Formation mechanism of dysprosium-doped manganese carbonate nanoparticles by thermal decomposition

Abstract

Herein, dysprosium-doped manganese carbonate nanoparticles (Dy-doped MnCO₃ NPs) were synthesized by thermal decomposition of Mn–oleate in the presence of Dy–oleate. The evolutional formation of MnCO₃ NPs was evidenced by the TEM, Raman and XRD. The formation mechanism of Dy-doped MnCO₃ NPs was studied for the first time by thermogravimetric-gas chromatography-mass spectrometry coupled with a Fourier transform infrared spectrometer. It was revealed that part of CO₂ and H₂O produced during the thermal decomposition could be retained by the Dy, which is responsible for the formation of Dy-doped MnCO₃ NPs. Additionally, the potential of Dy-doped MnCO₃ NPs as an efficient magnetic resonance imaging contrast agent was demonstrated in a brain glioma-bearing mice model.

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1. Introduction

Magnetic resonance (MR) imaging has become one of the most important clinical imaging tools for the diagnosis of brain tumors.^1–4 Clinically approved Gd-chelates that produce bright or positive contrast images can enhance the contrast between lesions and normal tissues by shortening the T₁ relaxation time of nearby protons.^5–8 However, these Gd-chelates could possibly be involved in nephrogenic systemic fibrosis (NSF).^9–11 Moreover, they are primarily used to image brain diseases with disrupted blood–brain barrier.^12–14

Recently, manganese (Mn)-based T₁ contrast agents, either in chelate or in nanoparticle forms, have received increased attention.^15–18 Especially, the Mn²⁺ ion is a calcium (Ca²⁺) analogue and can enter neurons through voltage-gated Ca²⁺ ion channels,^19,20 which makes them a superior T₁ contrast agent in imaging the central nervous system. For instance, Hyeon's group¹⁵ and Glomm's group¹⁶ have demonstrated that MnO nanoparticles (NPs) exhibit significantly enhanced contrast effect upon imaging brain tumor. Nevertheless, the relaxation rate MnO NPs is relatively low^21,22 in comparison with that of Gd₂O₃ NPs,^23–25 which may limit their uses in T₁-weighted MR imaging.

The MnO NPs were widely synthesized through thermal decomposition of organomanganese precursors in organic phase to ensure the uniform size and high crystalline.^15,26 To improve the T₁ relaxivity of MnO NPs, Gd–oleate was introduced into the thermal decomposition process²⁷ in line with the Mn–oleate because the Gd³⁺ ion having seven unpaired electrons produce large magnetic moments^14,28,29 and provide a high paramagnetic relaxivity. Unexpectedly, the oleate-capped, Gd-doped MnCO₃ NPs instead of Gd-doped MnO NPs was obtained. Nevertheless, the Gd-doped MnCO₃ NPs do exhibit a higher T₁ relaxivity of 6.08 mM⁻¹ s⁻¹ than that of MnO NPs. Although few mechanistic studies are reported to understand the growth kinetics and shape evolution of MnO and Fe₃O₄ NPs,^30–33 the underlying formation mechanism of MnCO₃ NPs has not been reported so far.

Herein, by using Dy–oleate as an alternative rare earth (RE) precursor, the Dy-doped MnCO₃ NPs were successful prepared by the thermal decomposition method. To trace the nucleation and growth of the MnCO₃ NPs, the solid samples collected at different stages of thermal decomposition were characterized by transmission electron microscopy (TEM), Raman, and X-ray diffraction (XRD). Meanwhile, the gaseous products yielded during the thermal decomposition were analyzed by thermogravimetric-gas chromatography-mass spectrometry coupled with a Fourier transform infrared spectrometer (TG-FTIR-GC/MS) to clarify the formation mechanism of MnCO₃ NPs. On the basis of the information obtained from the above-mentioned hyphen technique, the formation mechanism of MnCO₃ NPs through thermal decomposition of Mn–oleate in the presence of Dy–oleate was proposed. Additionally, the potential of Dy-doped MnCO₃ NPs as an MR contrast agent was explored in a brain glioma-bearing mice model.

