Summary

Copper ferrite nanoparticles, a subset of the well-known spinel ferrites, have garnered significant attention in recent years due to their outstanding magnetic, electrical, and optical properties. These nanoparticles, typically represented by the formula MFe₂O₄, where M denotes a divalent metal ion, possess a distinctive structure that has major implications for their use in various fields. This article provides a comprehensive examination of two types of copper ferrite nanoparticles, focusing on their elemental composition, the synthesis techniques used, and how these processes influence their intrinsic properties in the context of their innovative applications as biomedical contrast agents.
The structural complexity of copper ferrite nanoparticles is determined by the cation distribution, expressed as [Cu_x²⁺Fe^1−x3+]A[Cu^1−x2+Fe^1+x3+]BO₄, with the parameter ‘x’ playing a critical role in defining the crystal symmetry. Depending on the synthesis method, this cation arrangement can lead to either tetragonal or cubic symmetry. These structural subtleties are essential for understanding the unique characteristics of these materials. Various methods have been explored for synthesizing copper ferrite nanoparticles, each offering its own benefits and drawbacks. Techniques range from solid-state reactions to sol-gel processes, sonochemical methods, and hydrothermal techniques, all of which enable fine control over the nanoparticles’ size and shape. However, many of these methods are complex, expensive, require high temperatures, and involve toxic reagents, which can limit their scalability and environmental sustainability.
This article delves into the critical impact of solvothermal synthesis methods (microwave-assisted or reflux heating) on the properties of copper ferrite nanoparticles, providing insights that expand upon and refine the thermal treatment process, and potential uses in biomedical applications, as MRI contrast agents.
To fine-tune MRI contrast agents to specific applications, research has intently focused on the modification of key nanoparticulate properties. These properties include size, shape, composition, and capping agents. The composition of metal ferrite nanoparticles, represented as MFe₂O₄ (where M can be Ni, Co, Fe, Mn), holds a significant key to their efficacy as contrast agents. It has been observed that the composition of these metal ferrite nanoparticles plays a crucial role in dictating MRI performance, with magnetization being a central determinant of transverse relaxivity (r2)–a vital factor for T2-weighted MRI. The choice of capping agents that envelop nanoparticle surfaces has also been explored extensively. Small, hydrophilic coating molecules, such as ascorbate, citrate, and glutathione, have emerged as promising options. Further, two-stage synthesis methods have been employed to render these nanoparticles water-soluble while preserving capping agent integrity.
In this study, two solvothermal synthesis approaches have been compared for producing amine-functionalized copper ferrite: microwave irradiation and reflux boiling. Both methods utilized the same precursors and quantitative ratios. The resulting magnetic nanoparticles are analysed and compared in terms of size, morphology, magnetization properties, colloidal stability, and phase composition. Additionally, their performance as MRI contrast agents are evaluated. These findings allow the assessment and comparing the effectiveness of the two synthesis methods in generating copper ferrite.

Results from nanoScan® PET/MRI 3T

MRI measurements were performed with a nanoScan® PET/MRi 3T system (Mediso, Budapest, Hungary), having a 3 T magnetic field, 600 mT/m gradient system, and a volume transmit/receive coil with a diameter of 72 mm (for in vitro measurements) and 42 mm (for in vivo measurements). In vitro scans were performed on four different ferrite concentrations (0.02, 0.05, 0.1, and 0.2 mg/mL) of both samples (CuFe₂O₄-NH₂ Refl. and CuFe₂O₄-NH₂ MW) in 2 mL Eppendorf tubes. All relaxometry measurements were performed with the same geometrical parameters. One coronal slice was imaged with 4 mm of slice thickness, 50 mm of field of view, and 0.36 mm in-plane resolution. For determining T1 relaxation times, a Multi-IR FSE 2D sequence was used, with a repetition time of 5200 ms, echo time of 5.8 ms, and inversion times of 100, 400, 600, 800, 1000, 1300, and 2000 ms. The total measurement time was 21 min. The T2 relaxation times were determined using a Multi-echo SE 2D sequence with a repetition time of 3856 ms and a first echo time of 5.5 ms, followed by 31 echoes with echo spacing of 5.55 ms. The measurement time was 10 min. A Multi-echo GRE 2D sequence was used for the calculation of T2* relaxation times with a repetition time of 350 ms and a shortest echo time of 1.75 ms, which was followed by 31 echoes with echo spacing of 1.9 ms; the measuring time was 5 min.

