Facile solvothermal synthesis and functionalization of polyethylene glycol-coated paramagnetic Gd2(CO3)3 particles and corresponding Gd2O3 nanoparticles for use as MRI contrast agents

This work develops that study to produce functionalized gadolinium carbonate (Gd2(CO3)3) for use as an MRI contrast agent, characterizing and interpreting the effects of different heating times. The (Gd2(CO3)3) was then used as a single precursor for synthesizing Gd2O3 nanoparticles by a novel calcination pathway at different heating temperatures.

Journal of Science: Advanced Materials and Devices (2019) 72e79 Contents lists available at ScienceDirect Journal of Science: Advanced Materials and Devices journal homepage: www.elsevier.com/locate/jsamd Original Article Facile solvothermal synthesis and functionalization of polyethylene glycol-coated paramagnetic Gd2(CO3)3 particles and corresponding Gd2O3 nanoparticles for use as MRI contrast agents Atika Dougherty a, b, c, *, Erika L.Y Nasution a, Ferry Iskandar a, d, Geoff Dougherty c a Department of Physics, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Jl Ganesha 10, Bandung 40132, Indonesia Department of Physics, Faculty of Science and Technology, Nusa Cendana University, Jl Adi Sucipto, Kupang 85001, Indonesia Applied Physics and Medical Imaging, California State University Channel Islands (CSUCI), Camarillo, CA, 93012, USA d Research Center for Nanosciences and Nanotechnology, Institut Teknologi Bandung, Bandung 40132, Indonesia b c a r t i c l e i n f o a b s t r a c t Article history: Received 27 October 2018 Received in revised form 13 December 2018 Accepted 16 December 2018 Available online 23 December 2018 Paramagnetic particles and nanoparticles have been widely used in bioimaging and biomedical applications In this paper, functionalized gadolinium carbonate (Gd2(CO3)3) particles with polyethylene glycol (PEG) for use as an MRI contrast agent were produced These PEGylated particles were also used as a single precursor for synthesizing Gd2O3 nanoparticles by a novel calcination pathway The morphological, chemical, and structural properties of both the PEGylated Gd2(CO3)3 particles and Gd2O3 nanoparticles were examined using a scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), and energy dispersive X-ray spectroscopy (EDS) techniques After the calcination process at a temperature of 800  C, the amorphous, rhombus flakes of PEGylated Gd2(CO3)3 were converted into crystalline nanospherical Gd2O3 particles with an average diameter of 80 nm The hydrophilic polymer coating of PEG successfully attached to the Gd2(CO3)3 particles which resulted in high dispersibility and stability in a water based solution The magnetic properties were investigated using a vibrating sample magnetometer (VSM), which showed that the PEGylated Gd2(CO3)3 and Gd2O3 exhibit paramagnetic character Furthermore, in vitro magnetic resonance imaging (MRI) demonstrated that PEGylated Gd2(CO3)3 particles show a promising T1 weighted effect and could potentially serve as a T1 MRI contrast agent © 2018 The Authors Publishing services by Elsevier B.V on behalf of Vietnam National University, Hanoi This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Keywords: Gd2(CO3)3 Gd2O3 PEG Solvothermal Calcination Contrast agent Introduction Magnetic particles are a major class of material with potential applications in biomedicine Paramagnetic or superparamagnetic particles have been used in magnetic resonance imaging (MRI) contrast enhancement, tissue repair, hyperthermia, drug delivery, and in cell separation [1e5] Gadolinium is strongly paramagnetic at the ambient temperature and gadolinium complexes have been widely used as MRI contrast agents [6] * Corresponding author Applied Physics and Medical Imaging, California State University Channel Islands (CSUCI), Camarillo, CA, 93012, USA Fax: ỵ1 8054378864 E-mail addresses: atika.ahab@mail.com (A Dougherty), Erika.nasution@asiamail.com (E.L.Y Nasution), ferry.iskandar@email.com (F Iskandar), geoff dougherty@csuci.edu (G Dougherty) Peer review under responsibility of Vietnam National University, Hanoi Gadolinium ions (Gdỵ ) are toxic and must be transformed into a biocompatible, chelated form for biomedical applications For this purpose, two representative strategies are used to