Magnetic conducting polymer/mesoporous SiO₂ yolk/shell nanomaterials: multifunctional nanocarriers for controlled release of doxorubicin

Abstract

Fe₃O₄/polyaniline@mesoporous SiO₂ yolk@shell nanostructures have been synthesized as multifunctional drug nanocarriers: the nanocavity in the yolk@shell nanostructures ensures high encapsulation of drugs, the presence of conducting polymer and mesoporous SiO₂ shell guarantee controlled release of drugs, and the Fe₃O₄ core ensures targeted location through a magnetic response. Doxorubicin was incorporated into Fe₃O₄/polyaniline@mesoporous SiO₂ yolk@shell nanocarriers with remarkably high entrapment efficiency, and the delivery system has an obvious sustained release effect.

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Introduction

In the past few decades, advanced drug delivery systems capable of releasing active molecules in a controlled fashion have received significant attention with the rapid development of nanotechnology and biomedicine.^1–5 Among various potential delivery platform materials, mesoporous SiO₂ has received the most attention because of its well-defined morphology and tunable pore size, together with distinctive properties, such as facile functionalization, high surface area, excellent loading capacity, and good biocompatibility.^6–10 In order to realize targeted therapy, magnetic nanoparticles, such as iron-based nanoparticles which exhibit a strong response to a magnet, have been incorporated into mesoporous SiO₂.^11–13 Such magnetic mesoporous SiO₂-based nanocarriers can exhibit a strong response to a magnet, which can experience directional movement and therefore enrich the drug and release the drug to the desired area. However, most mesoporous SiO₂-based systems have their limitations, such as weak interracial interaction between SiO₂ and the drug molecule and therefore relatively low loading capacity particularly in the case of drug molecules with high hydrophobicity. In order to solve those problems, functional polymers are often utilized to functionalize the external surface of SiO₂ to develop gated mesoporous SiO₂ nanocarriers, which are able to demonstrate release in response to specific external stimuli.^14–16 However, on the one hand, the release of incorporated drugs in polymers cannot be controlled effectively due to their direct release into the surrounding phase (normally aqueous solution); on the other hand, the dispersity and stability of colloidal solutions containing nanocarriers will be decreased, which is disadvantageous for their practical applications.

Yolk@shell nanomaterials have received numerous attention due to their intriguing nanostructures with voids between core and shell, thus have potential applications in fields of catalysis, drug delivery systems and so on.^17–23 It is believed that if polymers are functionalized on surfaces of cores in yolk@shell nanomaterials, the dispersity and stability of particles can be retained, meanwhile, the release of drugs incorporated in polymers also can be controlled due to the outside barrier of mesoporous SiO₂ shell. In addition, the voids in yolk/shell nanostructures will enable high loading content of drugs. As a result, yolk@shell nanostructures with polymer functionalized magnetic cores and mesoporous SiO₂ shell are believed to be the potential alterative multifunctional nanocarriers for advanced drug controlled release system.

Herein, we reported the synthesis of such multifunctional yolk@shell nanostructures and demonstrated their superior performances in drug controlled release. Mesoporous SiO₂ was chosen as the shell, where conducting polymer coated superparamagnetic Fe₃O₄ spheres were chosen as the yolk. Conducting polymers, such as polyaniline (PANI), polypyrrole (PPY) and polythiophene (PTH), have been well recognized as functional polymers with distinguish properties and broad applications in diverse fields.^24–28 Their application as biomedical materials has also been established due to their tunable molecular structures and inherent multifunctional groups. For example, PANI nanotubes have been applied as drug controlled release materials with excellent performances.^29–31 It is anticipated that incorporation of conducting polymers within Fe₃O₄@mesoporous SiO₂ yolk@shell nanostructures may endow them with enhanced chemical properties that can be exploited as advanced nanocarriers for drug controlled release system with improved performance. The nanocarriers of Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell spheres were fabricated through sequence coating of conducting polymer and SiO₂ on Fe₃O₄ core, followed by selective etching of SiO₂ shell to realize the transformation of Fe₃O₄/conducting polymer/mesoporous SiO₂ core/shell into Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell nanostructures. Doxorubicin hydrochloride (DOX) was chosen as a model drug in this study to assess the drug loading and releasing behaviors of the obtained magnetic nanocarriers. Results have confirmed excellent performances of Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell nanomaterials as nanocarriers for DOX, which indicate their potential applications as advanced delivery platform materials.

