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

Synthesis products of gadolinium carbonate particles have a high T1 under clinical external magnetic ﬁelds [17] , and silica coated Gd 2 (CO 3 ) 3 particles have been reported as a mul[r]

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Original Article

Facile solvothermal synthesis and functionalization of polyethylene

Atika Doughertya,b,c,*, Erika L.Y Nasutiona, Ferry Iskandara,d, Geoff Doughertyc

a Department of Physics, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Jl Ganesha 10, Bandung 40132, Indonesia

b Department of Physics, Faculty of Science and Technology, Nusa Cendana University, Jl Adi Sucipto, Kupang 85001, Indonesia

c 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

a r t i c l e i n f o

Article history:

Received 27 October 2018

Received in revised form

13 December 2018

Accepted 16 December 2018

Available online 23 December 2018

Keywords:

Gd 2 (CO 3 ) 3

Gd 2 O 3

PEG

Solvothermal

Calcination

Contrast agent

a b s t r a c t

Paramagnetic particles and nanoparticles have been widely used in bioimaging and biomedical appli-cations 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 Gd2O3nanoparticles by a novel calcination pathway The morpholog-ical, chemmorpholog-ical, and structural properties of both the PEGylated Gd2(CO3)3particles and Gd2O3 nano-particles 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 calci-nation process at a temperature of 800C, the amorphous, rhombusﬂakes of PEGylated Gd2(CO3)3were converted into crystalline nanospherical Gd2O3particles with an average diameter of 80 nm The hy-drophilic polymer coating of PEG successfully attached to the Gd2(CO3)3particles 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)3and Gd2O3exhibit paramagnetic character Furthermore, in vitro magnetic resonance imaging (MRI) demonstrated that PEGylated Gd2(CO3)3particles 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/)

1 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]

Gadolinium ions (Gd3 þ) 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 biocom-patible 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 sharp-ened [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]

* Corresponding author Applied Physics and Medical Imaging, California State

University Channel Islands (CSUCI), Camarillo, CA, 93012, USA Fax: þ1

8054378864.

E-mail addresses: atika.ahab@mail.com (A Dougherty),

Erika.nasution@asia-mail.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.

Contents lists available atScienceDirect Journal of Science: Advanced Materials and Devices

j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / j s a m d

https://doi.org/10.1016/j.jsamd.2018.12.005

Journal of Science: Advanced Materials and Devices 4 (2019) 72e79

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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

car-bonate particles have a high T1 under clinical external magnetic

ﬁelds[17], and silica coated Gd2(CO3)3particles have been reported

as a multifunctional contrast agent [18] Ultra-small Gd2(CO3)3

nanoparticles have shown a strong performance in MRI

applica-tions[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 (T1and T2) MRI contrast agent[22]

The solvothermal method has become a promising method for

the fabrication of well crystallized and biocompatible

gadolinium-based 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

syn-thesis 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

Poly-ethylene 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

ma-terials such as antibodies, proteins, transferring agents, and folic

agent[25]

sol-vothermal method for the synthesis of PEGylated Gd2(CO3)3

par-ticles[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 Gd2O3nanoparticles 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

syn-thesis 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)3particles to the corresponding Gd2O3nanoparticles by

the solvothermal-calcination process The magnetization

proper-ties, including magnetization versus magneticﬁeld, were

investi-gated using a Vibrating Sample Magnetometer (VSM) Finally, the

colloid particles of PEGylated Gd2(CO3)3were investigated for an

in vitro MRI effect

2 Experimental

2.1 Synthesis of PEGylated gadolinium carbonate and gadolinium

particles

PEGylated Gd2(CO3)3particles were synthesized by a modiﬁed

solvothermal method In general, 40 g of polyethylene glycol

(PEG-1000, MW¼ 1000, Merck) was melted at 60C for 20 min 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

at a temperature at 180C for various heating times (3, 5, and 8 h) The precipitate formed was cooled to 60C and then 60 mL acetone and 3 mL hexane were added to facilitate the separation process At room temperature, this brown solution was centrifuged at

4000 rpm for 20 min and washed several times with acetone to remove the excess polymer The powders were obtained by drying the precipitates at 60C 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 (400C and 800C for 2 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

JCM-6000 X-ray diffraction (XRD) patterns of the samples were recor-ded by means of Philips Analytical PW 1710 based diffractometer

morphology of the particles were determined using Fourier trans-form infrared spectroscopy (Bruker Alpha I FTIR) The magnetiza-tion was measured using a Vibrating Sample Magnetometer (VSM 1.2 H Oxford) at 27C