2. Experimental

2.1 Materials

Manganese chloride tetrahydrate (MnCl₂·4H₂O) and sodium oleate (NaOA) were purchased from Sinopharm Chemical Reagent (Beijing, China). Dysprosium chloride hexahydrate (DyCl₃·6H₂O) was purchased from Sigma-Aldrich (St. Luis, MO, USA). N-(Trimethoxysilylpropyl) ethylene diamine triacetic acid (TETT) silane (45% in water) was supplied by Gelest, Inc. (Tokyo, Japan). Dulbecco's modified eagle's medium (DMEM) and fetal bovine serum (FBS) were purchased from Gibco (Basel, Switzerland). The 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay kit was obtained from Amresco (USA). All other chemicals and solvents purchased were analytical grade and used as received.

2.2 Preparation of Mn–oleate and Dy–oleate precursors

The first step in the preparation of oleate-coated MnCO₃–OA nanoparticles was the synthesis of the Mn–oleate and Dy–oleate precursor. Briefly, the mixture containing MnCl₂·4H₂O (20 mmol), NaOA (40 mmol), ethanol (40 mL), distilled water (30 mL), and n-hexane (70 mL) was heated to 70 °C for 4 h. After cooled to room temperature, the upper organic layer containing the Mn–oleate complex was separated, washed with distilled water and evaporated to collect the Mn–oleate precursor. Similarly, Dy–oleate precursor was synthesized.

2.3 Synthesis of oleate-coated Dy-doped MnCO₃ (Dy-doped MnCO₃–OA) NPs

For synthesis of the Dy-doped MnCO₃–OA NPs, 0.8 mmol of Dy–oleate, 3.2 mmol of Mn–oleate, and 50 mL of 1-octadecene was heated to 100 °C for 15 min in vacuum, then sequentially heated to 200 °C for 1 hour, 280 °C for 30 min, and 305 °C for 10 min under nitrogen atmosphere. The colour of reaction solution changed from transparent umber gradually to a yellow color, then to turbid gray-white at 280 °C, finally to pale green at 305 °C. After cooling to room temperature, the product was precipitated with the ethanol, washed with acetone, and centrifuged and re-dispersed in n-hexane.

2.4 Synthesis of water-dispersible Dy-doped MnCO₃ NPs

For synthesis of the water-dispersible MnCO₃ NPs, 100 mg of Dy-doped MnCO₃–OA NPs, 60 mL of anhydrous toluene, and 30 μL of acetic acid were mixed and sonicated for 15 min, followed by addition of 1 mL of TETT silane. The resultant mixture was stirred at 70 °C for 48 h. After cooling to room temperature, the precipitate was collected, washed with toluene and methanol, dialyzed against distilled water using a cellulose dialysis membrane (MWCO = 3500), and subjected to lyophilizing to obtain the water-dispersible Dy-doped MnCO₃ NPs.

2.5 Characterization

Transmission electron microscopy (TEM) images and high resolution TEM (HRTEM) images of Dy-doped MnCO₃–OA NPs were taken on a JEM-2100F (JEOL, Tokyo, Japan) at an operating voltage of 100 and 200 kV, respectively. X-ray diffraction (XRD) was carried out with a PANalytical X'pert Pro MPD diffractometer (Cu Kα radiation λ = 1.54056 Å) operating at 40 kV and 40 mA. Raman spectra were acquired by LabRAM HR Evolution spectrometer (HORIBA Jobin Yvon, France) equipped with CCD detector and a visible laser (λ = 532 nm). The elemental content was determined on an inductively coupled plasma atomic emission spectroscopy (ICP-OES, Varian 710-ES, USA). A superconducting quantum interference device (SQUID) was used to characterize the magnetic properties of the Dy-doped MnCO₃ NPs (MPMSXL-7, Quantum Design, USA).

2.6 Thermal behavior analysis

Thermal decomposition behavior of the Mn–oleate in the presence or absence of Dy–oleate was recorded on a Perkin-Elmer simultaneous thermogravimetric (TG) analyzer (STA8000), gas chromatography-mass spectrometry (SQ8 GC-MS) coupled with a Fourier transform infrared spectrometer (FTIR). The Mn/Dy–oleate and the pure Mn–oleate with equivalent amount of oleate were heated up from 30 to 500 °C at a heating rate of 10 °C min⁻¹ in the helium atmosphere for recording TG-DTG curves, respectively. Meanwhile, the composition of the evolved gas phase during thermal decomposition was monitored using a GC-MS, which was connected to the TG instruments with an overall scan in the mass range m/z = 1–200.

