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.