Experimental

Materials

Aniline, pyrrole and thiophene monomers were distilled under reduced pressure before use. All other reagents were of analytical grade and used without further purification. The water used in this study was deionized by milli-Q Plus system (Millipore, France), having 18.2 MΩ electrical resistivity.

Synthesis of Fe₃O₄ spheres

The magnetic Fe₃O₄ spheres were prepared through a modified solvothermal reaction.³² Briefly, FeCl₃·6H₂O (0.50 g), sodiumacrylate (1.4 g), and sodium acetate (1.4 g) were dissolved in ethylene glycol (30 mL) under vigorous magnetic stirring for more than 2 h at room temperature. The obtained yellow solution was transferred to a Teflon-lined stainless steel autoclave. The autoclave was then heated in an electric oven at 200 °C for 10 h, and then allowed to cool down to room temperature. The black products can be collected by magnetic separation. Finally, products were washed with deionized water and ethanol for three times respectively, and then dried in 60 °C for 12 h.

Synthesis of Fe₃O₄/conducting polymer core/shell spheres

In a typical synthesis, 20 mg Fe₃O₄ were dispersed in 25 mL deionized water, followed by the addition of 100 mg PVP (M_w = 59 000). After sonication for 30 min, 12 mg aniline (8.6 mg pyrrole or 10.8 mg thiophene) and 50 μL concentrated HCl was added into the mixture and the solution was stirred for 12 h at room temperature. Then, 20 mL deionized water was added and the mixture was further sonicated for 1 h at room temperature. After 1 h, an aqueous solution of ammonium peroxydisulfate (APS) oxidant (0.6 g APS in 20 mL deionized water) was added to start the oxidative polymerization under ultrasonic irradiation. The reaction was allowed to proceed for 2 h at room temperature. Finally, the product was magnetic separated and washed by deionized water and ethanol and then dispersed in 4 mL deionized water.

Synthesis of Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell spheres

Two different SiO₂ layers were coated on surfaces of Fe₃O₄/conducting polymer core/shell spheres, followed by selectively etching to remove the inner SiO₂ layer, resulting in the formation of Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell spheres. The first SiO₂ layer was synthesized following a modified Stöber method. Typically, the above-mentioned Fe₃O₄/conducting polymer colloidal solution (1 mL) was mixed a mixture of 20 mL ethanol, 1.5 mL deionized water, 1 mL aqueous ammonia (25–28 wt%). After 10 min ultrasonic treatment to disperse nanoparticles, 0.2 mL tetraethoxysilane (TEOS) was injected and the reaction was allowed to proceed for 6 h at room temperature under continuous mechanical stirring. The resultant Fe₃O₄/conducting polymer/SiO₂ products were separated and collected with a magnet, followed by washing with deionized water and ethanol and then dispersed in 4 mL deionized water. The second SiO₂ layer was synthesized with the assistant of surfactant hexadecyltrimethylammonium bromide (CTAB). In a typical synthesis, 1 mL of the as-prepared Fe₃O₄/conducting polymer/SiO₂ core/shell spheres was homogeneously dispersed in 10 mL of deionized water by ultrasonication for 10 min. The suspension was then added into a solution containing CTAB (75 mg), deionized water (15 mL), ethanol (15 mL), and ammonia solution (0.275 mL). After the mixture was stirred at room temperature for 0.5 h, 20 μL of TEOS was added quickly. After the reaction with stirring for 6 h, the products were collected by centrifugation, and redispersed in 10 mL of deionized water. Then the inner SiO₂ layer was etched out through the structural difference based selective etching strategy as reported.³³ In typical, 100 mg of Na₂CO₃ were added into the suspension with vigorous stirring. After the reaction was stirred at 50 °C for 10 h, the products were collected by centrifugation and extensively washed with deionized water and ethanol. The surfactant CTAB was removed according to the extraction process. The as-prepared products were dispersed in 80 mL of acetone and refluxed at 80 °C for 48 h. The extraction was repeated three times to fully remove CTAB. Finally, the products was washed with deionized water and ethanol for three times respectively, and then dried in 60 °C for 12 h for further use.

