[Gd.sub.n.sup.3+]@CNTs-PEG versus Gadovist[R]: In Vitro Assay.
Magnetic resonance imaging (MRI) is widely used as a powerful diagnostic tool in medical research due to its excellent temporal and spatial resolution, the absence of ionizing radiation, fast image acquisition, and deep penetration in tissues. (1,2) This modality depends on the hydrogen relaxation times in water molecules, (3) which simultaneously provides anatomic, functional, and molecular information. In addition to ongoing growth in the application of MRI in routine clinical practice and molecular imaging, there have been few reports on the application of MRI to visualize carbon nanotubes (CNT) due to their poor contrast. (4)
Contrast agents are used in most MRI diagnosis to enhance the signal level and improve tissue contrast. (5) Gadolinium (Gd) ions due to their physical properties such as large magnetic moment, relative long electron spin relaxation time, and high relaxivity compared to other paramagnetic metal ions, (5) are the most used contrast agents clinically in the form of paramagnetic Gd chelates such as Gd-DTPA (Magnevist[R]), Gd-DOTA (Dotarem[R]), Gd-HP-D03A (ProHance[R]), and Gd-BOPTA (Multihance[R]). They generally increase signal intensity by decreasing the longitudinal relaxation time of surrounding water protons. (6) Paramagnetic gadolinium (Gd3p) metal ion-based complexes are also used clinically as T1 relaxation agents, and the capability of Gd3p-containing CNT as MRI contrast agents has been assessed. (7-10)
Recently, CNT have been focused as agents for drug delivery, therapeutic, and diagnostic modalities. (11-15) In the last two decades, single-walled carbon nanotubes (SWCNT) have gained enormous attention in biomedical research. (16,17) Their structure enables them to be the choice for nanoscale confinement, external surface functionalization to be biocompatible for biological targeting, and multifunctional drug delivery agents. (18-23)
In this study, SWCNTs were functionalized, PE (polyethylene) gylated and loaded with Gd to enhance image contrast and the results were compared with commercial contrast agent Gadovist[R].
SWCNT (outer diameter 1-2 nm, and length of 5-30 [micro]m, US Research Nanomaterials Inc.) were oxidized according to the previously reported procedure. (24) SWCNTs 1.00 g was added to a 15 mL mixture of sulfuric acid and nitric acid (3:1 v/v) in a balloon and was bath-sonicated for 30 minutes (Pars Nahand Eng. Co., Tehran, Iran). It was then refluxed for 21 hours at 120[degrees]C, cooled and diluted with double distilled water (1 L), filtered and washed with deionized water to reach pH [approximately equal to] 4. Finally, the remaining yield was dried using an electric oven.
Oxidized SWCNT were loaded with gadolinium chloride (Gd[Cl.sub.3]) by mixing 0.84 mg of oxidized SWCNT (O-SWCNT) and 0.84 mg of Gd[Cl.sub.3].6[H.sub.2]O (REacton W, 99.9%) rigorously in 25 ml deionized water followed by bath-sonication (Pars Nahand Eng. Co., Tehran, Iran) for one hour. The mixture was placed overnight at room temperature undisturbed to flocculate [Gd.sup.3+]-loaded oxidized CNT ([Gd.sub.n.sup.3+]@CNTs) from the mix, and the supernatant was gently decanted. Any remaining sediment was dispersed in deionized water using a bath sonicator, and the previous step was repeated to remove any unabsorbed Gd[Cl.sub.3]. This procedure was repeated three times, and the product was dried in an electric oven.
To PEGylate the product, 89.00 mg of [Gd.sub.n.sup.3+]@ CNTs mixed with 1500.00 mg polyethylene glycol (PEG) bis (3-aminopropyl) terminated Mn~1500 (Sigma-Aldrich, Missouri, USA) and the mixture was stirred at a temperature of 120[degrees]C under a gentle nitrogen purge for one week. The product was dialyzed against water with a dialysis bag (~14KDa cut-off) for three days after the free PEG was removed completely. The remaining product in dialysis bag was centrifuged at 14000 rpm for 15 minutes three-times to remove large nanotube bundles and the supernatant was freeze-dried [Figure 1].
Transmission electron microscopy (TEM) (1) (LEO 906E, Carl Zeiss, Germany) and dynamic light scattering (DLS) (2) (Malvern Instruments, Malvern, UK) were performed to gather the size and morphology information of the final product.
