- Nano Express
- Open Access
Fabrication of Hybrid Nanostructures Based on Fe3O4 Nanoclusters as Theranostic Agents for Magnetic Resonance Imaging and Drug Delivery
© The Author(s). 2019
- Received: 31 January 2019
- Accepted: 20 May 2019
- Published: 7 June 2019
Combining anticancer drugs with inorganic nanocrystals to construct multifunctional hybrid nanostructures has become a powerful tool for cancer treatment and tumor suppression. However, it remains a critical challenge to synthesize compact, multifunctional nanostructures with improved functionality and reproducibility. In this study, we report the fabrication of magnetite hybrid nanostructures employing Fe3O4 nanoparticles (NPs) to form multifunctional magnetite nanoclusters (NCs) by combining an oil-in-water microemulsion assembly and a layer-by-layer (LBL) method. The Fe3O4 NCs were firstly prepared via a microemulsion self-assembly technique. Then, polyelectrolyte layers composed of poly(allylamine hydrochloride) (PAH) and poly(sodium 4-styrenesulfonate) (PSS) and doxorubicin hydrochloride (DOX) were capped on Fe3O4 NCs to construct the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures via LBL method. The as-prepared hybrid nanostructures loaded with DOX demonstrated the pH-responsive drug release and higher cytotoxicity towards human lung cancer (A549) cells in vitro and can serve as T2-weighted magnetic resonance imaging (MRI) contrast agents, which can significantly improve T2 relaxivity and lead to a better cellular MRI contrast effect. The loaded DOX emitting red signals under excitation with 490 nm are suitable for bioimaging applications. This work provides a novel strategy to build a Fe3O4-based multifunctional theranostic nanoplatform with T2-weighted MRI, fluorescence imaging, and drug delivery.
- Hybrid nanostructures
- Drug delivery
In recent years, various multifunctional drug delivery systems have been developed for future diagnosis and therapy in biomedical application [1–4]. Multifunctional hybrid nanostructures that are integrated favorable properties will possess significant applications such as multimodal imaging and simultaneous diagnosis and therapy [5–11]. Furthermore, these nanostructures are stimuli-responsive drug delivery systems for improved drug accumulation, enhanced therapeutic efficacy, and/or reduced side effects. Especially, these pH-responsive drug delivery systems have attracted extensive research interest. This is because most human tumors have a more acidic pH value, which provides a possible way to design the controlled release of drug molecules [12–16].
Over the past few decades, various hybrid nanostructures by combining inorganic nanomaterials with organic polymer [17–20] have been developed, including magnetic particles [21–23], upconversion nanoparticles (NPs) [17, 24], and mesoporous silica particles . Among those, magnetic hybrid nanostructures based on iron oxides with relatively large magnetization at room temperature have been widely used in the biomedical fields [26–29]. The functionalization of inorganic nanomaterials coated with polyelectrolyte layers can realize a pH-responsive encapsulation and release of drug molecules [12, 17, 30]. More recently, the polyelectrolyte layers composed of sodium poly (styrene sulfonate) (PSS) and the polycation poly(allylamine hydrochloride) (PAH) has been widely studied [31–36]. Polyelectrolyte layers combined with magnetic and luminescent NPs or drug molecules for multifunctional drug delivery systems have also been recently reported [37–39]. Iron oxide (Fe3O4) NPs are getting more and more attention in the field of magnetic resonance imaging (MRI) and drug delivery due to their unique superparamagnetic properties, biocompatibility, low-cytotoxicity, and flexibility [9, 11, 28, 29, 40–42]. In general, there are two methods to improve the magnetic responsiveness of Fe3O4 NPs. The first one is to synthesize the micrometer-sized magnetite particles. Due to large size, however, they tend to aggregate in aqueous solution, which is not beneficial to biomedical applications. The other approach is to assemble Fe3O4 NPs into nanoclusters (NCs). These Fe3O4 NCs greatly improved the magnetic responsiveness compared to individual Fe3O4 NPs [22, 43]. Therefore, if the self-assembled Fe3O4 NCs are adopted as the core to fabricate multifunctional hybrid nanostructures, the MRI performance will be improved by the collective effect of Fe3O4 NPs [43–45]. To our knowledge, the self-assembled Fe3O4 NCs functionalized with PAH/PSS multilayers for pH-responsive drug release have rarely been reported.