DOX drug loading

For DOX loading, 1.0 mL (2 mg mL⁻¹) DOX was added to 1.0 mL PBS buffer and 10.0 mg as-synthesized nanocarriers were dispersed in this solution and stirred for 24 h at room temperature. After this, the drug loaded nanocarriers were collected by a magnet and washed with water. The supernatant was kept for calculating the drug loading content. The amount of DOX loaded in nanocarriers was measured by UV-vis spectrophotometer at the wavelength of 480 nm. The entrapment efficiency was calculated according to the eqn (1):

In vitro release study

The release profiles of tilmicosin phosphate were determined by soaking 12 mg of sample into a dialysis membrane bag (width 27 mm, dialysis molecule <15 000, USA) in phosphate buffer solution (PBS, pH = 7.4). The aqueous solution was withdrawn from the release medium for determination of UV spectra at predetermined time intervals at 37 ± 0.1 °C. The curves of release rate for drug could be obtained from the relationship between cumulative release amount and time t.

Characterization

Morphology was examined by a transmission electron microscope (TEM, Tecnai-12 Philip Apparatus Co., USA). The energy dispersive X-ray spectroscopic (EDS) were obtained on a Bruker Quantax. The UV-vis spectra (UV-2501, Shimadzu Corporation, Japan) of samples were measured in the range between 200 and 800 nm. Fourier-transform infrared (FTIR) spectra of samples were recorded in the range of 400–4000 cm⁻¹ using FTIR spectroscopy (Nicolet-740, United States). Thermal studies were performed using a thermogravimetric analyzer (Pyris 1, PerkinElmer, United States) with approximately 10 mg of each sample that were analyzed in a mixed atmosphere of N₂ and O₂ with volume ratio of 4 : 1 to ensure the complete removal of polymer. The temperature was started from room temperature 26 to 580 °C with a heating rate of 10 °C min⁻¹. The samples were prepared in a pellet form with spectroscopic-grade KBr. Zeta potential studies of samples were performed with Zetasizer Nano ZS90 (Malvern Instruments, UK). N₂ adsorption–desorption measurements were conducted using Thermo Sorptomatic 1990 by N₂ physisorption at 77 K. The as-calcined samples were out gassed for 4 h at 60 °C under vacuum (p < 10⁻² Pa) in the degas port of the sorption analyzer. The BET specific surface areas of samples were evaluated using adsorption data in a relative pressure range from 0.05 to 0.25. The pore size distributions were calculated from the adsorption branch of the isotherm using the thermodynamic-based Barrett–Joyner–Halenda (BJH) method. Magnetic properties of the samples were measured vibrating sample magnetometer (VSM, Lake-shore 7410) at room temperature.