functionalize it They are the ligand exchange and the encapsulation within a biocompatible shell [7e9], among which the encapsulation method has several advantages and is an inexpensive process [10] Polyethylene glycol (PEG) is widely used as a highly biocompatible shell to encapsulate magnetic nanoparticles [11] Using PEG solvent as the liquid environment affects the generated particles since the PEG serves as a template that regulates the shape of the particles so that they become spherical, soluble, and form a biocompatible particle layer PEG also minimizes agglomeration, thus the particle size is reduced and its size distribution is sharpened [12] The functionalization of PEG to gadolinium complex particles produces PEGylated gadolinium with biocompatible and monodisperse properties, while largely maintaining the powerful magnetic moment of gadolinium [13] https://doi.org/10.1016/j.jsamd.2018.12.005 2468-2179/© 2018 The Authors Publishing services by Elsevier B.V on behalf of Vietnam National University, Hanoi This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) A Dougherty et al / Journal of Science: Advanced Materials and Devices (2019) 72e79 The hybrid forms of inorganic gadolinium nanoparticles, e.g gadolinium oxide (Gd2O3), gadolinium hydroxide (Gd(OH)3), and gadolinium carbonate (Gd2(CO3)3), are remarkable as T1 MRI contrast agents [8,13e16] Synthesis products of gadolinium carbonate particles have a high T1 under clinical external magnetic fields [17], and silica coated Gd2(CO3)3 particles have been reported as a multifunctional contrast agent [18] Ultra-small Gd2(CO3)3 nanoparticles have shown a strong performance in MRI applications [19,20] PEGylated Gd2O3 nanoparticles have been synthesized by a single step thermal decomposition method [21] In that work, molecules of PEG successfully attached to the nanoparticle surface allowing the nanoparticles to be dispersed and functionalized to other organic materials Encapsulating Gd2O3 nanoparticles in a dendrimer template, in a multi-step synthesis, could produce a dual (T1 and T2) MRI contrast agent [22] The solvothermal method has become a promising method for the fabrication of well crystallized and biocompatible gadoliniumbased magnetic particles [23] It is a single step, simple procedure at low temperature, cost effective and easy to scale However, for this method, the particles grow in one direction resulting in a 1D morphology of the particles To suppress this 1D growth, the synthesis procedure needs to be improved One simple strategy is by using a polymer as a liquid medium to encapsulate the particle surface and constrain the growing particle in all directions Polyethylene glycol (PEG) at a sufficient ratio is often used in procedures to obtain spherical particles with a sharpened size distribution [12] and a biocompatible shell [7,24] It disperses the magnetic particles which is important in functionalizing them to other organic materials such as antibodies, proteins, transferring agents, and folic agent [25] We have presented preliminary details of a modified solvothermal method for the synthesis of PEGylated Gd2(CO3)3 particles [26] This work develops that study to produce functionalized gadolinium carbonate (Gd2(CO3)3) for use as an MRI contrast agent, characterizing and interpreting the effects of different heating times The (Gd2(CO3)3) was then used as a single precursor for synthesizing Gd2O3 nanoparticles by a novel calcination pathway at different heating temperatures Special attention was given to the transformation of the PEGylated Gd2(CO3)3 particles to Gd2O3 nanoparticles by analyzing the collected samples at different synthesis steps using scanning electron microscope (SEM) data The crystallization and chemical structures were established by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) spectroscopy, and energy dispersive X-ray spectroscopy (EDS) We have proposed a schematic of the transformation of the PEGylated Gd2(CO3)3 particles to the corresponding Gd2O3 nanoparticles by the solvothermal-calcination process The magnetization properties, including magnetization versus magnetic field, were investigated using a Vibrating Sample Magnetometer (VSM) Finally, the colloid particles of PEGylated Gd2(CO3)3 were investigated for an in vitro MRI effect Experimental 