2.7 Cytotoxicity assay

The cytotoxicity of water-dispersible Dy-doped MnCO₃ NPs was evaluated by standard MTT cell viability assay. C6 glioma cells were seeded in a 96-well plate at a density of 1 × 10⁴ cells per well and incubated for 24 hours. The DMEM culture media containing various concentrations of Dy-doped MnCO₃ NPs was applied into the seeded cells and co-incubated for another 24 h. At the end of the incubation, the culture media were removed, and 100 μL of MTT solutions (dissolved in PBS with a finial concentration of 0.5 mg mL⁻¹) were added. After incubation for another 4 h, the medium was replaced with dimethyl sulfoxide (DMSO) to dissolve the purple formazan product. The optical density values were monitored by a microplate reader (Thermo Electron Corporation, USA) at the wavelength of 570 nm. The cytotoxicity was expressed compared to untreated control cells, and data were presented as the mean value with standard deviations from three independent experiments.

2.8 Relaxivity measurement

The TETT modified Dy-doped MnCO₃ NPs were dispersed in distilled water with a Mn concentration of 0.5, 0.25, 0.125, 0.0625, and 0.03125 mM. The relaxation rates (1/T₁) and T₁ maps of the dispersions of Dy-doped MnCO₃ NPs were acquired on a 7 T MR scanner (Bruker Pharmascan, Germany) with the following parameters: echo time (TE) = 11.00 ms, repetition times (TR) = 200, 400, 800, 1500, 3000, 5000 ms; field of view (FOV) = 4.0 × 4.0 cm², flip angle (FA) = 180° and slice thickness = 1 mm.

2.9 Brain glioma model

All animal experiments were in accordance with the National Institute of Health Guide for Care and Use of Laboratory Animals (publication no. 85-23, revised 1985) and the protocol approved by the ethical committee of Capital Medical University (Beijing, China). Mice were anesthetized with an intraperitoneal administration of 6% chloral hydrate at a dose of 0.10 mL/20 g of body weight. Approximately 5 × 10⁵ C6 glioma cells in 5 μL of PBS were injected into the left striatum with a 10 μL micro-injector. MR imaging was performed when the tumor size reached about 1.5–1.8 mm in diameter.

2.10 In vivo MR imaging of brain glioma

The glioma-bearing mice were anesthetized with 6% chloral hydrate at a dose of 0.10 mL/20 g of body weight. The glioma-bearing mice were then injected via tail vein at a dosage of 20 mg Mn per kg of body. The mice were imaged before and at different time points after the NPs injection by using RARE-T₁-map MRI sequence under the following parameters: TR/TE = 300/8 ms, matrix = 256 mm × 256 mm, FOV = 25 mm × 25 mm, slice thickness = 0.8 mm.

3. Results and discussion

3.1 Characterization of Dy-doped MnCO₃–OA NPs

The morphology and size of NPs obtained by thermal decomposition of Mn–oleate in the presence of Dy–oleate were examined by high resolution TEM (HRTEM). As shown in Fig. 1A, the resultant oleate-capped NPs are well separated and in rhombohedra shape with a size of about 9 nm, which is similar to that of Gd-doped MnCO₃ NPs. The crystallinity of NPs was evidenced by the well-resolved lattice fringes and the interplanar spacings of these lattice fringes were measured to be 0.247 nm and 0.377 nm, corresponding to the (110) and (012) planes of MnCO₃, respectively. The crystalline nature of NPs was further supported by polycrystalline diffraction rings in the selected area electron diffraction (SAED) pattern (Fig. 1B), which could be indexed to rhombohedral MnCO₃. Meanwhile, the elemental composition of NPs analyzed by energy dispersive spectroscopy (EDS) verified the presence of Dy in addition to Mn, O and C elements (Fig. 1C). The HRTEM characterization thus confirms that thermal decomposition of Mn–oleate in the presence of Dy–oleate also leads to the formation of MnCO₃ NPs. The successful preparation of Dy-doped MnCO₃ NPs in current study and Gd-doped MnCO₃ NPs in our previous work thereby suggests that thermal decomposition of Mn–oleate in the presence of RE–oleate could be applied as a general protocol to produce RE-doped MnCO₃ NPs.