Results and discussion

Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell nanocarriers: morphology and characterization

In this research, we have designed drug nanocarriers based on magnetic conducting polymer@mesoporous SiO₂ yolk@shell hybrids. The presence of Fe₃O₄ in core will impact the desirable magnetic property into magnetic conducting polymer@mesoporous SiO₂ for drug delivery systems. The overall procedures for making such multifunctional hybrids were displayed in Scheme 1. Firstly, Fe₃O₄ nanoparticles were synthesized through hydrothermal route, followed by conducting polymer coating on surfaces of Fe₃O₄ nanoparticles. Then two different SiO₂ layers of dense and mesoporous SiO₂ were coated on surfaces of Fe₃O₄/conducting polymer core/shell surfaces: the first layer was realized by the well-known Stöber method, and the second mesoporous SiO₂ was synthesized assisted by surfactant CTAB.^34–36 The last step was to create voids between conducting polymer and mesoporous SiO₂, and to make SiO₂ from dense to mesoporous structures. The structural difference based selective etching strategy has been applied to realize the transformation.^37–39 The as-synthesized Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell nanocarriers were further used for drug controlled release.

Scheme 1 Schematic illustration for the formation Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk/shell nanocarriers.

The morphology and size of intermediates during the synthetic processes were monitored as shown in Fig. 1. Typically, conducting polymers PANI was chosen in Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell nanocarriers, and the products were denoted as Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell nanocarriers.

Fig. 1 TEM images of (a and b) Fe₃O₄ spheres, (c and d) Fe₃O₄/PANI core/shell spheres, (e and f) Fe₃O₄/PANI/SiO₂ core/shell spheres, (g and h) Fe₃O₄/PANI/SiO₂/mesoporous SiO₂ core/shell spheres, and (i and j) Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres.

As shown in Fig. 1a, the original Fe₃O₄ core is estimated to be 300 nm in diameter. The rough surface as distinguished from Fig. 1b proves that each single sub-micrometer Fe₃O₄ particle is assembled from numerous Fe₃O₄ nanoparticles. The amount of PVP modifier on surfaces of Fe₃O₄ spheres is about 7.7% as measured from their thermogravimetric (TG) curve (Fig. S1†). Fig. 1c shows the TEM image of Fe₃O₄/PANI core/shell hybrids, where uneven PANI coating showing as rough surfaces with prominences can be evidenced. This may be ascribed from the rough and uneven surfaces of Fe₃O₄ cores. The PANI coating is estimated to be 15 nm in thickness (Fig. 1d) and the amount of PANI is measured to be 18.4% (Fig. S1†). As concluded from Fig. S1,† the weight ratio of PANI to PVP in Fe₃O₄/PANI core/shell spheres is about 3 : 1. Fe₃O₄/PANI/mesoporous SiO₂ core/shell hybrids as given in Fig. 1e show uniform coating of dense SiO₂ shell (∼60 nm in thickness) on surfaces of Fe₃O₄/PANI core/shell hybrids. Clear observation in Fig. 1f also discloses the uneven surfaces, however, they are much better than those in the case of Fe₃O₄/PANI (Fig. 1d) possibly due to thick SiO₂ coating. After another mesoporous SiO₂ coating, the total SiO₂ shell thickness increases to ∼80 nm (Fig. 1g and h). After selective etching process, the inner part of dense SiO₂ will be etched out, creating voids between Fe₃O₄/PANI core and outer mesoporous SiO₂ shell. Fig. 1i shows the TEM image of uniform Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell hybrids. The voids between Fe₃O₄/PANI yolk and mesoporous SiO₂ shell can be clearly seen, and the remaining mesoporous SiO₂ shell is about 20 nm in thickness (Fig. 1j). Result indicates that dense SiO₂ shell with inner 60 nm thickness was etched out. The surface distortion can be clearly observed as compared with their original structure in Fig. 1e. In addition, the porous frameworks of inner dense SiO₂ shells are believed to be left because most of the Fe₃O₄/PANI cores are found to be concentrically positioned inside SiO₂ shells. Through calculation by mass (with the assumption that the two SiO₂ shells are the same and the inner 60 nm SiO₂ shell is completely etched out), about 70% SiO₂ is removed. The EDS results (Fig. S2†) discloses that the amounts of PANI and SiO₂ in Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell hybrids are roughly estimated to be 7.8% and 23.6%. Due to the formation of mesoporous SiO₂ shell and void between PANI and mesoporous shell, Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell hybrids are believed to be potential nanocarriers for delivery platform materials.

