrometer (MB Series, Bomem Inc., Canada) was used for investigating the functional groups with KBr discs. The mass loss of MNPs was obtained through thermogravimetric analysis (TGA, Pyris 1 TGA, PerkinElmer Corp., USA). The mass loss measurements of the dried MNPs were carried out under N₂ with a heating rate of 10°C.min⁻¹ from 35 to 700°C. Scanning electron microscopy (SEM) imaging of the surfaces of the MNPs was carried out by using an AIS2300 C SEM device (Seron Technology Co., Korea). The dilute aqueous solution of the sample was sonicated for 15 min by a Misonix sonicator (S3000, Misonix Inc, USA), then multiple drops of the sample were dropped onto a small aluminum foil and it was dried at room temperature. Then, the specimen surface was coated with gold (gold thickness around 10 nm). The sample was observed by the SEM. The internal structure and core-shell morphology were observed by transmission electron microscopy (TEM, EM 900, Zeiss Co., Germany) operating at 100 kV. The dilute aqueous solution of the sample was also sonicated for 15 min by a Misonix sonicator (S3000, Misonix Inc, USA), then one drop of the sample was dropped onto a formvar carbon film on copper grid 300 mesh (EMS-USA) and it was dried thoroughly at room temperature. The sample was observed by the TEM. The magnetization measurements of the samples were obtained by a vibration sample magnetometer (VSM, Meghnatis Daghigh Kavir Co., Iran) with a field from 0 to 10,000 Oe at 300°K. Al samples were measured three times, and the average values were reported.

Preparation of Fe₃O₄ nanoparticles modified with OA

The MNPs were produced via a modified chemical co-precipitation method with the preparation being implemented under N₂. Two aqueous solutions, 75 mL containing 0.023 mol FeCl₂ and 75 mL containing 0.046 mol FeCl₃, were prepared separately. The molar ratio of FeCl₂/FeCl₃ was 1:2, based on Massart’s method for the preparation of Fe₃O₄ NPs.³⁹ The two aqueous solutions were mixed under N₂ and ultrasonic treatment (50 W, 2 cycles with 2 min duration) and then transferred to a 250 mL four-necked-flask equipped with a condenser, nitrogen inlet and a mechanical stirrer (400 r/min). Then, 50 mL of ammonium hydroxide (NH₃OH, 25%) was added in drops (fractionally) under vigorous stirring. Following the NH₃OH addition, after 30 min of stirring at 60°C, 2 mL of OA was added drop by drop under vigorous stirring (at 400 r/min), and then the flask contents were stirred for 1 h at 70°C. The resulting black oily product was collected on the flask wall by a magnet and washed 2 times with ethanol and 3 times with DI water in the presence of an external magnetic field, then dried in an oven at 60°C for 12 h. The washing procedure in this stage has an important effect on the next stages, and it was continued, as above until the pH of the remaining water reached 7.

Preparation of Fe₃O₄/PMMA nanoparticles

Fe₃O₄/PMMA NPs were produced via mini-emulsion polymerization. At first, 1 g magnetic modified NPs was added to 10 mL MMA under ultrasonics (80 W, 5 cycles with 2 min duration each) as the oil phase. SDS and CA, with a molar ratio of 1:3 (0.1 g SDS and 0.288 g CA), were dissolved in 100 mL DI water as a water phase. Then, the two phases were added together in the presence of ultrasonic treatment and N₂ to form a mini-emulsion oil in water system, and the resulting mini-emulsion was placed in a four-necked-flask in a water bath, with the flask equipped with an N₂ inlet, mechanical stirrer, and condenser. It was agitated for 30 min (400 r/min) and the temperature increased gradually to 60°C; 1 g benzoyl peroxide (BPO) was then added as an oil phase initiator to the flask and the polymerization proceeded under stirring for 5 h at 75°C. In the end, a brown product was separated by a strong magnet and washed with acetone 2 times and DI water 3 times under an external magnetic field until the remaining water became clear and the pH of the remaining media was 7.