In this work, a versatile theranostic nanoplatform based on Fe3O4 NPs was built up for MRI and drug delivery. In our approach, Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were obtained by combining an oil-in-water microemulsion method and a layer-by-layer (LBL) electrostatic adsorption method. It is expected that the packed Fe3O4 NC system can lead to enhanced T2 relaxivity and imaging contrast, and the large specific surface area of Fe3O4 NC/PAH/PSS hybrid nanostructures allows high loading of anticancer drugs. Moreover, in vitro experiment exhibits that the cellular MRI contrast of human lung cancer (A549) cells incubated with Fe3O4 NC/PAH/PSS/DOX has been significantly enhanced.
FeCl3·6H2O (99.99%), FeCl2·4H2O (99.99%), oleic acid (OA, 90%), and 1-octadecene (ODE, 90%) were purchased from Alfa Aeasar. Sodium oleate (NaOA), ethanol, hexane, cyclohexane, isopropanol, sodium dodecyl benzene sulfonate (SDBS), ammonium fluoride (NH4F), sodium hydroxide (NaOH), dimethyl sulfoxide (DMSO), and ammonia were purchased from Sinopharm Chemical Reagent Co., Ltd (China). Poly(allylamine hydrochloride) (PAH), poly(styrene sulfonate) (PSS), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide were purchased from Sigma-Aldrich. Anticancer drug doxorubicin hydrochloride (DOX, > 98%) was purchased from Shanghai Sangon Biotech Company (Shanghai, China). APMI 1640 growth medium and fetal bovine serum (FBS) were purchased from Hyclone. All reagents were used as received without further purification.
Preparation of Ferric Oleate
The synthesis of magnetic NPs started from the synthesis of ferric oleate. FeCl3·6H2O (2.59 g), NaOA (14.6 g), C2H5OH (32 mL), H2O (24 mL), and hexane (56 mL) were mixed together in a 150-mL three-neck flask and heated to 70 °C for reflux for 4 h to form a transparent ferric oleate complexes solution. After that, the liquid was separated by a separation funnel and the upper oil layer was preserved. Hexane in the liquid evaporated at 70 °C by rotating evaporation and dried for 48 h under vacuum. The prepared samples were stored in a vacuum glove box for further use.
Synthesis of Fe3O4 NPs
We synthesized Fe3O4 NPs following previously reported procedures with slight modification . Ferric oleate (7.2 g), OA (1.28 mL), and ODE (50 mL) were mixed together in a 100-mL three-neck flask and heated to 300 °C for 40 min under argon protection; after that, the mixture was cooled to room temperature and oxidized in air for more than 12 h. The resultant nanocrystals were precipitated by the addition of isopropanol, centrifuged, and washed twice with an ethanol–water mixture (1:1 v/v). The oleic acid-capped Fe3O4 NPs were finally dispersed in 200 mL cyclohexane, and the supernatant was sealed and stored for the subsequent experiments.
Preparation of Fe3O4 NCs
Fe3O4 NCs were prepared by a facile and straightforward microemulsion self-assembly technique as previously described with modification . Briefly, a 200-μL solution of Fe3O4 nanocrystals in cyclohexane was poured into 4 mL of aqueous solution containing 14 mg of SDBS. The mixed solution underwent ultrasonic treatment for 5 min for 4 times. The formed solid-in-oil-in-water (S/O/W) emulsion was stirred at room temperature for 6 h to evaporate the organic solvent following by the self-assembly of Fe3O4 NPs to form 3D NCs. The final products were washed with deionized water 3 times to remove the excess SDBS, unincorporated nanocrystals, and some possible larger contaminants.
Preparation of Fe3O4 NC/PAH/PSS/DOX Hybrid Nanostructures
The Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were prepared by electrostatic attractive interactions. The as-prepared Fe3O4 NCs are negatively charged owing to the encapsulation of the anionic surfactants. They were first turned to be positively charged by adsorption of a layer of positively charged polyelectrolyte, poly(allylamine hydrochloride) (PAH, MW 15 000). Specifically, a 300-μL Fe3O4 NC sample was firstly diluted 10 times to 3 mL using deionized water. The Fe3O4 NC mixture was subsequently added dropwise to an aqueous PAH solution (1 mL, 10 g/L, 4 mM NaCl) under vigorous stirring. After the solution was stirred for 24 h, the excess PAH was removed by centrifugation, and the resultant PAH-coated Fe3O4 NCs (Fe3O4 NC/PAH) were redispersed in water (3 mL).