In order to prove the formation of desired hybrids, FTIR technique was used to characterize the as-synthesized materials as shown in Fig. 2a. As for Fe₃O₄, the strong absorption band at the wavenumber 629 cm⁻¹ can be ascribed to the characteristic Fe–O stretching vibration. Besides, the weak absorption band at the wavenumber 1715 cm⁻¹ coming from the C=O stretching vibration, and the absorption band at the wavenumber 1563 and 1409 cm⁻¹ coming from dissymmetric and symmetric stretching vibration of COO⁻, indicate the sodium acrylate-modification of Fe₃O₄ spheres. As for Fe₃O₄/PANI core/shell hybrids, the characteristics for PANI, such as C=C stretching deformation of quinonoid and benzenoid rings at 1576 cm⁻¹ and 1503 cm⁻¹, respectively, are clearly seen. In the case of Fe₃O₄/PANI/SiO₂ core/shell hybrids, the characteristic for SiO₂ at 1576 cm⁻¹ is the most intense peak, indicating dense coating of SiO₂ on Fe₃O₄/PANI core/shell surfaces. However, as for Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell hybrids, the intensity of this peak decreases dramatically, suggesting the partial removal of SiO₂ shell. Fig. 2b shows the XRD pattern of Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell hybrids. The broad band between 2θ = 10–30° indicates the amorphous feature of PANI, whereas other peaks can be indexed to Fe₃O₄ (JCPDS 75-1609).

Fig. 2 (a) FTIR spectra of Fe₃O₄ spheres, Fe₃O₄/PANI core/shell spheres, Fe₃O₄/PANI/SiO₂ core/shell spheres, and Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres. (b) XRD pattern of Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres.

The surface area of Fe₃O₄/PANI/SiO₂ core/shell spheres as measured by the multi-point Brunauer–Emmett–Teller (BET) method from the adsorption branch is 59.2 m² g⁻¹, whereas that of Fe₃O₄/PANI@mesoporous SiO₂ yolk/shell spheres is 118.5 m² g⁻¹. Their corresponding pore size distribution profiles as determined using the Barrett–Joyner–Halenda (BJH) method from the desorption branch of the isotherms are shown in the inset in Fig. 3b, which indicate the mesoporous nature of the hybrids. The BET surface areas and BJH pore size and volume of Fe₃O₄/PANI/SiO₂ core/shell spheres and Fe₃O₄/PANI@mesoporous SiO₂ yolk/shell spheres are summarized in Table 1, where significant increase in pore size and volume can be clearly evidenced after etching process.

Fig. 3 N₂ adsorption–desorption isotherms and their corresponding pore size distribution of (a) Fe₃O₄/PANI/SiO₂ core/shell spheres and (b) Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres.

Table 1 BET surface area and BJH pore size and volume of Fe₃O₄/PANI/SiO₂ core/shell spheres and Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres

Samples	Surface area (m^2 g^−1)	Pore size (nm)	Pore volume (cm^3 g^−1)
Fe3O4/PANI/SiO2	59.2	4.8	0.29
Fe3O4/PANI@mesoporous SiO2	118.5	3.1	0.57