Preparation of (Fe₃O₄/PMMA)-SiO₂ nanoparticles

Before the silica coating of the above prepared NMPs, the surface chemical groups on the nanospheres needed to be hydrolyzed. A solution mixture containing 0.1 gr Fe₃O₄/PMMA NPs, 100 mL methanol and 2 mL ammonia were sonicated under mild power (40 W, 2 cycles each with 2 min duration). After that, the mixture was refluxed for 2 h in a flask and then washed with DI water. The NP surfaces were prepared for silica deposition according to the Stober method. In the first stage, 150 mL of a water/ethanol (1:4) solution containing 0.1 gr of the obtained nanoparticles was sonicated under weak power (20 W, 2 min). After transferring to a three-necked-flask equipped with a stirrer and a condenser, the temperature was set to 40°C, and after that 6 mL ammonia and 5 mL TEOS were added dropwise (fractionally). Then, the solution was agitated (400 r/min) for 12 h at 40°C. Finally, the obtained nanoparticles were separated and washed with DI water several times under a magnetic field (each time after washing, the samples were separated from the magnet and shaken several times) until the pH of the remaining water decreased to 7.

Results and discussion

The overall preparation of the PMMA (as core)/SiO₂ (as shell) nanoparticles which have Fe₃O₄ nanoparticles attached with raspberry-like morphology had three stages, as shown in Scheme 1. The first stage was the preparation of superparamagnetic hydrophobic Fe₃O₄ nanoparticles by incorporating oleic acid in the co-precipitation method. Adding OA fractionally in the synthesis process of MNPs led to nearly mono-dispersed hydrophobic Fe₃O₄ nanoparticles. The second stage was the polymerization of PMMA on the surface of the OA modified superparamagnetic Fe₃O₄ for their protection. The polymer’s encapsulation around the OA-modified Fe₃O₄ surface was feasible because of the interaction between the oleic acid chains on the Fe₃O₄ surfaces and the MMA monomers. In the last stage, the nanoporous silica shell was formed by hydrolysis and TEOS condensation on the surfaces of the hydrolyzed Fe₃O₄/PMMA superparamagnetic nanoparticles. The TEOS layer could be deposited with the Sol-Gel method on the hydrolyzed surfaces by the interaction of the hydrogen atoms of the TEOS monomers on the surface.²⁹ In the ultrasonication process in the final stage, in the TEOS droplets containing Fe₃O₄/PMMA nanoparticles some of the Fe₃O₄ nanoparticles were released from the PMMA encapsulation to the TEOS droplets, (because of the power of ultrasonic waves); hence, these nanoparticles located on the outer shell of silica and the raspberry-like morphology was prepared. The silica shell with a high surface area has sufficient space for drug loading¹¹ but the size of nanoparticles should be controlled in the range of the optimum diameter (50–200 nm).⁴⁰ After every step, the nanoparticles were washed while on a magnet and the washing procedure is shown in the box in Scheme 1.

Scheme 1.

The complete process of synthesize of the (oleic acid-Fe₃O₄/PMMA)-SiO₂ magnetic nanoparticles, the PMMA and SiO₂ structure, and the method of washing after each step are shown.

Morphological and structural characterization of the MNPs

In Figures 1(a) and (b) TEM images of the final nano-sized MNPs with narrow polydispersity are shown. Figure 1(a) represents the raspberry-like morphology distribution of the Fe₃O₄ nanoparticles (black dots) in both the PMMA (core) and SiO₂ (shell), which shows the effective encapsulation of Fe₃O₄ nanoparticles by the polymer core and silica shell (black dots in gray surroundings). Figure 1(b) shows the spherical shape, narrow polydispersity and fine dispersion of the (Fe₃O₄/PMMA)-SiO₂ nanoparticles. The polymer core encapsulates the hydrophobic OA-modified Fe₃O₄ nanoparticles, while the silica shell encapsulates the hydrophilic Fe₃O₄ nanoparticles which were released from the PMMA encapsulation due to using the ultrasonic waves, this is the reason for the formation of the raspberry-like morphology. Three regions of different electron densities confirm the formation of the dispersed Fe₃O₄ NMPs in the PMMA core and the outer shell of SiO₂. The Fe₃O₄ nanoparticles, due to the electron beam absorption, appear as dark spots, while both the PMMA cores and Silica shells appear brighter. The average diameter of the nanospheres observed by TEM was approximately between 70 and 85 nm, and the core diameter of the PMMA/SiO₂ was measured as <50 nm; thus, the thickness of the SiO₂ layer was about 14 nm and the Fe₃O₄ nanoparticles were less than 10 nm in diameter. Also, SiO₂ formed on the surface of the hydrolyzed Fe₃O₄/PMMA nanoparticles. The diameter of the PMMA core embedded hydrophobic Fe₃O₄ nanoparticles can become larger by increasing the PMMA to Fe₃O₄ weight ratio,⁸ while the thickness of the SiO₂ can be adjusted by the TEOS and ammonia content; an ultrathin silica shell can be obtained by using only a small amount of the aqueous droplets of TEOS and this methodology was used in this work. However, in order to have a high thickness coating, a large aqueous domain is essential.⁴¹ In this article, an average thickness of a silica shell of 15 nm was observed. In order to avoid silica particles without the magnetic core, one of the effective strategies was adding the TEOS content dropwise,⁴¹ and for preventing the formation of these core-free particles, hydrolysis of the nanoparticles before applying the Stober method was used. The Stober method is a sol-gel method that is used to prepare monodisperse silica microspheres; ammonia and tetraethyl orthosilicate (TEOS) are used as the catalyst and the silicon source, respectively.⁴² Moreover, we did not find any silica nanospheres without the embedded Fe₃O₄/PMMA nanoparticles in our product (every PMMA (core)/SiO₂ (shell) nanoparticle had magnetic NPs); this indicates the high yield of the OA-modified Fe₃O₄ nanospheres.

