Synthesis route and three different core-shell impacts on magnetic characterization of gadolinium oxide-based nanoparticles as new contrast agents for molecular magnetic resonance imaging
© Azizian et al.; licensee Springer. 2012
Received: 10 April 2012
Accepted: 22 September 2012
Published: 3 October 2012
Despite its good resolution, magnetic resonance imaging intrinsically has low sensitivity. Recently, contrast agent nanoparticles have been used as sensitivity and contrast enhancer. The aim of this study was to investigate a new controlled synthesis method for gadolinium oxide-based nanoparticle preparation. For this purpose, diethyleneglycol coating of gadolinium oxide (Gd2O3-DEG) was performed using new supervised polyol route, and small particulate gadolinium oxide (SPGO) PEGylation was obtained with methoxy-polyethylene-glycol-silane (550 and 2,000 Da) coatings as SPGO-mPEG-silane550 and 2,000, respectively. Physicochemical characterization and magnetic properties of these three contrast agents in comparison with conventional Gd-DTPA were verified by dynamic light scattering transmission electron microscopy, Fourier transform infrared spectroscopy, inductively coupled plasma, X-ray diffraction, vibrating sample magnetometer, and the signal intensity and relaxivity measurements were performed using 1.5-T MRI scanner.
As a result, the nanoparticle sizes of Gd2O3-DEG, SPGO-mPEG-silane550, and SPGO-mPEG-silane2000 could be reached to 5.9, 51.3, 194.2 nm, respectively. The image signal intensity and longitudinal (r1) and transverse relaxivity (r2) measurements in different concentrations (0.3 to approximately 2.5 mM), revealed the r2/r1 ratios of 1.13, 0.89, 33.34, and 33.72 for Gd-DTPA, Gd2O3-DEG, SPGO-mPEG-silane550, and SPGO-mPEG-silane2000, respectively.
The achievement of new synthesis route of Gd2O3-DEG resulted in lower r2/r1 ratio for Gd2O3-DEG than Gd-DTPA and other previous synthesized methods by this and other groups. The smaller r2/r1 ratios of two PEGylated-SPGO contrast agents in our study in comparison with r2/r1 ratio of previous PEGylation (r2/r1 = 81.9 for mPEG-silane 6,000 MW) showed that these new three introduced contrast agents could potentially be proper contrast enhancers for cellular and molecular MR imaging.
where TR is the repetition time and TE is the echo time of MRI pulse sequence which determine the contrast between tissues.
Contrast agents can modify the signal intensity in different tissues and enhance intrinsic contrast. These are categorized according to the signal intensity produced on T1- and T2-weighted images: ‘positive’ (high signal intensity) or ‘negative’ (low signal intensity)[4, 5].
where (1/Ti)obs and (1/Ti)d are the relaxation rates (R1 and R2, s−1) of the sample and aqueous solution, respectively; ri is longitudinal and transverse relaxivity of the sample (relaxation rates per concentration unit, s−1 mM−1), and [Gd3+ is the gadolinium concentration (mM).
Despite the good magnetic properties, the free Gd3+ ion is extremely toxic. To reduce its toxicity, it must be complexed by strong organic chelators, e.g., diethylene triamine pentaacetic acid (DTPA) which has been used conventionally in daily MRI examinations. However, these chelates cause low sensitivity and, thus, requiring a high tissue concentration of the contrast agent to be effective for MR imaging.
Recently, studies have shown high efficiency and sensitivity of contrast agents when they have been used in nanoparticles form. The size of the nanoparticles that can be used in MRI is about 3 to 350 nm that might be comparable or smaller than a cell (10 to 100 μm), a virus (20 to 450 nm), a protein (5 to 50 nm), or a gene (2 nm wide and 10 to 100 nm long)[8, 9].