The Fe3O4 NC/PAH were then turned to be negatively charged by adsorption of a layer of negatively charged polyelectrolyte, poly-(sodium 4-styrenesulfonate) (PSS, MW 70 000). Specifically, a 3-mL Fe3O4 NC/PAH sample solution was added dropwise to an aqueous PSS solution (1 mL, 10 g/L, 4 mM NaCl) under vigorous stirring. After the solution was stirred for 24 h, the excess PSS was removed by centrifugation, and the resultant PSS-coated Fe3O4 NC/PAH (Fe3O4 NC/PAH/PSS) were redispersed in water (3 mL).
The DOX aqueous stock solution was first prepared . The concentration was 5.0 mg/mL. The hybrid nanostructure solution was obtained by mixing the Fe3O4 NC/PAH/PSS solution (3 mL, 32 mg/mL) and the stock DOX solution (60 μL) in a small plastic tube with stirring for 24 h in the darkroom. After centrifugation, the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were obtained finally.
The MRI measurements were performed in an 11.7 T micro 2.5 micro-imaging system (Bruker, Germany). The different amount of the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were dispersed in 1.2 mL agarose aqueous solution and then loaded into the microtubes for MRI measurements. The final Fe ion concentration were 0 mM, 0.013 mM, 0.026 mM, 0.032 mM, 0.041 mM, 0.052 mM, and 0.065 mM, respectively. The measurement parameters are as follows: repetition time (TR) = 300 ms, echo time (TE) = 4.5 ms, imaging matrix = 128 × 128, slice thickness = 1.2 mm, field of view (FOV) = 2.0 × 2.0 cm, and number of averages (NA) = 2.
Cellular Uptake and MR Imaging
To demonstrate efficient cellular uptake, the A549 cells were seeded on the coverslip in the confocal dish and incubated in a humidified 5% CO2 atmosphere for 4 h at 37 °C. Then, the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were added into the incubation medium at the different concentration and incubated for 2 h. The final Fe ion concentrations were obtained as 0, 2.2, 4.5, 9.0, and 13.5 μM, respectively. After the medium was removed, the cells were washed twice with PBS (pH = 7.4, 20 mM) and directly used for MR imaging.
Standard Curve of DOX
A suitable quantity of DOX was dissolved in water by oscillation. Then, a series of different concentrations of DOX aqueous solution were prepared (0–0.03 mg/mL). The fluorescence intensity of different concentrations of DOX solution was measured (λex = 490 nm). Finally, the standard curve of DOX was determined through the curve fitting of the fluorescence intensity vs the DOX concentration.
The area standard curve: Y = 447.4423 + 69745.08457X.
Precision rate of standard curve: R2 = 0.9992.
DOX Loading and Release
where W0 and Ws represent the initial DOX mass and the DOX mass in the supernatants, respectively.
For the cumulative DOX release studies in PBS buffer solutions (pH 5.0 and 7.4) with the same NaCl concentration of 0.15 M, the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were dispersed in 1.0 mL of buffer solution and then transferred into a dialysis bag. Then, it was kept in buffer solution and gently shaken at 37 °C in the darkroom. At selected time intervals, 100 μL of solution was withdrawn and analyzed by fluorescence spectrum, and then returned to the original solution.
In Vitro Cytotoxicity of Fe3O4 NC/PAH/PSS/DOX Hybrid Nanostructures
In vitro cytotoxicity of the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures was assessed against A549 cells based on the standard methyl thiazolyltetrazolium (MTT) assay. A549 cells were cultured in APMI 1640 growth medium complemented with 10% fetal bovine serum (FBS), streptomycin at 100 μg/mL, and penicillin at 100 μg/mL. The cells were maintained at 37 °C in a humidified atmosphere of 5% CO2 in air. The assay was performed in triplicate with the same manner. Briefly, A549 cells were seeded into 96-well plates at a density of 8 × 103 cells per wells in 100 μL of media. After overnight growth, the cells were then incubated at various concentrations of free DOX, Fe3O4 NC/PAH/PSS, and Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures (0.1, 0.2, 0.4, 0.8, 1.2, 1.6, 2.0 μM) for 24 h. After being incubated for 24 h, the 10 μL 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide solution (5 mg/mL) was then added each well and the cells were further incubated for 4 h at 37 °C. After the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide solution was removed, 150 μL of dimethyl sulfoxide (DMSO) was added to each well and the plate was gently shaken for 10 min to dissolve the precipitated violet crystals. The optical density (OD) was measured at 490 nm using microplate reader (Perkin Elmer, Victor X4). Cell viability was evaluated as a percentage compared to control cells.