Figure 1.

Transmission electron microscopy images of the (oleic acid-Fe₃O₄/Polymethyl methacrylate (PMMA))-SiO₂ magnetic nanoparticles.

An SEM image of the (Fe₃O₄/PMMA)-SiO₂ nanoparticles is shown in Figure 2(a). The relatively broad particle size distribution and the spherical shape of these MNPs is shown in the image. It is noted, the SEM image has a larger size variation of the particles than the TEM image both much smaller (upper right) and larger (scattered) than 100 nm, which we attribute to the much larger number of particles imaged, with some of the imaged particles being aggregated. The polydispersity index (PDI) can be obtained from the DLS test through optical detection of the Brownian motion of nanoparticles in a liquid.⁴³ The PDI of (Fe₃O₄/PMMA)-SiO₂ MNPs was about 0.101, which indicates the homogenous and uniform formation of MNPs in the aqueous medium. Besides this fact, the hydrodynamic diameters of the particles, as determined by the DLS test, was between 90 and 200 nm, and this narrow range represents the monodispersity of the MNPs. We note there was a difference between the hydrodynamic diameter of the particles from the DLS test and the diameter of particles measured in the TEM test. Also, the average hydrodynamic diameter of the OA modified-Fe₃O₄ was 10 nm (Figure 2(c)), and the particle diameter range was from 8 to 20 nm with a PDI of 0.14, indicating, the small size and monodispersity of the hydrophobic Fe₃O₄ nanoparticles. In the TEM test, because of how the sample was prepared and the nanometric scale of the test, we can observe the nanospheres separately depending on the magnification, hence, the observed size range was 60–90 nm with an average diameter of 79 nm. The SEM test is based on detecting the reflected or knocked-off electrons and it shows the surface morphology of the nanoparticles, but TEM creates images by electron transmission (passing electrons through the sample) and it shows the composition, morphology and size of the nanoparticles. We note the curves from the DLS tests represent the hydrodynamic diameter of the nanoparticles dispersed in water; their size was affected by the liquid medium and higher than the diameters calculated from the TEM test^43,44; hence, the size of MNPs in these curves was from 90 to 200 nm. Based on these three supplementary tests the average diameter of single,⁴⁵dry MNPs was 78 nm and the maximum hydrodynamic diameter, affected by the Brownian motions (random motion in a medium (liquid or gas) with particles suspended in it) in the water was about 200 nm.

Figure 2.

Scanning electron microscopy image of (OA-Fe₃O₄/PMMA)-SiO₂ (a), Dynamic light scattering of (OA-Fe₃O₄/PMMA)-SiO₂ composite nanospheres (b), and OA-Fe₃O₄ nanoparticles (c). OA: oleic acid.