2.1 Synthesis of PEGylated gadolinium carbonate and gadolinium particles PEGylated Gd2(CO3)3 particles were synthesized by a modified solvothermal method In general, 40 g of polyethylene glycol (PEG1000, MW ¼ 1000, Merck) was melted at 60  C for 20 3.6 mmol gadolinium acetate hydrate (Gd(CH3CO2)3$XH2O, Aldrich) was dispersed to the solution After the formation of a clear solution, the solution was put into a Teflon-lined stainless steel autoclave at room temperature The autoclave was then sealed and maintained 73 at a temperature at 180  C for various heating times (3, 5, and h) The precipitate formed was cooled to 60  C and then 60 mL acetone and mL hexane were added to facilitate the separation process At room temperature, this brown solution was centrifuged at 4000 rpm for 20 and washed several times with acetone to remove the excess polymer The powders were obtained by drying the precipitates at 60  C for 24 h The resulting PEGylated Gd2(CO3)3 powders were taken as a precursor for the synthesis of Gd2O3 nanoparticles The dried powder precursor was calcined at different temperatures (400  C and 800  C for h) 2.2 Characterization The morphology and elemental contents of the samples were examined by scanning electron microscopy (SEM) and Electron Dispersive X-Ray spectroscopy (EDS), using a JeolBenchtop JCM6000 X-ray diffraction (XRD) patterns of the samples were recorded by means of Philips Analytical PW 1710 based diffractometer with CuKa ¼ 1.54 Å The chemical composition and surface morphology of the particles were determined using Fourier transform infrared spectroscopy (Bruker Alpha I FTIR) The magnetization was measured using a Vibrating Sample Magnetometer (VSM 1.2 H Oxford) at 27  C 2.3 Magnetic Resonance Imaging Magnetic Resonance Imaging (MRI) was performed at 1.5 T with a clinical MRI instrument (GE Healthcare) using a spin echo (SE) sequence with TE ¼ ms, TR ¼ 100 ms, and a 90 flip angle An channel head coil was used for RF transmission and reception For in vitro T1 weighted imaging, agarose phantoms were constructed We chose PEGylated Gd2(CO3)3 samples for the phantoms because the samples have high dispersibility properties in water based solutions In our protocol, the Gd2(CO3)3@PEG powder was dispersed in 0.3% agarose gel (Agarose BioReagent, Sigma Aldrich) with various gadolinium mass variations (0, 0.05, 0.010, 0.015, and 0.020 g) The T1 weighted images were analyzed using MIPAV software (NIH, Bethesda, Maryland) to investigate the correlation between the phantom intensity and concentration of the powder samples Results and discussion The morphology of the solvothermal products were determined using SEM micrograph images of the samples, as shown in Fig Fig 1(aec) showed that the Gd2(CO3)3 powder was composed of agglomerated particles of micrometer size which were formatted as flakes with a rhombus shape The size of the Gd2(CO3)3 particles increased as a function of the heating time The agglomeration could be due to the use of the high weight polymer of PEG as the liquid medium in the solvothermal process The long chain of the PEG polymer contains many hydrogen bonds which induce dipole interactions causing particle agglomeration [27] The size and shape of rare-earth carbonate particles is known to depend on reaction time [9] The morphology of the Gd2O3 powder obtained at a calcination temperature of 400  C (Fig 1(d)) shows the appearance of a molten material which indicates that the PEG is not completely released from the Gd2O3 products At a calcination temperature of 800  C (Fig 1(e)), the PEG is completely released and this results in homogenous spherical particles with a size of about 80 nm PEG encapsulated in the core of the particle prevents the growth in all directions during the calcination process [28] This resulted in the production of spherical and uniform Gd2O3 particles of 74 A Dougherty et al / Journal of Science: Advanced Materials and Devices (2019) 72e79 Fig SEM micrograph of solvothermal products decomposed at 180  C for (a) 3, (b) 5, (c) h, and the subsequent calcination products at (d) 400  C and (e) 800  C nanometer size Although functionalized Gd2O3 with PEG could not be achieved in this process, the nanospherical shape has a higher surface energy due to its high surface to volume ratio [29] For