Fig. 1 High-resolution TEM image (A), SAED pattern (B), EDS spectrum (C), and M–H curve (D) of the Dy-doped MnCO₃–OA NPs. Inset in (D) shows an enlarged view of the hysteresis loop at 5 K and 300 K, respectively.

Additionally, the magnetic properties of the Dy-doped MnCO₃–OA NPs were investigated by SQUID magnetometer. The field-dependent magnetization (M–H) curves of the Dy-doped MnCO₃–OA NPs in Fig. 1D showed a smooth straight line with the zero coercivities and remanances at 300 K, while the coercivity and remanence at 5 K were 20 Oe and 0.1 emu g⁻¹, respectively. This confirms that Dy-doped MnCO₃–OA NPs are paramagnetic at room temperature while ferromagnetic at low temperature. Such paramagnetic behavior suggests the potential of MnCO₃ NPs to enhance the MR T₁ contrast.

3.2 Evolutional formation of MnCO₃ NPs

To trace the nucleation and growth progress of Dy-doped MnCO₃–OA NPs during the thermal decomposition process, the solid samples collected at different stages were characterized by TEM, Raman and XRD. Fig. 2A presents the TEM image of solid samples collected at 280 °C for 12 min when the reaction solution changed from transparent to cloudy. It was noted that these intermediate species were in irregular spherical shape with an average size of about 4.55 ± 0.67 nm as measured from 100 individual particles (inset, Fig. 2A). While at 280 °C, 30 min, the size of intermediate species increased to 6.78 ± 0.78 nm (inset, Fig. 2B). When the temperature was raised to 305 °C for 10 min, a significant shape change from spherical to rhombus (Fig. 2C) was observed, indicating the formation of MnCO₃ NPs and the size further increased to 9.27 ± 0.72 nm (inset, Fig. 2C). Note that the size distribution revealed that the NPs undergoes a size broadening and then focusing process, indicative of the Ostwald ripening process.³⁴

Fig. 2 TEM images and their size distribution (inset) of solid samples collected at 280 °C, 12 min (A), 280 °C, 30 min (B), and 305 °C, 10 min (C). Raman spectra (D) and XRD patterns (E) of corresponding solid samples.

The evolutional formation of MnCO₃ NPs observed on the TEM images was further supported by Raman spectra. In Raman spectra (Fig. 2D), the peaks at 1300 and 1438 cm⁻¹ are assigned to –CH₂– group of capping oleate acid molecules and another peak at 1085 cm⁻¹ is attributed to the characteristic CO₃²⁻ group of MnCO₃. Obviously, the intermediate species collected at 280 °C, 12 min displayed a strong –CH₂– band of oleate acid while the characteristic CO₃²⁻ band was negligible. However, at 280 °C, 30 min, a broad CO₃²⁻ band appeared, indicating the formation of MnCO₃ with low crystallinity. This CO₃²⁻ band became sharp and intensive at 305 °C, 10 min, suggesting the formation of high crystalline MnCO₃ NPs.³⁵

The evolutional formation of MnCO₃ NPs was additionally proved by XRD (Fig. 2E). As can be seen, the XRD patterns of both intermediate species were different from that of the MnCO₃ NPs and hard to interpret. However, the characteristic diffraction peaks at 2θ = 31.4°, 45.2° and 51.7° of MnCO₃ could be observed in the XRD patterns. The XRD pattern of final product collected at 305 °C, 10 min showed a pure MnCO₃ phase (JCPDS card no. 44-1472), suggesting the formation of highly crystalline MnCO₃ NPs.

3.3 Formation mechanism of MnCO₃ NPs

The thermal decomposition of metal–oleate leads to the formation of metal oxide along with byproducts such as CO₂, H₂, water, ketones, esters, and hydrocarbons with various chain lengths.³¹ When RE–oleate was introduced, however, thermal decomposition of Mn–oleate led to the formation of MnCO₃ NPs instead of MnO NPs. To understand the underlying formation mechanism of MnCO₃ NPs, the evolved gaseous products during the thermal decomposition of Mn–oleate in the presence of Dy–oleate were analyzed by TG-FTIR-GC/MS. For comparison purpose, the gaseous products during the thermal decomposition of pure Mn–oleate under the same conditions were also analyzed.