For nanoparticles, various coating materials can reduce their toxicity and increase their biocompatibility. As a new surface covering material, this group in a previous study reported some of the primary magnetic properties of diethyleneglycol (DEG) in combination with Gd oxide-based nanoparticles. However, still further researches on the matters of the synthesis procedure, effective size, and agglomeration of gadolinium nanoparticles coated with DEG materials are needed to be done[11–13]. On the other hand, polyethylene glycol (PEG), due to its considerable physicochemical properties, has an especial interest as covering of nanoparticle surfaces[13–17]. Also, it should be noted that PEG has different molecular weights from 350 to 30,000 (and more) Da that could be used alone or in conjunction with other substances such as polylactide-polyethylene glycol and polylactide-co-glycolide[18–20]. For this reason, these two groups of surface conjugate materials (DEG and PEG) could be even useful for covering nanoparticles in biomedical cellular and molecular imaging applications. Therefore, here in continuing our previous works, the assessment of a new supervised DEG synthesis route in addition to a gadolinium PEGylated (PEG) method in comparison to the conventionally Gd-DTPA contrast agent has been determined as the aim of this study. For this purpose, Gd2O3-DEG was prepared in new synthetic controlled method, and mPEG-silane grafting at the surface of a new core contrast agent (small particulate gadolinium oxide, SPGO < 40 nm) was obtained using two molecular weights of methoxy polyethylene glycol-silane: 550 and 2,000 Da as SPGO-mPEG-silane550 and SPGO-mPEG-silane2000. Physicochemical characterizations and magnetic properties of those three contrast agents in comparison with conventional Gd-DTPA were evaluated to find the optimum method and the more effective contrast agent nanomagnetic for cellular and molecular magnetic resonance imaging.
The synthesis of the Gd2O3-DEG nanoparticles
In a new supervised polyol route, for the synthesis of gadolinium oxide nanocrystals, 2.5 mmol GdCl3-6H2O dissolved in 12.5 ml DEG was heated to 140°C until a clear solution was obtained. Then, 3 mmol solid NaOH was dissolved in 6 ml DEG and then added to the Gd-containing solution; the temperature of the mixture was raised to 180°C and held constant for 4 h under reflux and magnetic stirring, yielding a dark yellow colloid. After cooling, the nanocrystals formed were separated and purified from agglomerations or large-size particles by centrifuge filtration for 30 min at 40°C and 2,000 rpm (filters: polyethersulfone, 0.2 μm, Vivascience Sartorius, Hannover, Germany). Free Gd3+ ions and excess DEG in the solution were eliminated by 1,000 MW membrane (dialysis tubing, benzoylated, Sigma-Aldrich, USA) for 24 h and by 12,000 MW membrane (dialysis tubing cellulose membrane, Sigma-Aldrich, USA) for 24 h across deionized water, which these sections were not included in our previous study.
The synthesis of the SPGO-mPEG-silane550 and SPGO-mPEG-silane2000
The process of SPGO-mPEG-silane nanoparticle synthesis was performed using SPGO nanoparticles (<40 nm) purchased from Sigma-Aldrich (99.999% pure). Briefly, a solution was prepared by dissolving SPGO (1 g) and 15 mg ml−1 mPEG-silane (mPEG-Silane, MW550, Nanocs, Inc. (MA, USA) or mPEG-Silane, MW 2000, Laysan Bio, Inc. (AL, USA)) in deionized water (10 mL); then, the resulting solution was sonicated at 40°C for 2 h. Large-size particles were separated by centrifugation (2,000 rpm, 30 min) and the suspension was dialyzed (1,000 and 12,000 MW) as described above.
Characterization of the contrast materials
Nanoparticle size measurements were performed three times repeatedly by dynamic light scattering (DLS, Brookhaven Instruments, USA). Also the morphological information of the nanoparticles was done by transmission electron microscopy (TEM, CM120 model, Koninklijke Philips Electronics, Netherlands).
The effects of surface coating in composition with nanomagnetic particles, received from their spectra, was recorded by FTIR spectrometer (Tensor27, Bruker Cor., Germany) over a range between 400 and 4,000 cm−1, at room temperature (26°C ± 1°C). Moreover, structural characterization of the SPGO was collected on an X-ray diffractometer (XRD, PW1800, Philips). After filtration and dialysis, the nanoparticle concentrations were determined by induced coupled plasma-atomic emission spectroscopy (Varian-Liberty 150 AX Turbo, USA). In addition, magnetic strength measurements of SPGO and Gd2O3-DEG were executed with commercial vibrating sample magnetometer (VSM, 7400 model, Lakeshore Cryotronics Inc, OH, USA).