Microstructural study

FTIR spectroscopy was used to examine the as-synthesized Fe₃O₄-OA modified and Fe₃O₄/PMMA nanoparticles and the (Fe₃O₄/PMMA)-SiO₂ composite nanospheres. Figure 3, curve a, shows the spectrum of the Fe₃O₄-OA modified nanoparticles; the absorption band at 573 cm-1 corresponds to the stretching vibrations of the Fe-O bonds and the double peaks near 2920 and the peak at 3433 cm-1 are related to the C-H groups of the OA segments. In the spectrum of Fe₃O₄/PMMA (Figure 3 curve b), the strong absorption band at 574 cm-1 is assigned to the Fe-O groups, which confirms the existence of Fe₃O₄. The new peak, at 625 cm-1, is due to the O-H and C-H groups of PMMA and the new peak at 1717 cm-1 is attributed to the ester bonds (-C(=O)OC-) of the PMMA, while the absorption bands at 2851 and 2920 cm-1 are due to the C-H groups of the PMMA as well as the C-H groups of OA and the absorption band at 3433 is assigned to the stretching of the O-H groups in PMMA. In Figure 3, curve c the peak at 574 cm-1 showed the Fe-O bonds and the peaks at 1717 and peaks at 2851 and 2920 cm-1 are assigned to the PMMA core. The broad absorption peak at 3433 cm-1 is due to O-H groups in the SiO₂ coating due to condensation of incomplete silanol group (Si-OH) or absorbed water; four main characteristic SiO₂ absorption bands were observed, Si-O-Si stretching, Si-OH stretching, Si-O bending and Si-O-Si bending⁴⁵ with their absorption peaks at 471, 801, 949, and 1095 cm-1, respectively. These peaks are due to the stretching vibrations of the SiO₂ framework and terminal Si-O-Si (silanol) groups. Thus according to our FTIR analysis, magnetic Fe₃O₄ particles, PMMA and SiO₂ existed in our nanoparticles.

Figure 3.

Fourier transform infrared spectra of (a) Fe₃O₄-OA modified nanoparticles, (b) OA-Fe₃O₄/PMMA nanoparticles, and (c) (OA-Fe₃O₄/PMMA)-SiO₂ composite nanospheres. OA: oleic acid.

Thermogravimetric measurements

Figure 4(a) shows the TGA curves of the Fe₃O₄-OA modified/PMMA and OA modified-Fe₃O₄ NPs. The upper curve of Figure 4(a) shows the TGA of the OA-modified Fe₃O₄ NMPs; it is clear that the OA-modified Fe₃O₄ NMPs decomposed in 2 steps, the first mass loss, from 100 to 210°, might be due to the moisture evaporation (at 100°C) and free or loosely bound OA molecules (at a temperature between 170 and 210°C), and the second mass loss may be attributed to the OA chemically bound to the Fe₃O₄ NPs at temperatures between 280 and 42°C. The overall mass loss in this portion of the curve was about 12%. The lower curve shows the TGA curve of the Fe₃O₄-OA/PMMA nanospheres. The first mass loss from 100 to 250°C is again due to the moisture evaporation and loss of loosely bound OA molecules, as well as unreacted MMA monomers. The OA chemically bound with Fe₃O₄ NPs, based on the upper curve, decomposed between 320 and 420°C and the PMMA based on the excess decomposition, decomposed in the temperature range from 350 to 550°C, and the overall mass loss was about 19% at 550°C. The OA and PMMA mass loss peaks overlap because both of these materials have ester groups but according to the upper curve, the decomposition range of OA can be defined. In Table 1, the mass loss and the Fe₃O₄ content are listed. Based on the TGA curve, about 19% of the coating was the organic layer (OA+polymer), and 81% was the mineral content; here is the Fe₃O₄ content. In this research, this test was used as a validation for the VSM test because, through its results, the mineral content, which is here the Fe₃O₄ content, was obtained (Fe₃O₄ content is 81%), and by a simple equation (formula (1), defined in the magnetic characterization section below), the magnetic saturation can be calculated.

Figure 4.

a) Thermogravimetric analysis curves of OA modified Fe₃O₄ nanoparticles and OA-Fe₃O₄/PMMA nanoparticles and b) Vibrating sample magnetometry curves of Fe₃O₄ nanoparticles, OA-Fe₃O₄, OA-Fe₃O₄/PMMA nanoparticles, and (OA-Fe₃O₄/PMMA)-SiO₂ composite nanospheres (b). OA: oleic acid.

Table 1.

The magnetic measurement from TGA and VSM.

Samples	Mass loss (%) at 600°C	Magnetic content from TGA (wt%)	Ms (emu g⁻¹) from TGA	Ms (emu g⁻¹) from vibration sample magnetometer
OA-modified Fe₃O₄ nanoparticles	12	88	54	55
OA-Fe₃O₄/PMMA composite nanospheres	19	81	49	47

TGA: thermogravimetric analysis; OA: oleic acid.