Inductively coupled plasma (ICP) (3) (Agilent Series 4500; Agilent, Santa Clara, USA) analysis was performed to determine the Gd content in the final product in PEGylated and non-PEGylated forms. The product was digested with nitric acid (a strong oxidizing agent) to prepare the samples.
Finally, the solutions were poured into identical vials at different known concentrations for MRI, which was performed using a 1.5T clinical MRI Scanner (GE Healthcare, USA) at 27[degrees]C.
The imaging parameters are given in Table 1 and applied spin echo sequence and quadknee[R] coil. After completing the imaging procedure, the obtained images were analyzed off-line using the software available on the MRI unit.
The T1-W images and quantitative signal intensity of [Gd.sub.n.sup.3+]@CNTs-PEG, Gd-CNT and Gadovist[R] samples with different Gd concentrations were demonstrated in Figure 2 and Table 2. The signal intensities of vials with corresponded Gd concentrations, which were serially diluted, were recorded after image acquisition and analysis.
We loaded Gd on PEGylated SWCNT. The relaxivity of Gd-based contrast agents is partly dependent on the number of Gd per nano-carrier and their exchange rate with surrounding water protons. (25) The relaxivity of the synthesized [Gd.sub.n.sup.3+]@CNTs-PEG, Gd-CNT, and commercial contrast agent, Gadovist[R] are given in Figure 3.
The size of particles was identified by DLS and TEM and are shown in Figure 4 and Figure 5, respectively.
Results of ICP analysis revealed that the [Gd.sub.n.sup.3+] content of [Gd.sub.n.sup.3+]-CNTs and [Gd.sub.n.sup.3+]@CNTs-PEG is 2.1% and 0.031% (w/w), respectively, and no free Gd ion was detected in the sample eventually. MRI of the vials obtained using a 1.5T MR scanner (GE, Healthcare, USA) and a standard quadknee[R] coil [Figure 6].
Figure 2 demonstrates the signal intensity of Gadovist[R] and [Gd.sub.n.sup.3+]@CNTs-PEG with the same protocol and a similar percentage concentrations (100%, 50.0%, 25.0%, 12.5%, and 6.3%).
After analyzing images obtained from each vial, the signal intensity was plotted versus Gd concentration [Figure 7].
We oxidized SWCNT in harsh acidic conditions and loaded them with [Gd.sub.n.sup.3+]. Oxidization was performed with a mixture of nitric and sulfuric acid (1:3). This procedure removes any impurity (metal catalysts) and produces open end terminals in the structure and sidewall defects stabilized by -COOH and -OH groups. (26-28) These hydrophilic holes are appropriate for accumulating [Gd.sup.3+] (hydrophilic metallic ions) at the surface or inner side of the CNT28-30; besides, the -COOH group might be coupled to biochemical or chemical groups. (28,30,31) CNTs have a rigid structure and are insoluble in any solvents, and solubilization of CNT with chemical functionalization has been studied briefly. (12,27,32,33) Among hydrophilic polymers, PEG is attractive for use with CNT as it is biocompatible, nontoxic, stable, and low immunogenicity. (12,31,33,34) [Gd.sub.n.sup.3+]-CNT was functionalized using PEG1500N ([Gd.sub.n.sup.3+]-CNT-PEG). The attachment of PEG with [Gd.sub.n.sup.3+]-CNT was performed via a thermal reaction and zwitterion interaction between oxidized CNT carboxylic groups and terminated amines in PEG. (31) The [Gd.sub.nsup.3+] CNT-PEG solution had more stability than [Gd.sub.n.sup.3+]-CNT in phosphate buffered saline. The [Gd.sub.n.sup.3+]-CNT-PEG remained homogeneous in an observation time of two months while in the [Gd.sub.n.sup.3+]-CNT black precipitation was observed after a few days. In oxidized SWCNT, a weight loss was observed at 470[degrees]C, which might be due to thermally unstable functional groups (e.g., OH and COOH on SWCNT) formed during oxidation. These findings show that PEG chains have successfully covered the SWCNT surfaces. (35)
Gd chelates shorten T1 relaxation times and therefore lead to higher signal intensity on T1-W images. In fact, beyond a certain concentration (depending on pulse sequence), the signal intensity starts to decrease with increased Gd concentration. The main reason for the unexpected relationship between Gd concentration and MRI signal intensity is that Gd contrast agents shorten not only T1 but also T2 relaxation times. At high concentrations of Gd chelate, T2 shortening is substantial enough to cause signal loss, overcoming the effect of T1 shortening. (36) At low concentrations where T1 effects dominate, the signal intensity increases nonlinearly with concentration. However, above a certain concentration (depending on the characteristics of the pulse sequence), the T2 effects become more important and lead to signal loss. (36)
According to the findings, increasing the concentrations of Gd in contrast agent results to increased signal intensity in T1-W images; but above a certain Gd concentration, the reverse phenomena (signal reduction) is observed. Gadovist[R] was diluted as recommended by the company, (37) and was poured into the vials as for [Gd.sub.n.sup.3+]@CNTs-PEG and GdCNT for imaging phase. Comparing the obtained T1-W images from different vials at considered concentrations, we observed that the signal intensity of the [Gd.sub.n.sup.3+]@CNTs-PEG with Gd concentration of 0.01 mg/mL was comparable with the Gadovist[R] with a concentration of 0.01 mg/mL.