The signal intensity (SI) and longitudinal (T1) and transverse (T2) relaxation times were measured by 1.5 T MRI scanner (Siemens AG, Germany) using the head coil. After both types of dialyses (1,000 and 12,000 Da), nanomagnetic concentration measurements done by ICP, then T1 and T2 changes in aqueous solution for Gd-DTPA, and three synthesized nanomagnetic particles of Gd2O3-DEG, SPGO-mPEG-silane550 and 2000 were accomplished by diluting them in 5 ml water with Gd concentration at a range of 0.1, 0.3, 0.6, 0.9, 1.2, 1.5, 2, and 2.5 mM (mmol/L). T1 relaxation time for each sample was obtained by varying repetition times (TR = 100, 200, 400, 600, 2,000 ms) with fixed echo time at TE = 15 ms. Similarly, T2 relaxation times were measured by varying echo times (TE = 30, 60, 90, 120 ms) and fixed TR = 3,000 ms, and imaging parameters of slice thickness of 5 mm, 1 mm gap, 512 × 384 matrix size, and 25 cm2 field of view. Signal intensities were obtained with manually drawn regions of interest for each sample. Relaxation rates of R1 (1/T1) and R2 (1/T2) were calculated by exponential curve fitting of the signal intensity vs. time (TR or TE) according to Equation 1. After relaxation rate determination for different concentrations, the R1 or R2 vs. concentration curve were plotted and, thereby, the relaxivities (r1 and r2) as the slope of Equation 2 could be calculated.
Characterization of the contrast materials
DLS size and PdI measurements for the three nanoparticle contrast agents
5.9 ± 0.13
51.3 ± 1.46
194.2 ± 22.1
Results of relaxometry for three nanoparticle contrast agents and Gd-DTPA
r2 (mM−1 s−1)
r1 (mM−1 s−1)
Determination of maximum signal intensities for different concentrations
Figure 8 shows the signal intensity curves for Gd-DTPA, Gd2O3-DEG, SPGO-mPEG-silane550, and SPGO-mPEG-silane2000 using TR/TE = 600/15 ms. The maximum signal intensities for Gd2O3-DEG, SPGO-mPEG-silane550, and SPGO–mPEG-silane2000 were found in 0.6, 0.6, and 0.9-mM concentrations, respectively.
Contrast agents can modify the signal intensity in different tissues to enhance their contrast and improve the low sensitivity of magnetic resonance imaging. The efficiency of the contrast agents according to different absorption of agents is determined by ri that changes the longitudinal and transverse relaxation times to result differences among adjacent tissues. These changes are categorized according to the signal intensity produced on T1 and T2-weighted images: ‘positive’ known as high signal intensity or ‘negative’ as low signal intensity. Recently, studies have shown high efficiency and sensitivity of contrast agents when they have been used in nanoparticle forms. To have higher relaxivity, reduce toxicity, increase biocompatibility and half-life, besides preventing the nanoparticle aggregations, contrast agents in MRI should be coated with various materials. Different factors could affect the sizes of nanoparticles including type of the core, coating molecular weights, nanoparticle aggregation and, thereby, the synthesis route. Theoretically, by increasing molecular weights of nanoparticle coatings, their average size could be increased as well. For this reason, in this study, we investigated magnetic properties of three Gd-based nanoparticles with different coatings of DEG, mPEG-silane550, and mPEG-silane2000 comparing to conventionally extracellular Gd-DTPA contrast agent. For nanoparticle synthesis, two different methods were used. Firstly, the preparation and coating of Gd2O3 by previous polyol route besides 0.2-μm filtration, and two 1,000 and 12,000 Da dialysis membranes led to reach the good and desirable smaller size of approximately 5 nm of gadolinium crystal nanoparticles covered by DEG in Gd2O3-DEG compounds. Secondly, for mPEG-silane550 and mPEG-silane2000, despite using filtration and sonication after PEG coating method for elimination aggregated particles prior to DLS measurement, PEGylated nanoparticles even still had relatively larger sizes of approximately 51.3 and approximately 194.2 nm. For this, part of that increase size should be due to the effect of their molecular weights. In our study, molecular weights of three materials were as follows: MWSPGO-mPEG-silane2000 > MWSPGO-mPEG-silane550 > MW Gd2O3-DEG. As seen in Table 1, the measured particle sizes have an incremental behavior as the molecular weight has increased, which are in accordance with their appearance in related TEM images.