biomedical applications, it also has a higher blocking temperature which is useful for hyperthermia treatment [30] Furthermore, the uptake of spherical nanoparticles by cells is found to be considerably easier providing superior drug delivery and targeting compared to other shaped nanoparticles, resulting in its possible use as an effective and efficient contrast agent [31] It has been reported that magnetic materials with various morphologies such as sphere, porous, hollow, wire, rods, and flakes can be prepared by various solution-based methods [32e34] Such methods are convenient for synthesizing biomaterials, since they allow easy modification of synthesis parameters such as pH values, solute/ solvent ratios, and reaction temperatures/times EDS analysis was performed on the PEGylated Gd2(CO3)3 particles and the Gd2O3 nanoparticles produced after calcination of the Gd2(CO3)3 to determine the components that exist in the samples (Fig 2) The detailed composition of the samples before and after calcination are shown in Tables and respectively For Gd2(CO3)3, Gd, C, and O elements were detected, however, the corresponding composition is not in agreement with the stoichiometry of Gd2(CO3)3 Instead, it exhibited the presence of high C and O contents from PEG molecules which confirms that PEG successfully attached to Gd2(CO3)3 as PEGylated Gd2(CO3)3 particles Table shows an increase in Gd and O content after the calcination process for samples under investigation The calcination at high temperature leads to a loss of the C and O elements and thus it is free from the PEG content However, traces of C and O from the PEG at 400  C can still be detected This is demonstrated by the slight difference between the molar ratio and the stoichiometric ratio After calcination at 800  C, the molar ratio of Gd to O for calcined samples was close to the stoichiometric ratio, suggesting the formation of Gd2O3 This indicates that C from the PEG could be easily removed via thermal treatment at high temperatures The solvothermal products decomposed with heating times of 3, 5, and h (Fig 3(a)) and the calcined products at 400 and 800  C (Fig 3(b)) were analyzed by XRD measurements to identify the resulting particles and to examine the crystallinity and the phase of the samples In Fig 3(a), the XRD patterns of the sample at h heating time showed no apparent peaks which indicates an amorphous crystal structure The XRD patterns obtained for the samples at and h heating times exhibited a highly crystalline structure and the peaks closely coincided with JCPDS 37-0559 Both results suggest that the samples could be assigned to the rhombus gadolinium carbonate Gd2(CO3)3 with hexagonal phase [35] The strongest diffraction peaks at 2q ¼ 11.75 were used to calculate the average crystallite size of Gd2(CO3)3 heated for h and h by using the Scherrer's formula, D ¼ kl/b cos q, where D is the average crystallite size, k (0.9) is the shape factor, l is the X-ray wavelength (1.5 Å), b is the line broadening at half the maximum intensity (FWHM) and q is the diffraction angle of an observed peak, respectively This yields an average crystallite size of about 4.6 nm (at h) and about 3.5 nm (at h) As can be seen in Fig 3(a), the intensities of the main peaks broaden and decrease with increased heating time, indicating that the crystallinity of the sample Gd2(CO3)3 synthesized in h had the highest crystallinity The broadening diffraction peaks were caused by a large amount of carbon and water molecules coordinating to gadolinium carbonate during the longest synthesis time [36,37] The diffraction spectra for the and h heated samples also show additional peaks at the 2q z 10e11 region which can be attributed to neither Gd(OH)3 nor Gd2O3 [21,38] When the Gd2(CO3)3 A Dougherty et al / Journal of Science: Advanced Materials and Devices (2019) 72e79 75 Fig Energy dispersive X-ray spectroscopy (EDS) images of the PEGylated Gd2(CO3)3 particles decomposed at 180  C for (a) 3, (b) 5, (c) h and the calcined products at (d) 400  C and (e) 800  C precursor sample at h heating time was calcined at 400  C the phase transition from Gd2(CO3)3 to Gd2O3 took place with broadening peaks assigned to the (222) and (431) planes (Fig 3(b)) with an average crystallite size, D z 24.5 nm A broadened band at the peaks