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 TE¼ 9 ms, TR ¼ 100 ms, and a 90ﬂip angle An 8 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)3samples for the phantoms because the samples have high dispersibility properties in water based so-lutions 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

3 Results and discussion The morphology of the solvothermal products were determined using SEM micrograph images of the samples, as shown inFig 1

Fig 1(aec) showed that the Gd2(CO3)3powder was composed of agglomerated particles of micrometer size which were formatted as ﬂakes with a rhombus shape The size of the Gd2(CO3)3particles 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 raearth carbonate particles is known to depend on re-action time[9]

The morphology of the Gd2O3powder obtained at a calcination temperature of 400C (Fig 1(d)) shows the appearance of a molten material which indicates that the PEG is not completely released from the Gd2O3products At a calcination temperature of 800C (Fig 1(e)), the PEG is completely released and this results in ho-mogenous 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

A Dougherty et al / Journal of Science: Advanced Materials and Devices 4 (2019) 72e79 73

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nanometer size Although functionalized Gd2O3with 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

consider-ably 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, andﬂakes can be prepared by

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

parti-cles and the Gd2O3nanoparticles produced after calcination of the

Gd2(CO3)3to determine the components that exist in the samples

(Fig 2)

The detailed composition of the samples before and after

calcination are shown inTables 1 and 2respectively 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

con-tents from PEG molecules which conﬁrms that PEG successfully

attached to Gd2(CO3)3as PEGylated Gd2(CO3)3particles

Table 2shows an increase in Gd and O content after the

calci-nation process for samples under investigation The calcicalci-nation 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 400C can still be detected This is demonstrated by the

slight difference between the molar ratio and the stoichiometric

ratio After calcination at 800C, 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 8 h (Fig 3(a)) and the calcined products at 400 and 800C (Fig 3(b)) were analyzed by XRD measurements to identify the resulting particles and to examine the crystallinity and the phase of the samples InFig 3(a), the XRD patterns of the sample at 3 h heating time showed no apparent peaks which indicates an amorphous crystal structure The XRD patterns obtained for the samples at 5 and 8 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)3with hexagonal phase[35] The strongest diffraction peaks at 2q ¼ 11.75 were used to calculate the average crystallite size of Gd2(CO3)3heated for 5 h and

8 h by using the Scherrer's formula, D¼ kl/bcosq, where D is the average crystallite size, k (0.9) is the shape factor,lis the X-ray wavelength (1.5 Å),bis the line broadening at half the maximum intensity (FWHM) andqis the diffraction angle of an observed peak, respectively This yields an average crystallite size of about 4.6 nm (at 5 h) and about 3.5 nm (at 8 h)

As can be seen inFig 3(a), the intensities of the main peaks broaden and decrease with increased heating time, indicating that the crystallinity of the sample Gd2(CO3)3synthesized in 5 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 5 and 8 h heated samples also show additional peaks at the 2qz 10e11region which can be attributed

Fig 1 SEM micrograph of solvothermal products decomposed at 180 C for (a) 3, (b) 5, (c) 8 h, and the subsequent calcination products at (d) 400 C and (e) 800 C.

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precursor sample at 5 h heating time was calcined at 400C the

phase transition from Gd2(CO3)3to Gd2O3took place with

broad-ening peaks assigned to the (222) and (431) planes (Fig 3(b)) with

an average crystallite size, Dz 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 Gd2O3nanocrystals as reported by

S€oderlind et al.[40], Faucher et al.[7], and Ahab et al.[21] This indicates that after being calcined at 400 C, PEG molecules still attach to the calcination product The complete amorphous-crystalline 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

Fig 2 Energy dispersive X-ray spectroscopy (EDS) images of the PEGylated Gd 2 (CO 3 ) 3 particles decomposed at 180 C for (a) 3, (b) 5, (c) 8 h and the calcined products at (d) 400 C and (e) 800C.

Table 1

Elemental analysis of PEGylated Gd 2 (CO 3 ) 3 particles obtained by modiﬁed

sol-vothermal method.