Magnetic properties in MRI were related to relaxivities (r), especially, r2/r1 ratio that defines the potential for being a positive or negative contrast agent. Meanwhile, several studies have investigated the size effects on magnetic properties and relaxivities, e.g., SPIO nanoparticles with hydrodynamic diameters of 9, 12, and 15 nm had r2/r1 ratio of 2.75, 5.95, and 13.08, respectively[22, 23]. Some other studies have also showed that the r2/r1 ratio increases with larger sizes of nanoparticles[14, 25, 26]. Consequently, in this study, the changes of coating materials with various molecular weights on a similar core were also studied in terms of r2/r1 ratios which have been shown in Table 2. Thereby, it is clear that those r2/r1 ratios for Gd2O3-DEG were much lower than that of other two PEGylated materials. Meanwhile, even for SPGO-mPEG-silane2000, the said ratio was a bit higher than SPGO-mPEG-silane550.
For positive contrast agents, r2/r1 ratio is described to be 1 to 2 and for negative ones; however, it is between 2 and 40. Thus, in our study, Gd2O3-DEG (with r2/r1 ratio = 0.89) could reveal good results as a positive contrast agents even better than Gd-DTPA (with r2/r1 ratio = 1.13)[10–12], that is in part because of such small size nanoparticles that could be yielded in the new synthetic method in this research. However, r2/r1 ratios for PEGylated nanoparticles are relatively high. In one study, PEGylated SPGO with higher MW (MW = 6,000 Da) resulted to an r2/r1 ratio equal to 81.6. In this study, we used polymers with a lower molecular weight (i.e., 550 and 2,000) and so the r2/r1 ratios could be reached to 33.34 and 33.72, respectively. These decreased ratios in our study should be mostly related to the selected lower molecular weight materials. Furthermore, the relaxivity results in Figure 7a, b indicate that Gd2O3-DEG nanoparticles (with lower r2/r1 ratio) as positive contrast agents are clearly more appropriate than Gd-DTPA. SPGO-mPEG-silane550 and 2000 due to having both high r2 and high r2/r1 ratio appear to be proper contrast agents for T2-weighted MR imaging methods, as well.
According to Equations 1 and 2, signal intensities change with T1, T2, and the concentration of contrast agents. Therefore, short T1 leads to a signal increase, whereas, short T2 decreases the signal. A maximum signal occurs at intermediate concentrations; such expectations could be seen clearly in Figure 8a, b. In addition, the maximum signal intensity for Gd2O3-DEG occurred at similar daily clinical concentration relative to Gd-DTPA with similar intensity (0.6 mM near to 0.1 mM; Figure 8a). Also, signal intensities for SPGO-mPEG-silane550 and SPGO-mPEG-silane2000 were much less than the two other contrast agents (Figure 8b). This is another conformation that they can be considered as negative or T2-wieghted contrast agents. This could be remained for future experiment for them to be compared with other negative contrast agents such as iron oxide-based ones.
The synthesis controlled method making use of dialysis, filtration, and sonication could have direct effect on the nanosize scale and magnetic characterization of nanoparticles, consequently on their r2/r1 ratio as providing and giving them a positive or negative signal properties of contrast agents. Thereby, in our study, the Gd2O3-DEG with r2/r1 lower than Gd-DTPA and other previously synthesized Gd2O3-DEG could be achieved. Moreover, for preparation of PEGylated contrast agents, polymers with lower molecular weights could potentially have better contrast properties as behaving like negative contrast agents that should be compared with other similar negative ones.
Therefore, among different group coating materials, DEG and PEG, due to their considerable properties and not having fixed sizes (different molecular weights), were selected as useful surface covering of nanomagnetic particles that could reveal noticeable relaxivity, magnetic property, and signal intensity that are proper for cellular and molecular MRI applications that would be remained for future in vivo studies.