The obtained TG and corresponding differential thermogravimetry (DTG) curves were employed to investigate the mass loss event. As presented in Fig. 3A, thermal decomposition of organic component, e.g. the oleate, started at 250 °C for either pure Mn–oleate or the mixture of Mn/Dy–oleate. The mass-loss rate for pure Mn–oleate, however, was faster than that of Mn/Dy–oleate. As a result, the TG curve of pure Mn–oleate in the temperature range of 250–305 °C, during which the nucleation and growth of the NPs occurred, revealed a weight loss of 9.72%, whereas, only 6.56% in weight loss was found for Mn/Dy–oleate in the same temperature regime (inset in Fig. 3A). Such difference was more pronounced in DTG profiles and thus suggests that part of gaseous products is retained in the system due to the presence of Dy.

Fig. 3 (A) TG and DTG curves of the thermal decomposition of Mn–oleate (black) and Mn–oleate/Dy–oleate (red). (B) Selected MS scans of the decomposition products. Fragments: m/z = 18 (H₂O), m/z = 44 (CO₂), m/z = 56 (C₄H₈), m/z = 58 (C₄H₁₀), m/z = 70 (C₅H₁₀) and m/z = 84 (C₆H₁₂). (C) FTIR spectra of gaseous products from the decomposition at the temperature from 250 to 310 °C with a 15 °C increment. (D) The normalized absorbance of FTIR bands for CO₂ at 2350 cm⁻¹ and H₂O at 1518 cm⁻¹.

To identify the products corresponding to the weight loss, GC-MS was applied. Fig. 3B illustrates the mass chromatograms of the products with high-abundance fragments released from the thermal decomposition. It was revealed that the weight loss in the temperature range of 250–305 °C was primarily due to CO₂ (m/z = 44) and H₂O (m/z = 18). The release of CO₂ is due to the ketonic decarboxylation reaction while the release of H₂O might originate from the recombination and decomposition of radical species produced in the thermal decomposition process.³¹ Notably, the CO₂ and H₂O released from the thermal decomposition of Mn–oleate in the presence of Dy–oleate (red line) is much less than that of pure Mn–oleate (black line), which is in good agreement with TG analysis. It is known that rare earth ion could coordinately adsorb H₂O and CO₂. Thus, it is rational to propose that part of evolved H₂O and CO₂ could be adsorbed by Dy in this case, which are subject to converting to CO₃²⁻, and then reaction with Mn to ultimately form MnCO₃ NPs (Fig. 4). In addition, it was found that the oleate continued to decompose when temperature was above 320 °C and generated a variety of hydrocarbon fragments with m/z values in the range of 40–150. As a representative example of these fragments, Fig. 3B shows the curves for m/z = 56, 58, 70 and 84.

Fig. 4 Schematic illustration of proposed formation mechanism of Dy-doped MnCO₃ NPs through thermal decomposition of Mn–oleate in the presence of Dy–oleate.

The production of CO₂, H₂O, and hydrocarbon fragments during the thermal decomposition was further confirmed by the FTIR spectra. The FTIR spectra collected at temperature between 250 and 310 °C with a 15 °C increment are presented in Fig. 3C. Noted that all acquired FTIR spectra showed characteristic bands of water vapor (i.e. the broad band at 3500–4000 cm⁻¹ and the band at 1518 cm⁻¹ assigned to the stretching and bending modes of O–H, respectively) and CO₂ gas (i.e. the band at 2350 cm⁻¹ due to the C=O stretching vibrations mode). Nevertheless, the normalized absorbance (Fig. 3D) of IR bands for CO₂ at 2350 cm⁻¹ and H₂O at 1518 cm⁻¹ in case of thermal decomposition of Mn/Dy–oleate was less than that of pure Mn–oleate indicated, verifying that the decreased release of CO₂ and H₂O due to the presence of Dy. In addition, the –CH₂ and –CH₃ bands between 2800 and 2950 cm⁻¹ due to the hydrocarbon fragments was observed above 280 °C, which is consistent with the results of TG/DTG and GC-MS.