The sizes and morphologies of Fe3O4 NPs and Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were examined by a FEI Tecnai G2-F20 transmission electron microscope (TEM) at an accelerating voltage of 200 kV. Dynamic light scattering (DLS) measurements were performed on a particle size and zeta potential analyzer from Malvern (Zetasizer Nano ZS90). The UV–vis absorption spectra were acquired by a Perkin Elmer Lambda-25 UV–vis spectrometer. The fluorescence spectra were recorded using a Hitachi F-4600 fluorescence spectrophotometer. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) (Agilent 5100) was used to analyze the element Fe concentrations in the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures.
These results indicate that both free DOX and Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures have dose-dependent cytotoxicity to cancer cells. The cytotoxicity originates from the loaded DOX rather than Fe3O4 NC/PAH/PSS hybrid nanostructures. Cell uptake of free DOX is faster than that of DOX-loaded hybrid nanostructures. This reason is that small DOX molecules can quickly spread into cells, while Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures must be endocytosis in order to enter cancer cells. Because of the hypoxia-induced coordinated upregulation of glycolysis, the acidic extracellular environment of solid tumors is stronger than that of normal tissues . At the cellular level, the internalization of most of the hybrid nanostructures will take place through endocytosis. With the increase of DOX concentration, more and more hybrid nanostructures loaded with DOX are endocytosed into cancer cells. After cellular endocytosis, the DOX-loaded hybrid nanostructures usually enter the early endosomes, then enter the late endosomes/lysosomes, and finally fused with lysosomes. Furthermore, both endosomes (pH 5.0–6.0) and lysosomes (pH 4.5–5.0) have an acidic microenvironment. In our study, the pH-responsive Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were more likely to decompose and release drugs in acidic environments, thus effectively reducing side effects, prolonging half-life of drugs, and providing more effective and lasting treatment. Due to the main target of DOX being cell nucleus, DOX can bind to double-stranded DNA to form DNA adducts, inhibit the activity of topoisomerase and induce cell death (apoptosis) . As a result, the released DOX molecules were located in the cell nucleus. Therefore, the obtained Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures may have good potential for cancer chemotherapy.
The multifunctional Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures were developed as the pH-triggered drug delivery system for effective cancer chemotherapy and MRI. The quasi-spherical Fe3O4 NCs can significantly improve the contrast ability of MRI compared with Fe3O4 NPs. The Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures can act as contrast agents to enhance MRI and as a fluorescence probe for cell imaging. The DOX can be released from the Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures at acidic environment and exhibit an excellent cellular cytotoxic effect on A549 cells. The Fe3O4 NC/PAH/PSS/DOX hybrid nanostructures as multifunctional theranostic platform have great potential for biomedical application, including MRI, fluorescence imaging, and stimuli-responsive drug delivery nanocarriers.
This work was financially supported by the National Natural Science Foundation of China (Nos.11774384, 11174324, and 11204122) for the synthesis of materials, the Youth Innovation Promotion Association of Chinese Academy of Sciences (Nos.2011235) for the synthesis of materials, the characterizations of the as-synthesized samples, the Natural Science Research Project of the Education Department of Henan Province (Grant no.12B430016), and the Science and Technology Development Program of Henan Province (Nos.172102210402), Henan Provincial Youth Backbone Teachers (Nos.2015GGJS-110) for analysis of the data.
JZ and XW (corresponding author) contributed to the analysis of the data and writing the manuscript. XL carried out the synthesis of materials and the characterizations of the as-synthesized samples. XW contributed to the discussion and analysis of the data. XW (corresponding author) contributed to the conception and design of the experiment. All authors reviewed the manuscript. All authors read and approved the final manuscript.
The authors declare no competing financial interests.
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