Element Weight %

Theory 3 h 5 h 8 h

C 7.28 10.48 26.84 48.87

O 29.12 13.53 24.23 11.63

Gd 63.60 75.98 48.95 41.63

Table 2 Elemental analysis of Gd 2 O 3 nanoparticles obtained by calcination treatment Element Weight %

Theory 400 C 800 C

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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)3are

given inTables 3 and 4 InTable 3and the corresponding IR spectra

of PEG 1000 are illustrated inFig 4(a) It is clearly seen that, the PEG

has a IR characteristic absorption spectrum at 3458 cm1which is assigned to ʋas-OeH stretching The peaks at 2875, 1342, and

950 cm1are due to the presence of characteristic bands ofʋ-CeH

1104 cm1is assigned toʋ-CeOeC stretching[24,41] When gad-olinium acetate hydrate samples were decomposed at 180C with different heating times, the IR spectrum still exhibites CeOeC and

Fig 3 Evolution of XRD patterns at different heating times for the solvothermal products (a) and at different heating temperatures for the calcined products (b).

Fig 4 FTIR spectra of (a) PEGylated Gd 2 (CO 3 ) 3 particles at different heating times with (b) the magniﬁed absorption spectra in the region 500e1000 cm 1 of the sample

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CeH bands, although their intensity had decreased and additional

peaks appeared at 1542 and 1465 cm1which are assigned to the

ʋas-OeCeO band This band is a result of the partial oxidation of the

CH2eOH PEG band at temperatures above 150C[7,42]and also

indicates the formation of gadolinium carbonate[17,19,43]

More-over, absorption spectrum with lower intensity occurred at

947 cm1due to CH2bending 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 cm1for the sample decomposed in 8 h

assigned by three characteristic IR absorption peaks (Table 4),

OeCeO,p-CO3 e(848 cm1), andd-CO3 e(729 cm1)[17,18,35,43]

which only appear after 8 h of heating Thep-CO3 eand d-CO3 e

are related to the gadolinium acetate hydrate decomposition to

form the gadolinium carbonate[7].Fig 4(b) also shows the

pres-ence of absorption peaks in the region of 668 cm1e 804 cm1

which are due to the interaction betweend-OeCeO and

gadolin-ium metal oxide[44]

The PEGylated Gd2(CO3)3product at 5 h heating was used in

the calcination process to produce Gd2O3 nanoparticles When

the sample calcined at 400C (Fig 4(c)), CO2 molecules were

ʋas-OeCeO, and CeOeC absorption bands (at 3302, 1512, and

precursor sample The high intensity vibration characteristic of

GdeO presented at 521 cm1[39,45], which was conﬁrmed by XRD results Upon further calcination at 800 C, the character-istic PEGylated carbonate molecule bands completely vanished which resulted in a sharper GdeO peak The sharpness of the

GdeO peak after calcination at 800C indicates that the PEGy-lated 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 sol-vothermale calcination process (Fig 5) This pathway is an alter-native 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 tem-perature The obtained magnetization curves (M-H) are shown in

Fig 6 Notes that, for both samples, a near-linear relationship be-tween magnetization and appliedﬁeld 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)3is less than that of Gd2O3, i.e 8.08 105emu/g in compare with 1.12 104emu/g, respectively The higher susceptibility value of the Gd2O3nanoparticles can be attributed to their high surface-to-volume ratio due to a consider-able 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)3would 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 concentra-tions (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]

Table 3

FTIR spectroscopy absorption bands of PEG-1000.

Assignments FTIR (cm1)

ʋ as -OeH 3458

ʋ s -CeH 2875

d-CeH 1342 and 950

Table 4

FTIR spectroscopy absorption bands of Gd 2 (CO 3 ) 3

Assignments FTIR (cm1)

ʋ as -OeCeO 1536 and 1417

ʋ s -CO 3 e 842

Fig 5 Synthesis and morphological transformation of PEGylated Gd 2 (CO 3 ) 3 particles to the corresponding Gd 2 O 3 nanoparticles by the solvothermal e calcination process.

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4 Conclusion

PEGylated Gd2(CO3)3rhombus ﬂake particles were

success-fully synthesized by a modiﬁed solvothermal method With the

PEGylated Gd2(CO3)3particles as precursor, Gd2O3nanoparticles

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, Indonesia, and an ITB

Research and Innovation Grant 2016

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Fig 6 Hysteresis curves obtained by VSM for (a) pegylated Gd 2 (CO 3 ) 3 particles and (b)

Gd 2 O 3 nanoparticles.

Fig 7 (a) T1 weighted images of various amounts of Gd 2 (CO 3 ) 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.

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