However, Gd concentration in Gadovist[R] was 12.2% higher than [Gd.sub.n.sup.3+]@CNTs-PEG, but the signal intensity of the [Gd.sub.n.sup.3+]@CNTs-PEG was approximately 3.3% times greater than Gadovist[R]. It suggests a potentially higher imaging ability in [Gd.sub.n.sup.3+]@CNTs-PEG than Gadovist[R] at the same Gd concentration, which could increase the sensitivity of MRI and early diagnosis of tumors. Our findings are in agreement with another study that showed a better imaging potential in [Gd.sub.n.sup.3+]@CNTs-PEG compared to Magnevist[R] (another Gd-based contrast agent). The synthesized [Gd.sub.n.sup.3+]@CNTs-PEG led to a much higher contrast and better image quality. (35)
The most important criteria for optimization diagnostic efficacy and patient safety are relaxivity and stability of contrast agents. (38)
The first contrast agent approved for in vivo usage was Gd-DTPA (Magnevist[R]), which is still among the most frequently used contrast agents. (39) Relaxivity of Gadovist[R] and Magnevist[R] are 5.2 and 4.1 L/mmol/s at 1.5 Tesla scanner (r1 in plasma at 37[degrees]C), respectively. (40) There are two structural classes of Gd chelate complexes: macrocyclic and linear. Macrocyclic structures impart added strength compared to a linear structure. Gadovist[R] and Magnevist[R] have a macrocyclic structure and linear structure, respectively. (40) The higher signal seen with higher-relaxivity agents affords the potential for contrast agents to be used at lower doses in patients at risk of developing NSF. (4,41-46) Besides, stability is an important consideration because the [Gd.sup.3+] is toxic and the ability of a ligand to bind tightly to the Gd ion is an important safety consideration. (47)
The authors of another study concluded that [Gd.sup.3+]n-US-tube species are linear super paramagnetic molecular magnets with MRI efficacies 40-90 times higher than any current [Gd.sup.3+]-based contrast agent in clinical usage. (8) The results of this study and ours are not exactly comparable as they used Magnevist[R] while we used Gadovist[R], but the efficacy of our synthesized [Gd.sub.n.sup.3+]@CNTs-PEG was better than Gadovist[R]. Nevertheless, it seems that gadonanotube can be used as a new high-performance MRI contrast agent and, compared to other commercial gadolinium-based contrast agents, is safe and produce higher signal intensity.
Superparamagnetic [Gd.sub.n.sup.3+]@CNTs-PEG displayed highly significant MRI positive contrast enhancement. In vitro MRI studies showed that gadonanotube enhanced signal intensity in T1-W images, therefore suggesting the potential application as MRI contrast agents. The amount of Gd chelates lo ade d on nanotubes is much lower than commercial contrast agents, but the relaxivity of Gd-CNT is higher and, as a result, we observed an enhancement of signal intensity in T1-W images. Although the Gd concentration in Gadovist[R] is higher the signal intensity of the [Gd.sub.n.sup.3+]@ CNTs-PEG was approximately 3.3% times greater. As there is a difference of Gd ion concentrations in Gadovist[R] and synthesized [Gd.sub.n.sup.3+]@CNTsPEG, we were unable to use same concentrations of the Gd ion in the two contrast agents, and we used different dilations to get the optimized image. Further studies are needed to compare the bio-distribution and kinetics of such complexes in vivo.