3.4 Cytotoxicity

For biomedical application, it is essential to render the Dy-doped MnCO₃ NPs water dispersible. This was accomplished by replacing the oleate with TETT silane. The hydrodynamic diameter of TETT modified Dy-doped MnCO₃ NPs were approximately 100 nm. Note that the increase in size, an indicative of aggregation of NPs, is the common phenomenon when converting hydrophobic NPs to hydrophilic ones. Nonetheless, no significant change in the hydrodynamic diameter of TETT modified Dy-doped MnCO₃ NPs up to 48 h (Fig. S1†), suggesting the good colloidal stability.

Cytotoxicity is usually considered as one of the most crucial factors to determine whether the NPs could be ultimately applied in small-animal experiments. Therefore, prior to the in vivo MR imaging application, the cytotoxicity of TETT modified Dy-doped MnCO₃ NPs towards C6 cells was evaluated by MTT assay. Fig. 5 presents the obtained viability of C6 cells upon incubation with Dy-doped MnCO₃ NPs at different Mn concentrations. As can be seen, even the concentration of Mn was up to 200 μM, the cell viability was still higher than 85%, suggesting that Dy-doped MnCO₃ NPs have a relatively low cytotoxicity.

Fig. 5 The viability of C6 glioma cells after 24 h incubation of Dy-doped MnCO₃ NPs at various Mn concentrations. Each data represents the mean ± SD of three independent experiments.

3.5 MR imaging

To evaluate the efficiency of Dy-doped MnCO₃ NPs as an MR T₁ contrast agent, the relaxation times and the corresponding T₁ maps of Dy-doped MnCO₃ NPs dispersed in water at different Mn concentrations were measured on a 7 T MRI scanner. The r₁ relaxivity value of Dy-doped MnCO₃ NPs was then calculated from the slope of the linear curve of inverse relaxation time. As plotted in Fig. 6A, the r₁ of Dy-doped MnCO₃ NPs was determined to be 4.536 mM⁻¹ s⁻¹, which is greater than that of most MnO NPs reported in the literature.^{18,21,22,36,37} The corresponding T₁ maps exhibited a continuous increase in brightness, further demonstrating the potential of Dy-doped MnCO₃ NPs as an efficient T₁ contrast agent.

Fig. 6 (A) The relaxivity (T₁) measurement of the water dispersible Dy-doped MnCO₃ NPs. (B) T₁-Weighted MR images of mice brain harbouring glioma pre- and 30 min post-injection of MnCO₃ NPs.

Inspired by the high r₁ relaxivity and low cytotoxicity, the feasibility of Dy-doped MnCO₃ NPs as an MR contrast agent was explored in vivo using the glioma-bearing mice on a 7 T MRI scanner. The obtained T₁-weighted MR images before and after injection of Dy-doped MnCO₃ NPs at a dosage of 20 mg Mn per kg body are shown in Fig. 6B. Apparently, Dy-doped MnCO₃ NPs exhibited a notable contrast enhancement in the glioma 30 min post-injection compared to the pre-injection image, verifying the applicability of Dy-doped MnCO₃ NPs as an effective MR contrast agent for the brain glioma imaging.

4. Conclusions

In summary, the Dy-doped MnCO₃ NPs were synthesized through the thermal decomposition of Mn–oleate in the presence of Dy–oleate. Base on the information provided by TG-FTIR-GC/MS, it is proposed that part of CO₂ and H₂O produced during the thermal decomposition process could be adsorbed by Dy, which is responsible for the formation of Dy-doped MnCO₃ NPs. Our findings suggest that the thermal decomposition of Mn–oleate in the presence of RE–oleate could be applied as a general and straightforward protocol to prepare RE-doped MnCO₃ NPs, which hold great potential in serving as novel bio-imaging agents.

Acknowledgements

The authors gratefully acknowledge the financial supports from the National Natural Science Foundation of China (81271639), the Key Project from Beijing Commission of Education (KZ201610025022), and the Beijing Natural Science Foundation (7162023).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra20347g

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