Magnetic characterization

The magnetic properties of the Fe₃O₄, OA-Fe₃O₄, OA-Fe₃O₄/PMMA, and (OA-Fe₃O₄/PMMA)-SiO₂ NPs were characterized by a vibration sample magnetometer (VSM). Figure 4(b) shows the VSM curves for each sample. As shown in Figure 4(b) and Table 2, after the synthesis of PMMA and SiO₂ around the OA-Fe₃O₄ MNPs the magnetic content (magnetic saturation) declined in each step of sample preparation, attributed to the encapsulation of non-magnetic materials around the Fe₃O₄ nanoparticles. The magnetic saturation (M_S) was significant for each type of nanoparticle and declined with each successive non-magnetic material encapsulation. Figure 5 shows the VSM plots of OA-Fe₃O₄ NPs, OA-Fe₃O₄/PMMA, and (OA-Fe₃O₄/PMMA)-SiO₂ nanospheres; near the zero points of the graph; from the curves, the magnetic remanence (M_R) and the hysteresis values of these nanoparticles were measured and are reported in Table 2. The magnetic remanence (M_R) and the hysteresis values were negligible but the M_S values were high, indicating the superparamagnetic nature of all 3 types of nanoparticles. Also, the magnetic remanence (M_R) and hysteresis increased after silica coating due to the presence of the non-magnetic shell, but still, the nanoparticles were superparamagnetic. In Table 2, the magnetic saturation hysteresis remanence and coercivity (M_R/M_S) were listed. The visual observation of the as-synthesized magnetic nanoparticles suspensions is shown in the small pictures at the lower right in Figure 4(b). As can be seen in the right side picture, in the external magnetic field, the magnetic nanospheres were attracted by the magnetic bar. When the external magnetic field was removed they easily redispersed in the water without agitation or shaking and, through this observation, their superparamagnetic behavior was again concluded.

Table 2.

Table of magnetic parameters of Fe₃O₄ NPs, (Oleic acid) OA-Fe₃O₄, OA-Fe₃O₄/PMMA, and (OA-Fe₃O₄/PMMA)-SiO₂ nanospheres.

Samples	Magnetic saturation (M_S)	Magnetic remanence (M_R)	Hystersis	M_R/M_S
Pure Fe₃O₄ MNPs	61	0.39	1.5	0.006
OA-Fe₃O₄ MNPs	55	0.35	2.2	0.006
OA-Fe₃O₄/PMMA MNPs	47	0.33	4.5	0.007
(OA-Fe₃O₄/PMMA)-SiO₂ MNPs	9.5	0.12	6.7	0.013

OA: oleic acid; MNPs: magnetic nanoparticles.

Figure 5.

Magnified vibrating sample magnetometry plots of OA-Fe₃O₄, OA-Fe₃O₄/PMMA, and (OA-Fe₃O₄/PMMA)-SiO₂ nanospheres, A, B, C, respectively. OA: oleic acid.

M. Das et al.⁴⁶ proposed that one could derive the M_s content from the mass loss percent in the TGA

M_{S} = M_{S}^{F e_{3} O_{4}} (1 - ω)

(1)

where

M_{S}^{F e_{3} O_{4}}

is the magnetic saturation obtained from the plateau of the VSM test of

{Fe}_{3} O_{4}

(the blue line) nanoparticles and

ω

is the mass loss percent at the plateau in TGA test. Based on this formula, the magnetic content was calculated. Here,

M_{S}^{F e_{3} O_{4}}

was obtained from the M_S value of the pure Fe₃O₄ nanoparticles. This formula is in accordance with the TGA results because the residual mass after TGA represents the mineral material and the mass loss happens because of degradation of the organic materials. In Table 1, the calculated M_s for OA modified Fe₃O₄ was 54 emu.g⁻¹ (M_s from TGA) which was near the VSM result. Similarly, for Fe₃O₄/PMMA, the calculated magnetic saturation was close to the VSM results (M_s from VSM). After PMMA deposition on the Fe₃O₄, the calculated magnetic content decreased due to the added PMMA. Also, in the TGA test, as the encapsulation became thicker for a fixed

{Fe}_{3} O_{4}

content, more mass loss happened due to the existence of the non-magnetic shell (OA and PMMA), this is validated by the VSM test in which the magnetic saturation decreased more in the further encapsulation of the nanoparticles by the PMMA. The data about magnetic content, calculated magnetic saturation according to formula (1) and mass loss data are listed in Table 1.