NRA was born in 1960 in Shiraz, Iran, received his BSc in Nuclear Physics from Shiraz University, Shiraz, Iran, in 1986, his MSc and Ph.D. in Medical Physics (Medical Imaging) from Nagoya University, Nagoya, Japan in 1995. At present, he is a professor in the Medical Physics at the Department of Medical Physics & Biomedical Engineering, School of Medicine, Tehran University of Medical Sciences (TUMS). His research interests during Ph.D. graduation was in computer-aided diagnostic (CAD) systems for the detection of cancer on digital mammograms, leading to development of software algorithms and CAD systems for mammographic cancer detection. As a PIP member of the American Association in Medical Physics (AAPM) and other scientific forums, he published many articles and several books in Medical Imaging aspects, achieved awards in innovation, scientific hypothesis and inventions, and paper awards in world conferences. Recently, his research interests have been focusing on the development of nanomagnetic particles for MRI applications. The development of the present work in combination with the magnetoliposomes as tumor cell tracking and drug delivery system for liver specific target detection has been accepted and will be presented in RSNA2012.
SH was born in 1960 in Abadan, Iran, and received her BSc and MSc in Analytical Chemistry from Shiraz University, Shiraz, Iran, in 1990, and her Ph.D. in Pharmaceutics from Nagoya University in Japan in 1995. Her Ph.D. research was related to pharmacokinetics of drugs, especially drug characterization in brain distribution. At present, she is an associate professor in the Pharmaceutical Department, Food & Drug Laboratory Research Center, Food & Drug Organization (FDO), Ministry of Health, Tehran, Iran. She is the head of QC approving of herbal medicine and supplements in Iran FDO and also has been the lecturer of GLP and GMP at the universities while performing many workshops for drug factories. Her recent research interest is in the synthesis and analytical method development of nanosized molecules for drug delivery applications.
HRM received his Pharm D from Tabriz University and his Ph.D. in Pharmaceutics from the University of Bradford, England in 1995. He has been a member of the Fellowship in Liposomal Gene Delivery in Cancer, University of Alberta, Canada. At present, he is a professor of Pharmaceutics in School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. His research interests have been related to transdermal drug delivery, modeling biological barriers, gene delivery, liposomal drug delivery, and lyotropic liquid crystals. He has been also the Director General of some drug factories.
GA is a Ph.D. candidate who received his BSc in Physics from Bu Ali Sina University in 1991, his MSc in Medical Physics from Tehran University of Medical Sciences (TUMS) and now is going to graduate in Medical Physics from Tehran University. He has been the employee and the lecturer of Medical & Radiation Physics in School of Medicine of Hamadan University of Medical Sciences since 2000. His research interests during his MSc has been related to medical imaging and now during his PhD graduation he has been involving with the development of magnetic nanoparticle sizes for MRI applications.
RZ, a Ph.D. candidate, received his BSc in Physics from Tehran University of Medical Sciences in1999, his MSc in Medical Physics from Tabriz University of Medical Sciences and now is going to graduate in Medical Physics from Tehran University. His research interest is related to magnetoliposome nanosize particles application for MRI applications.
EG received her BSc in Chemistry from the Islamic Azad University of Tehran University and her MSc from the University of Zanjan (ZNU). She is a research fellow in Food & Drug Laboratory Research Center, Food & Drug Organization (FDO), Ministry of Health, Tehran, Iran. Her research interests in MSc has been in the preparation of gold nanoparticles coated by amino acids and the study of the kinetically influence tubulin protein in vitro, and at present, is working on the synthesis development for contrast agent nanosize particles for MRI applications.
BR received his BSc in Radiology from Iran Medical University in 1990 and his MSc in Medical Physics from Iran Medical University in 2001. At present, he is an employee of Medical Imaging Center in Emam Hospital Complex, School of Medicine. He has been contributing to so many researches with different departments and researchers; he is qualified in developing different MRI imaging protocols. At present he is responsible for performing new and proper MRI data acquisitions in nanomagnetic contrast agents and MRI neuroimaging applications.
This paper is supported by the Chancellor Research of Tehran University of Medical Sciences (TUMS).
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