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In our experiments, it was observed that Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell hybrids showed high colloidal stability (zeta potential at +35 mV) and strong magnetic property (which could be easily collected using a permanent magnet), and their colloidal stability could be preserved after removal of the magnet (inset in Fig. 4, left-handed). The colloidal solution could be stable within 2 days without apparent sedimentation. In order to quantify the magnetism, the magnetic hysteresis loops were measured by a vibrating sample magnetometer. As illustrated in Fig. 4, all of the samples were superparamagnetic and both the remanent magnetizations and coercivities were closed to zero. The saturation magnetization value of the Fe₃O₄ spheres was 81.95 emu g⁻¹. The inset in Fig. 4 (right-handed) shows the magnetic hysteresis loop at a lower field, indicating that the remnant magnetization is very small (2.96 emu g⁻¹). After PANI coating, the saturation magnetization value of Fe₃O₄@PANI core/shell spheres was 75.92 emu g⁻¹. As for Fe₃O₄/PANI@mesoporous SiO₂ yolk/shell spheres, the saturation magnetization value was 71.40 emu g⁻¹. As a result, the coating of PANI and the further coating of mesoporous SiO₂ shell could weaken the magnetic saturation value of the sample. However, the magnetic saturation value of Fe₃O₄/PANI@mesoporous SiO₂ yolk/shell spheres still remains at a high level, which makes the magnetic actuation of the hybrids feasible.

Fig. 4 Magnetization versus applied magnetic field at room temperature for (a) Fe₃O₄ spheres, (b) Fe₃O₄/PANI core/shell spheres, and (c) Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres. Left-handed inset shows the Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres aqueous suspensions before and after magnetic separation by an external magnet, and finally removal of the external magnet through gentle shaking. Right-handed inset the magnetic hysteresis loop of Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres at a lower field.

Nanocarriers for drug controlled release

The last step was to load drugs in Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell nanocarriers and to investigate their controlled release properties. In addition, other conducting polymers, such as PPY and PTH, were also introduced in Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell nanospheres to disclose the effect of conducting polymer on their drug controlled release properties. We chose DOX as a model drug due to its well-characterized spectral characteristics and its use in chemo-therapy.^40–42 For comparison, Fe₃O₄/PANI/SiO₂ core/shell spheres and Fe₃O₄@mesoporous SiO₂ yolk@shell spheres were also used as nanocarriers. As shown in Table 2, the entrapment efficiency of DOX in Fe₃O₄/PANI/SiO₂ core/shell nanospheres is relatively low (25.1%, according to eqn (1)), whereas that for Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell nanospheres can reach as high as 96.8%. It is believed that the adsorption on outer surfaces and penetration into interior cavities are the main two ways for incorporation drugs in yolk@shell nanocarriers. The high surface area of Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell nanospheres is beneficial for the adsorption of drugs, and the large pore size of mesoporous SiO₂ shell is favorable for the transfer of drugs to into inner nanocavities. As for Fe₃O₄@mesoporous SiO₂ yolk@shell nanospheres without conducting polymer, the entrapment efficiency is 58.6%, which is lower than that of Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell nanospheres in the presence of conducting polymer. Therefore, it is concluded that the presence of PANI conducting polymer shows excellent adsorption ability towards drugs. When the PANI conducting polymer was changed to PPY and PTH in Fe₃O₄/conducting polymer@mesoporous SiO₂ yolk@shell spheres, the entrapment efficiencies are 85.3% and 79.6%, for Fe₃O₄/PPY@mesoporous SiO₂ and Fe₃O₄/PTH@mesoporous SiO₂ yolk@shell spheres, respectively. The highest entrapment efficiency comes from Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres, possible due to the amino group interactions and strong π–π stacking interactions between DOX and PANI that contributing to the increased drug adsorption ability. In the following study, Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres were chosen as model nanocarriers for controlled release study.