was attributed to carbon materials from the molecular coating of the particles with polyethylene glycol [39] This is similar to those observed in PEGylated Gd2O3 nanocrystals as reported by Table Elemental analysis of PEGylated Gd2(CO3)3 particles obtained by modified solvothermal method Element C O Gd Total Weight % Theory 3h 5h 8h 7.28 29.12 63.60 100 10.48 13.53 75.98 100 26.84 24.23 48.95 100 48.87 11.63 41.63 100 € derlind et al [40], Faucher et al [7], and Ahab et al [21] This So indicates that after being calcined at 400  C, PEG molecules still attach to the calcination product The complete amorphouscrystalline pure cubic phase conversion of Gd2O3 was identified with increasing the temperature to 800  C In this case, all the diffraction peaks are in good agreement with the standard JCPDS 43-1014 The calcination process at higher temperatures reduced the average crystallite size to 2.2 nm Table Elemental analysis of Gd2O3 nanoparticles obtained by calcination treatment Element O Gd Total Weight % Theory 400  C 800  C 13.24 86.76 100 14.73 85.27 100 13.30 86.70 100 76 A Dougherty et al / Journal of Science: Advanced Materials and Devices (2019) 72e79 Fig Evolution of XRD patterns at different heating times for the solvothermal products (a) and at different heating temperatures for the calcined products (b) The FTIR characteristic spectra were determined to study the chemical composition of the PEGylated Gd2(CO3)3 at different heating times (Fig 4(a)), and the calcined (Gd2O3) nanoparticles samples at different temperatures (Fig 4(c)) Assignments of vibration modes for PEG 1000 and Gd2(CO3)3 are given in Tables and In Table and the corresponding IR spectra of PEG 1000 are illustrated in Fig 4(a) It is clearly seen that, the PEG has a IR characteristic absorption spectrum at 3458 cmÀ1 which is assigned to ʋas-OeH stretching The peaks at 2875, 1342, and 950 cmÀ1 are due to the presence of characteristic bands of ʋ-CeH and d-CeH, respectively The absorption band occurring at 1104 cmÀ1 is assigned to ʋ-CeOeC stretching [24,41] When gadolinium acetate hydrate samples were decomposed at 180  C with different heating times, the IR spectrum still exhibites CeOeC and Fig FTIR spectra of (a) PEGylated Gd2(CO3)3 particles at different heating times with (b) the magnified absorption spectra in the region 500e1000 cmÀ1 of the sample decomposed in h and (c) the Gd2O3 nanoparticles produced as a function of calcination temperature A Dougherty et al / Journal of Science: Advanced Materials and Devices (2019) 72e79 Table FTIR spectroscopy absorption bands of PEG-1000 Assignments FTIR (cmÀ1) ʋas-OeH ʋs-CeH d-CeH ʋ-CeOeC 3458 2875 1342 and 950 1104 Table FTIR spectroscopy absorption bands of Gd2(CO3)3 Assignments FTIR (cmÀ1) ʋas-OeCeO ʋs-CO2e d-CO2e 1536 and 1417 842 797 CeH bands, although their intensity had decreased and additional peaks appeared at 1542 and 1465 cmÀ1 which are assigned to the ʋas-OeCeO band This band is a result of the partial oxidation of the CH2eOH PEG band at temperatures above 150  C [7,42] and also indicates the formation of gadolinium carbonate [17,19,43] Moreover, absorption spectrum with lower intensity occurred at 947 cmÀ1 due to CH2 bending from PEG which indicates that PEG molecules still attach to the Gd2(CO3)3 samples as PEGylated Gd2(CO3)3 Fig 4(b) demonstrates a magnification of the absorption spectra in the region 500 - 1000 cmÀ1 for the sample decomposed in h The figure shows the formation of the gadolinium carbonate assigned by three characteristic IR absorption peaks (Table 4), 2e À1 À1 OeCeO, p-CO2e (848 cm ), and d-CO3 (729 cm ) [17,18,35,43] 2e which only appear after h of heating The p-CO2e and d-CO3 are related to the gadolinium acetate hydrate decomposition to form the gadolinium carbonate [7] Fig 4(b) also shows the presence of absorption peaks in the region of 668 cmÀ1 e 804 cmÀ1 which are due to the interaction between d-OeCeO and gadolinium metal oxide [44] The PEGylated Gd2(CO3)3 product at h heating was used in the calcination process to produce Gd2O3 nanoparticles When the sample calcined at 400  C (Fig 4(c)), CO2 molecules were released so that the intensity of the characteristic ʋ-OeH, 77 ʋas-OeCeO, and CeOeC absorption bands (at 3302, 1512, and 1383 cmÀ1) decreased compared to the gadolinium carbonate