2.1.1. Methods for Synthesis of Magnetic Nanomedicines

The various types of synthesis strategies for MNP can be separated into two approaches: top-down and bottom-up. The "bottom-up approach" starts from metal ions in solution via chemical methods and is probably the most commonly used strategy. The top-down approach starts with bulk material, which is further processed, i.e., by laser ablation [72–76] or lithography [77–79] including that of nanospheres [80]. The lithography techniques have broad control on the shape of nano or microstructures; however, the scaling of this method to large-scale production was reported to be challenging [81]. The laser ablation method offers the building of quite complicated structures such as core-shell MNPs and has a lot of degrees of freedom for adjustment by variation of the environment, material of target, laser regime, as well as external stimulus, for example, magnetic or electrical field to change the shape and structural properties of MNPs [72,75]. This method beats some drawbacks of more common chemical methods; for example, it does not require high temperature, pressure, or organometallic precursors to obtain MNPs with excellent magnetic properties [76,82]. Thus, the laser ablation method has great potential to set higher standards in nanoparticle production.

However, many methods are combinations of both types of methods. For example, the known ball milling method of the MNP preparation is popular for permanent magnet fabrication [83]. It allows one to scale up the synthesis to an industrial scale, although the control of particle shape and size is difficult. Potential agglomerations of nanoparticles can occur which makes the particles unsuitable for biomedical applications [83]. Nevertheless, in combination with chemistry, the ball milling equipment can be used in the so-called mechanochemical process. Here, for instance, a nanocomposite of MNPs in the benzene-1,3,5-tricarboxylic acid matrix was obtained via a mechanochemical process [84]. The obtained material was porous and defined as a metal-organic framework. This nanocomposite was tested for a drug delivery application to release doxorubicin as a model drug. The authors noted that the high surface area of such porous materials favors an increased loading rate, while the magnetic properties of this material offer novel perspectives for diagnostic systems [84].

Typical synthesis steps of chemical methods consist of different steps, particularly burst nucleation, and the following nanocrystal grow, which is called Ostwald ripening [85,86]. Control of reaction kinetics by varying temperature, solvent or other conditions, and operation with the Ostwald process by pH control and electrostatic repulsion of nuclei allow us to systematically vary the size of the particles [86]. It is of utmost importance to obtain nanoparticles with precise and predefined size, shape, and phase composition [87,88]. It was suggested to evaluate the most commonly used synthesis strategies by the four-word strengths, weaknesses, opportunities, and threats (SWOT) analysis for applications in molecular recognition [88]. The research group evaluated the co-precipitation, thermal decomposition (HTD), microemulsion, and microfluidic synthesis method and studied dual-particles consisting of several materials. The first one, co-precipitation, is an easy to use technique to obtain large amounts of MNPs by alkalization of metal salt solutions. First demonstrated in 1981 by Massart, this method is beneficial and allows us to produce well-crystallized iron oxide or ferrite MNPs in the size range of 10−30 nm [89–91]. The drawbacks of this method are the poor control of shape and size distribution; moreover, for smaller particles, less than 10 nm, the quality of crystals decreases and the number of disordered spins leads to a change in the magnetic properties [64,92]. Advanced co-precipitation methods are performed at high temperature and pressure, by hydrothermal surface treatment, or hydrothermal routes [93–95], as well as in non-aqueous medium by solvothermal methods [96–98]. The polyol process is another interesting method which is a cost-effective and easily scalable method to produce MNPs of high quality and variety morphology, from simple pseudo-spherical to multi-core nanoflowers of core-shell MNPs [99–101]. In the polyol process, solvents also play the role of a reducing agent and a surfactant.

Invented in 2004 for the synthesis of MNPs, the HTD method allows us to obtain MNPs with a narrow size distribution and high crystallinity [102–104]. MNPs produced with this method have a high value of magnetization, favoring their use in many biological applications, including sensors and detection [92,105]. According to the SWOT analysis above described [88], a drawback of this method is that it is time consuming and expensive. Precise shape control can be achieved by varying the experimental conditions. For instance, a variation of ligands and surfactants offers advantages for both magnetic properties and the related behavior in biological environments [87,106,107]. The group of Jinwoo Cheon [108] demonstrated higher magnetization values of cubic MNPs (165 emu/gFe+Zn) compared to spherical (145 emu/gFe+Zn) particles. The difference can be attributed to the lower amount of disordered spins on the surface. It was also reported that cubic shaped MNPs on the sensor's surface exhibit a higher binding ability because of the higher contact area of planar interface compared to the spherical one [106]. Furthermore, cubic MNPs exhibited stronger signals, as evaluated by giant magnetoresistive sensing (GMR) and force-induced remnant magnetization spectroscopy (FIRMS).

There are various methods for co-precipitation with different modifications, which, together with HTD, are the most frequently used methods for MNP synthesis [60,88]. Co-precipitation represents the most important production method: it is easy, cheap, and enables a rapid synthesis. The generated particles have hydrophilic surfaces, which can be functionalized in situ. The second most important method, HTD, allows one to produce MNPs with well-defined shape and narrow size distribution. However, the low amount of reaction products, high-cost reagents, and hydrophobic surfaces, which can be functionalized in the multi-step process, make this method currently mostly interesting only for research activity.