Fig 10. shows T1-maps were based on Multi-IR fast spin echo (FSE) scan, the T2-maps were based on Multi-echo FSE scan and the T2*-maps were based on Multi-echo GRE scan of the ferrite sample in different dilutions. The longitudinal relaxation times of each sample were calculated using the Multi-IR FSE scan, while the transverse relaxation times were calculated using the Multi-echo SE and Multi-echo gradient-echo (GRE) scans. All three types of relaxation times are decreasing with increasing ferrite concentration (Fig 11.) as it was expected from an MRI contrast agent.

For the in vivo measurements, n = 2 female, 10-week-old BalbC mice were used. The 0.2 mL of the 1 mg/mL contrast material was injected into the tail vein of the animals. In vivo measurements were performed with the mice under isoflurane anesthesia (5% for induction and 1.5–2% to maintain the appropriate level of anesthesia (Arrane®, Baxter, Newbury, UK). After the measurements, the animals were sacrificed using anaesthesia overdose of Euthasol.
The T2*-weighted gradient echo (GRE) scans were collected at two different time points (pre-injection and 10 min p.i.). A 80 × 50 mm FOV on 7 coronal slices was acquired, with a matrix size 256 × 200, slice thickness of 0.8 mm, slice gap of 0.2 mm, 4 averages and TR/ TE/FA 270 ms/5.2 ms/90°. The scan time was 3 min.
In InterView™ Fusion software (Mediso Ltd., Budapest, Hungary) 8 ROIs (liver, spleen, visceral fat tissue, renal pelvis, brain, muscle in the leg, cortex and medulla of the kidneys) were manually drawn on the pre-scans of each mouse. Images were normed to have same signal intensities in the muscle in order to have comparable signal intensity (SI) values. Relative signal changes were calculated in each ROI by the formula (SI_pre−SI_post) / SI_pre to determine the biodistribution of the nanoparticles. The higher the measured signal intensity decrease, the more the accumulated nanoparticles.

Fig 12. shows T2*-weighted gradient echo (GRE) scans of a mouse at 2 different timepoints—before injection and 10 min after intravenous injection of CuFe₂O₄-NH₂ samples (A image). The liver, spleen and kidney cortex are highlighted (A image). The ROI-wise relative change of T2*-weighted intensities (B image) shows the highest uptake in the liver. T2* contrast refers to the decay of transverse magnetization seen with gradient-echo (GRE) sequences. Identical signal-intensity levels were measured in the case of both samples.

• The comparison analysis of CuFe₂O₄-NH₂ Refl. and CuFe₂O₄-NH₂ MW nanoparticles clearly indicated that the novel method is more beneficial. CuFe₂O₄-NH₂ MW is excellent performance as an MRI contrast agent is further demonstrated by its exceptional colloidal stability and uniformly homogenous MRI signals at multiple ferrite concentrations.
• This work shows the practical advantages of choosing the best species of nanoparticle for a given diagnostic application, while also offering insightful information about the subtle characteristics of copper ferrite nanoparticles. The exceptional colloidal stability and imaging properties of CuFe₂O₄-NH₂ MW present intriguing opportunities for MRI improvements that could have a substantial influence on the area of diagnostic imaging.
• Furthermore, based on the results presented, the refluxing process can be used to successfully produce particles with a core-shell structure, featuring copper particles inside and nanoparticles on the outside. The excellent thermal conductivity of the copper raises the possibility that these core-shell particles could be used in magnetic hyperthermia treatment for cancer.

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