In the past few years, there has been an immense development in the field of SPIONs, which have shown the capability for both, medical imaging and therapeutic applications, for instance drug delivery and magnetic hyperthermia (MH). These particles are needed in the imaging fields like MRI (magnetic resonance imaging) as tracers and particularly MPI , . For MPI the SPIONs should have high magnetization values, a hydrodynamic diameter <150 nm and narrow particle size distribution.
To understand the behaviour of the SPIONs and to tailor the particles for the specific modality, a careful study of the different parameters controlling the final output is desired. In this study, the focus is on the classical synthesis process called co-precipitation . The co-precipitation technique is one of the simplest and straight forward processes to obtain a large quantity of SPIONs. Through this process iron oxides (Fe3O4) could be easily prepared by adding a mixture of ferric and ferrous salts in an aqueous solution and precipitating with a base (ammonia, CH3NH2, or NaOH).
The co-precipitation process comprises of two stages: a short burst of nucleation, once the concentration of the species reaches critical supersaturation.
Followed by a slow growth of the nuclei through the diffusion of the solutes to the surface of the nanoparticles.
2 Material and methods
As mentioned earlier, in this research the co-precipitation technique is followed. The iron salts: iron(III) and iron(II) in a ratio of 2:1, dextran and demineralized water are placed in a three neck flask in an ice bath, followed with addition of base at a constant rate under ultrasonic control : Iron(III) (FeCl3 ⋅ 6H2O ≥ 99% obtained, from Carl Roth GmbH Karlsruhe, Germany) and Iron(II) (FeCl2 ⋅ 4H2O ≥ 99% obtained, from Merck kGaA, Darmstadt, Germany) is used. In two different synthesis series; two kinds of dextran are used, T40 with molecular mass of approx. 35,000–40,000 (Carl Roth GmbH Karlsruhe, Germany) and T70 with molecular mass of approx. 70,000 (AppliChem GmbH, Darmstadt, Germany).
The flow rate of the base (here ammonia) is controlled with the help of an infusion pump (PERFUSOR secura FT, B. Brown) which is 99 ml/h and the temperature of the reaction mixture is measured continuously with a fibre optic thermometer (FOTEMP 4, OPTOCON AG). This comprises of the nucleation phase followed by the slow growth. In the growth phase the mixture is heated to a definite temperature.
In this research, two sets of experiments are performed. In the first shown experiment, the effect of dextran on the synthesis process is evaluated by keeping all the parameters constant except using different dextran of different molecular weights (T40 and T70). In the second experiment, the growth phase is analysed by taking out samples at different temperatures to visualize the growth of SPIONs with respect to final co-precipitation temperature. In these experiments dextran T70 is used. All the SPIONs are analysed with the MPS . The size distribution of the SPIONs is measured with NANOPHOX (Sympatec GmbH).
For characterization, the magnitude spectrum and the hysteresis curve are obtained by measuring MPS operating at a frequency of approx. 25 kHz with a magnetic field strength of 20 m/T.
3.1 Effect of dextran
As shown in Figure 1, the SPIONs with T70 dextran have higher harmonics value as compared to T40 dextran. Moreover, the area enclosed by the hysteresis curve generated with T70 dextran is bigger than T40 dextran as shown in Figure 2.
This represents that the heating of the SPIONs with T70 dextran in a field (or in the presence of a magnetic field) will be higher, thus making these SPIONs.
More suitable for both hyperthermia and imaging. One hypothesis could be that the SPIONs coated with T70 dextran have higher core diameter in comparison to T40 due to difference of folding mechanisms of long chains of dextran enabling more or less transport of iron precursors through the dextran shell.
The hydrodynamic size distribution of the SPIONs coated with T40 and T70 dextran is shown in Figure 3. SPIONs coated with T70 dextran have smaller hydrodynamic diameter and give better amplitude and hysteresis characteristics.
3.2 Effect of co-precipitation temperature on synthesis
In this experiment, the SPIONs with T70 dextran are prepared by following the same principle as stated in materials and methods. In this study, the main focus is on the growth phase of the synthesis. To get an insight in the growth phase different samples are taken out at temperature of 20°C, 30°C, 50°C, 60°C, 70°C and 80°C and analysed by MPS. The amplitude spectra are shown in Figure 4 and the hysteresis curves obtained are shown in Figure 5.
Up to 30°C there is a weak or negligible signal from the SPIONs, hence the nanoparticles are very small. Around 50°C to 80°C the SPIONs show an increased amplitude signal, which makes them useful for imaging. The best signal is obtained at a temperature of 50°C.
The same phenomena is observed in the hysteresis curve. At initial temperatures up to 30°C the area within the hysteresis loop is negligible. After 30°C there is a rise in the area of hysteresis curves with 50°C showing the best result. Moreover, at higher temperatures all the curves show saturation making them suitable for imaging as well as hyperthermia. The hydrodynamic size distributions of the SPIONs at different co-precipitation temperatures are shown in Figure 6. All the SPIONs have the same distribution of approx. 200 nm but different hydrodynamic diameters except at 20°C the distribution is large as the growth phase has just initialized and there are very large particles present in the solution.
4 Discussion and outlook
In this study, the effect of dextran and temperature on the co-precipitation process for synthesizing SPIONs for MPI and hyperthermia is evaluated. It has been found that the type of dextran or the molecular mass of the dextran plays a significant role in the amplitude spectrum as well as hysteresis which are the essential parameters for quantifying the response of the SPIONs for imaging as well as hyperthermia. With this study, it also has been found that higher molecular mass dextran (T70) increases the core diameter and hence better signal response from the SPIONs. Temperature of the synthesis also plays a characteristic role in the final outcome of the SPIONs in terms of amplitude response and hysteresis. It is established that in co-precipitation method, high temperature leads to better results but the effect is not so evident, after raising the temperature to 50°C.
Research funding: We would like thank the German Federal Ministry of Education and Research (BMBF SAMBA-PATI 13GW0069A) for supporting this project. Conflict of interest: Authors state no conflict of interest. Material and Methods: Informed consent: Informed consent is not applicable. Ethical approval: The conducted research is not related to either human or animal use.
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About the article
Published Online: 2016-09-30
Published in Print: 2016-09-01
Citation Information: Current Directions in Biomedical Engineering, Volume 2, Issue 1, Pages 529–532, ISSN (Online) 2364-5504, DOI: https://doi.org/10.1515/cdbme-2016-0117.
©2016 Ankit Malhotra et al., licensee De Gruyter.. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. BY-NC-ND 4.0