Discussion

Our proposed synthesis process and details about the preparation of (OA-Fe₃O₄/PMMA)-SiO₂ composite nanospheres are presented in Scheme 1. The Fe₃O₄ magnetic nanoparticles are hydrophilic, and they can disperse in the water medium. Poly (methylmethacrylate) is a hydrophobic monomer and, in mini-emulsion polymerization, it serves as an oil phase. In order to encapsulate the Fe₃O₄ with poly (methylmethacrylate), the Fe₃O₄ NPs were modified with oleic acid. Oleic acid can alter the surface characteristics of the Fe₃O₄ spheres and make them hydrophobic; it serves as a coating for the Fe₃O₄ NPs and an osmotic pressure agent for the formation of a stable mini-emulsion system.^8,47 Modification with OA is the most critical stage in this procedure because it initiates all processes. Hence, for efficient modification, the nanoparticles should be modified homogeneously. We incorporated a facile way of modification in the conventional co-precipitation approach. If the modification process of the Fe₃O₄ NPs occurs accompanied by the nucleation and growth of the Fe₃O₄ nanospheres in the co-precipitation method, the Fe₃O₄ nanoparticles become hydrophobic and homogeneous in size. Another advantage of this kind of modification is that the nanoparticles are synthesized with a hydrophobic surface with a minimum size, about 6 nm, and with less aggregation of the Fe₃O₄ NPs. However, after the modification step, an excellent and facile way of washing with ethanol should be implemented to avoid an excess amount of OA; based on visual experiments, an extra amount of oleic acid causes inhomogeneity in the mini-emulsion, which is probably due to the formation of hydrophobic particles with inhomogeneous size. In other publications, in the synthesis of the Fe₃O₄ coated nanospheres, some Fe₃O₄ NPs without polymer coating existed, as shown by Yan et al.²²; also, the magnetic content of each composite particle differed. As shown in the TEM images in Figure 1, in our study free Fe₃O₄ nanoparticles not incorporated in the manufactured nanospheres were not observed, attributed to the significant modification of the Fe₃O₄ MNPs with OA and effective polymerization of the PMMA and SiO₂ coverings on the Fe₃O₄ nanoparticles. Thus, our implementation of the modification with OA to avoid aggregation succeeded. In our mini-emulsion polymerization, because of the hydrophobic surface modification of the Fe₃O₄ NPs with oleic acid, the OA-Fe₃O₄ nanoparticles became dispersed in an oil phase; hence, ionic and nonionic surfactants could form the well-defined oil in water system containing the magnetic nanoparticles in the oil phase with a stable, narrow size distribution,^48–50 this phenomenon is the basis for the formation of our monodisperse OA-Fe₃O₄/PMMA nanoparticles.

In our study, SDS (anionic surfactant) and CA (co-surfactant),⁵¹ with a molar ratio of 1:3, were chosen as mixed surfactants for achieving system stability and narrow size distribution of the Fe₃O₄/PMMA nanospheres. The SDS chains located around the MMA droplets containing the OA-Fe₃O₄ nanoparticles and, because the CA co-surfactant is a fatty acid, it located in the oil phase (MMA droplets). Under ultrasonic force, the MMA monomer droplets containing the OA-Fe₃O₄ dispersed homogeneously in the water phase. Hybrid oil droplets with outer SDS and inner CA in the water phase formed by hydrophobic, solvophobic, and van der Waals forces. This stage is the most important and the sizes of the magnetic polymer composite nanospheres were determined in this stage. The initiator (BPO) was added after the gradual temperature increase to 60° and located in the oil phase; then, the Fe₃O₄ nanoparticles were covered with PMMA. In our research, we could synthesize separated, individual Fe₃O₄ nanoparticles encapsulated with PMMA and SiO₂. The encapsulation by PMMA around the Fe₃O₄ was enough for stabilizing the Fe₃O₄ nanoparticles and preventing them from agglomerating.