The authors declared no conflicts of interest. No funding was received for this work.
Received: 03 October 2017
Accepted: 16 October 2018
Online: DOI 10.5001/omj.2019.27
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Ghazal Mehri-Kakavand , Hadi Hasanzadeh  *, Rouzbeh Jahanbakhsh , Maryam Abdollahi , Reza Nasr , Ahmad Bitarafan-Rajabi , Majid Jadidi , Amir Darbandi-Azar  and Alireza Emadi 
 Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
 Cancer Research Center and Department of Medical Physics, Semnan University of Medical Sciences, Semnan, Iran
 Arak Zist Darou Co, Health Technology incubator Center, Semnan University of Medical Sciences, Semnan, Iran
 Department of Medical Physics, Semnan University of Medical Sciences, Semnan, Iran
 Biotechnology Research Center, Semnan University of Medical Sciences, Semnan, Iran
 Cardiovascular intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
 Deputy of Research and Technology, Semnan University of Medical Sciences, Semnan, Iran
Caption: Figure 1: Synthesized Gd-CNT and [Gd.sub.n.sup.3+]@CNTs-PEG.
Caption: Figure 2: Signal intensity versus concentration of gadolinium
Caption: Figure 3: Relaxivity curves of (a) [Gd.sub.n.sup.3+]@CNTs-PEG, (b) Gd-CNT, and (c) Gadovist*.
Caption: Figure 4: DLS results of (a) Gd-CNT, (b) [Gd.sub.n.sup.3+]@CNTs-PEG, and (c) filtered- [Gd.sub.n.sup.3+]@CNTs- PEG.
Caption: Figure 5: Transmission electron microscopy images of (a) raw CNT, (b) oxidized CNT, (c) Gd-CNT, and (d) [Gd.sub.n.sup.3+]@CNTs-PEG.
Caption: Figure 6: (a) Vials and (b) magnetic resonance imaging scanner.
Caption: Figure 7: Mean signal intensity versus concentration for (a) [Gd.sub.n.sup.3+]@CNTs-PEG, (b) Gd-CNT, and (c) Gadovist[R].
Table 1: Magnetic resonance imaging scan parameters. Imaging parameters Measurements Time of repetition 200.0 ms Time of echo 2.6 ms Field of view 16 x 16 [cm.sup.2] Matrix size 384 x 192 [mm.sup.3] Number of excitation 1.0 Slice thickness 2.0 mm Spacing 0.2 mm Table 2: Concentrations of [Gd.sub.n.sup.3+]@CNTs-PEG, Gd-CNT, Gadovist', and signal intensity. Sample Vial Concentration, Concentration, % number mg/mL [Gd.sub.n.sup.3+] 1 0.11 6.3 @CNTs-PEG 2 0.05 12.5 3 0.02 25.0 4 0.01 50.0 5 0.00 100 Gd-CNT 1 0.05 6.3 2 0.11 12.5 3 0.22 25.0 4 0.44 50.0 5 0.88 100 Gadovist[R] 1 0.00 0.001 2 0.01 0.01 3 0.15 0.1 4 1.57 1.0 5 9.81 6.3 6 19.62 12.5 7 21.16 25.0 8 39.25 50.0 9 78.50 100 Sample Vial Signal number intensity [Gd.sub.n.sup.3+] 1 274.74 @CNTs-PEG 2 345.59 3 400.07 4 367.20 5 0 Gd-CNT 1 320.49 2 308.92 3 356.00 4 365.64 5 385.62 Gadovist[R] 1 247.85 2 334.53 3 443.49 4 432.42 5 150.52 6 0* 7 0* 8 0* 9 0* * The value is due to high gadolinium (Gd) concentration in vials.
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|Title Annotation:||ORIGINAL ARTICLE; carbon nanotubes-polyethylene glycol|
|Author:||Mehri-Kakavand, Ghazal; Hasanzadeh, Hadi; Jahanbakhsh, Rouzbeh; Abdollahi, Maryam; Nasr, Reza; Bitar|
|Publication:||Oman Medical Journal|
|Date:||Mar 1, 2019|
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