precursor sample The high intensity vibration characteristic of GdeO presented at 521 cmÀ1 [39,45], which was confirmed by XRD results Upon further calcination at 800  C, the characteristic PEGylated carbonate molecule bands completely vanished which resulted in a sharper GdeO peak The sharpness of the GdeO peak after calcination at 800  C indicates that the PEGylated molecules did not absorb onto the Gd2O3 nanoparticle surface Based on the morphological and chemical analysis, we propose the following schematic transformation of PEGylated Gd2(CO3)3 particles to the corresponding Gd2O3 nanoparticles by the solvothermal e calcination process (Fig 5) This pathway is an alternative to the recently proposed direct functionalization of gadolinium oxide nanoparticles by pulsed laser ablation in a liquid medium (PLAL) [46] The magnetic properties of the PEGylated Gd2(CO3)3 particles and Gd2O3 nanoparticles were measured by VSM at room temperature The obtained magnetization curves (M-H) are shown in Fig Notes that, for both samples, a near-linear relationship between magnetization and applied field is exhibited The positive slope and lack of coercivity or remanence indicates that both these samples were paramagnetic The magnetic susceptibility (the slope of the curve) of pegylated Gd2(CO3)3 is less than that of Gd2O3, i.e 8.08 Â 10À5 emu/g in compare with 1.12 Â 10À4 emu/g, respectively The higher susceptibility value of the Gd2O3 nanoparticles can be attributed to their high surface-to-volume ratio due to a considerable fraction of the Gd atoms being located at the surface of the crystals [9,47] Because of the functionalization of PEG on Gd2(CO3)3, these particles exhibit dispersibility properties in a water based medium We evaluated whether pegylated Gd2(CO3)3 would be useable as an MRI contrast agent by running in vitro assays of the T1 weighted of the samples in agarose gel using a series of Gd2(CO3)3 concentrations (Fig 7(a)) The resulting signal intensities (Fig 7(b)) are consistent with the concentrations of Gd2(CO3)3 particles in the samples, confirming that it is the PEGylated Gd2(CO3)3 particles which produce the T1 contrast enhancement The enhanced contrast intensity is due to the increased relaxation rate of the surrounding protons [22] Fig Synthesis and morphological transformation of PEGylated Gd2(CO3)3 particles to the corresponding Gd2O3 nanoparticles by the solvothermal e calcination process 78 A Dougherty et al / Journal of Science: Advanced Materials and Devices (2019) 72e79 References Fig Hysteresis curves obtained by VSM for (a) pegylated Gd2(CO3)3 particles and (b) Gd2O3 nanoparticles Fig (a) T1 weighted images of various amounts of Gd2(CO3)3 particles in agarose gel and (b) their resulting mean intensities (brightnesses) The images were obtained using standard spin echo (SE) sequence imaging for TE/TR ¼ 9/100 msec Conclusion PEGylated Gd2(CO3)3 rhombus flake particles were successfully synthesized by a modified solvothermal method With the PEGylated Gd2(CO3)3 particles as precursor, Gd2O3 nanoparticles of spherical shape were produced by a novel calcination pathway The XRD patterns confirmed the phase transition from a hexagonal carbonate phase to a pure cubic phase Gd2O3 Based on the morphological and chemical observations a formation mechanism was proposed The PEGylated Gd2(CO3)3 particles are highly dispersed and have been demonstrated to show a T1 enhancing effect, making them an attractive choice as a MRI contrast agent Acknowledgments The work was supported by a PKPI scholarship to A.D (9709/ D3.2/PG/2016) from the Directorate General of Higher Education and Ministry of Research and Technology, 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as an MRI contrast agent, characterizing and interpreting the effects of different heating times The (Gd2(CO3)3) was then used as a single precursor for synthesizing Gd2O3. .. modification of synthesis parameters such as pH values, solute/ solvent ratios, and reaction temperatures/times EDS analysis was performed on the PEGylated Gd2(CO3)3 particles and the Gd2O3 nanoparticles. .. direct functionalization of gadolinium oxide nanoparticles by pulsed laser ablation in a liquid medium (PLAL) [46] The magnetic properties of the PEGylated Gd2(CO3)3 particles and Gd2O3 nanoparticles