Table 2 Drug entrapment efficiency in different nanocarriers

Samples	Entrapment efficiency (%)
Fe3O4/PANI/SiO2 core/shell spheres	25.1
Fe3O4@mesoporous SiO2 yolk@shell spheres	58.6
Fe3O4/PANI@mesoporous SiO2 yolk@shell spheres	96.8
Fe3O4/PPY@mesoporous SiO2 yolk@shell spheres	85.3
Fe3O4/PTH@mesoporous SiO2 yolk@shell spheres	79.6

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The in vitro release of drugs from Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell nanospheres was performed as a function of time and the results are shown in Fig. 5. The release profiles were studied at pH values between 7.4 (blood circulation) and 5.5 (endosomes) at 37 °C (body temperature). The release kinetics of DOX at 37 °C was evaluated through UV-vis spectra. The release rate was significantly high when the DOX in pure water was dialysed at 37 °C. The maximum of DOX was defused out from the dialysis membrane in 3 h (Fig. 5a). As for Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell nanocarriers, the release amount of DOX was about 30% at pH 7.4. The releasing of DOX increases when pH decreased. The release amount of DOX increases from 30% to 56% with pH decreasing from 7.4 to 5.5, indicating that the release of DOX exhibits a pH-responsive pattern (Fig. 5a). This phenomenon can be attributed to the increase in electrostatic repulsion between PANI and DOX with decreasing pH value.

Fig. 5 (a) The releasing curves of DOX in pure water and colloidal solution containing Fe₃O₄/PANI@SiO₂ yolk@shell nanocarriers at different pH values. (b) The releasing curves of DOX in different nanocarriers: Fe₃O₄/PANI@SiO₂ yolk@shell spheres, Fe₃O₄@SiO₂ yolk@shell spheres, and Fe₃O₄/PANI/SiO₂ yolk@core/shell spheres.

In order to disclose the effect of conducting polymer PANI on the release kinetic, Fe₃O₄@mesoporous SiO₂ yolk@shell nanocarriers were also used for comparison. It was found that the release amount of DOX was about 60% at pH 7.4 with 10 d, which was more than twice higher that of Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell nanocarriers (Fig. 5b). The drug release profile at initial stages showed the explosive release in the absence of polymer, whereas the controlled release could be maintained in the presence of polymer. As a result, the presence of PANI on surfaces of yolk showed significant effect in diffuse control release. Furthermore, Fe₃O₄/PANI/SiO₂ core@shell nanocarriers showed the release amount of DOX about 96% at pH 7.4. More interesting, the drug release profile at initial stages showed the most obvious explosive release, indicating that most of DOX molecules might be adsorbed on outer surfaces of SiO₂ shells. Therefore, it can be speculated that the drug molecules in Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres should be mostly located in the voids and solubilized in PANI. During the release process, drug molecules should firstly travel through mesoporous SiO₂ shell, leading to a controlled release manner (in comparison Fe₃O₄@mesoporous SiO₂ yolk@shell with Fe₃O₄/PANI/SiO₂ core@shell nanocarriers). In addition, the outside diffusion of drugs will be retarded due to their interaction with PANI polymer (in comparison Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell with Fe₃O₄@mesoporous SiO₂ yolk@shell nanocarriers). As a conclusion, Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres show highly potential as multifunctional nanocarriers for controlled drug release: Fe₃O₄ will impact the desirable magnetic property for targeted location, mesoporous SiO₂ shells act as channels and barriers for drug entrapment and release, and PANI conducting polymer will ensure increased entrapment efficiency and controlled release of drugs.

Conclusions

Yolk@shell nanostructures of Fe₃O₄/PANI@mesoporous SiO₂ hybrid spheres have been developed as multifunctional nanocarriers for controlled release of drugs. The drug entrapment and release studies of DOX loaded Fe₃O₄/PANI@mesoporous SiO₂ yolk@shell spheres indicating their superior performances with high entrapment efficiency and sustained control release properties. It is believed that the proposed synthetic strategy will be instructive for designed synthesis of other multifunctional nanocarriers for active molecules with broader applications.

Acknowledgements

The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 20573091) and Ordinary University Graduate Research Innovation programme of Jiangsu Higher Education Institutions (CXZZ13_0893). We would also like to acknowledge the technical support received at the Testing Center of Yangzhou University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: EDS analysis and TGA curves of samples. See DOI: 10.1039/c5ra23580d

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