For the next encapsulation by the Stober method with SiO₂, a modification method needed to be implemented previously to alter the nanospheres' surface properties. The synthesized OA-Fe₃O₄/PMMA nanospheres have hydrophobic surfaces and the silica shell cannot deposit on such surfaces. Based on the report by Wang et al.,²⁹ before silica deposition, we used a hydrolysis process to make the nanospheres hydrophilic; after the hydrolysis, the nanospheres can undergo interactions with TEOS by their -OH groups. Due to the PMMA coating of the Fe₃O₄ nanoparticles, there were many ester bonds on the surface of the nanospheres. These ester bonds reacted with hydroxyl groups due to catalysis of the base groups on the NH₃OH and were hydrolyzed into the hydroxyl groups.⁵² Hence, after hydrolysis, the carboxyl groups for silica deposition on OA-Fe₃O₄/PMMA nanospheres were present. After that, the best way for the synthesis of silica on the surface of nanoparticles is the Stober method because it produces a controllable and uniform covering; in this process, ethanol solvent was used to adjust the hydrolysis process and condensation with TEOS. A lower ratio of ethanol results in agglomerated silica particles; thus, for narrow size distribution, a sufficient proportion of ethanol should be employed.^53,54 The resultant -OH groups act as alkaline groups, supplied by the ethanol solvent.⁵⁵ The silica shell is formed by hydrolysis and TEOS condensation, and this outer layer makes the magnetic nanoparticles stable to agglomeration. Silanol groups obtained by TEOS hydrolysis are absorbed on the hydrolyzed surfaces of the magnetic nanospheres by the reaction between the hydroxyl groups on the surface with silanol groups. The condensation process of the TEOS is needed for further silica deposition.^29,55 Without the SiO₂ layer, the MNPs tend to aggregate because of their dipole attractions.⁵⁵ Hence, a SiO₂ shell with nanometric thickness is needed for stabilization and biomedical applications.

Conclusions

In summary, we successfully synthesized PMMA (core)/SiO₂ (shell)-Fe₃O₄ nanoparticles with an average diameter between 70 and 90 nm. At first, we implemented a facile, modified co-precipitation method combined with oleic acid modification of the Fe₃O₄ to synthesize monodisperse, hydrophobic magnetic particles with a diameter of about 6 nm. After washing with ethanol to remove excess amounts of oleic acid, these magnetic particles were used in a mini-emulsion process for PMMA encapsulation to form the cores. After this step, the hydrophobic PMMA nanospheres’ outer surface was modified with ethanol and ammonia to permit the addition of a silica shell. The hydrophilic OA-Fe₃O₄/PMMA nanospheres were used in a modified Stober reaction to synthesize the SiO₂ shell. In the PMMA encapsulation process, some of the Fe₃O₄ nanoparticles were released from the PMMA encapsulation due to the power of the ultrasonic waves, the silica shell encapsulates these released hydrophilic nanoparticles while the OA-modified nanoparticles stayed in the PMMA shell and this is the reason for the formation of the raspberry-like morphology. Given the excellent homogeneity, superparamagnetism, high magnetic content, and stability of the PMMA (core)/SiO2 (shell)-Fe₃O₄ nanoparticles, this new platform offers tremendous potential for magnetic particles with clinical application that can be used for magnetic resonance imaging contrast agents.

Footnotes

Acknowledgments

We wish to express our gratitude to Amirkabir University of Technology (AUT) and the Laboratory of Polymers and the Laboratory of Coating and Magnetic Molecules at Shahid Beheshti University for supporting this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Roxana Moaref

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Synthesis and characterization of nearly monodisperse superparamagnetic (Fe 3 O 4 /Poly(methyl methacrylate))-SiO 2 nanoparticles with raspberry-like morphology

Abstract

Keywords

Introduction

Materials and methods

Materials

Characterization

Preparation of Fe3O4 nanoparticles modified with OA

Preparation of Fe3O4/PMMA nanoparticles

Preparation of (Fe3O4/PMMA)-SiO2 nanoparticles

Results and discussion

Morphological and structural characterization of the MNPs

Microstructural study

Thermogravimetric measurements

Magnetic characterization

Discussion

Conclusions

Footnotes

Acknowledgments

Declaration of conflicting interests

Funding

ORCID iD

References

Preparation of Fe₃O₄ nanoparticles modified with OA

Preparation of Fe₃O₄/PMMA nanoparticles

Preparation of (Fe₃O₄/PMMA)-SiO₂ nanoparticles