3.3.2 Inorganic Coatings
Various preparation methods of magnetic clusters considered inorganic coatings for the stabilization of multistructures. The magnetic nanoparticles encapsulation within a silica sphere is one of the most followed approaches, as described and developed by Taboada et al. First, the nanoparticles were aggregated in a controlled manner by a sol‐gel method in a mixture of acetone and hexane. The magnetic clusters served as nucleation sites for the subsequent condensation of hydrolyzed tetramethoxy silane (TMOS), leading to the formation of the silica shell. The obtained structures had a diameter of approximately 100 nm, and the production of grams of magnetic clusters was demonstrated (Taboada et al. 2009). Also, Niu et al. chose the encapsulation into silica for the preparation of their nanocomposite (Niu et al. 2010). By using an oil‐in‐water approach, the hydrophobic magnetic nanoparticles were first incorporated into the copolymer micelles core composed of polystyrene100‐block‐poly(acrylic acid)16. Therefore, a silica layer was grown on top of the micelles by using 3‐mercaptopropyltrimethoxysilane (MPMTS) as priming molecule. Also, in that case, nanostructures with a final diameter smaller than 100 nm were fabricated.
Kralj and Makovec (2015) assessed the preparation of superparamagnetic nanostructures with highly anisotropic shapes, called nanochains. In this work, their group used some commercial nanoclusters, obtained through a nanoemulsion process and finally stabilized by a tuned silica shell. These nanostructures were formed by interaction between nanoclusters and a controlled magnetic field in presence of PVP molecules. By this way, the authors achieved the formation of small chains composed of different monomers, by tuning the field strength and exposure duration, the PVP concentration, and the stirring speed. The purpose of this clustering approach should lead to applications of the nanochains in the cancer treatment and in the ability to magnetically manipulate liquid and photonic crystals (Kralj and Makovec 2015).
Recently, Tregubov et al. used a metal‐organic framework as a substrate for the magnetic nanoclusters coating. The authors used the citrate‐capped iron oxide nanoparticles as starting material, obtained by autoclave and by using urea as precipitant. This magnetic core with a size of 80 nm and composed by several single magnetic domains was further coated by a matrix of iron(III) trimesate (also known as MIL‐100(Fe)) and synthesized by autoclaving the mixture of nanoparticles and metal precursor. Finally, a carboxymethyl dextran layer was grafted onto the surface of the system for achieving optimal colloidal stability. An advantage of such multilayered object was the assessed biocompatibility since the iron(III) trimesate can be readily degraded in physiological conditions because of the collapse of the framework in the presence of phosphates (Tregubov et al. 2018).
3.3.3 Polymer‐Assisted Clustering
Polymers, large molecules composed of many repeated subunits, are probably the most studied class of molecules used in the nanoparticle clustering. These compounds have several specific physical–chemical properties that allow to, first, help the nanoparticles assembly and, second, provide some specific functional groups on the surface for the conjugation of ligands.
Di Corato et al. developed a strategy to cluster hydrophobic magnetic nanoparticles within a shell of an amphiphilic polymer, namely poly(maleic anhydride alt‐1 octadecene) (Di Corato et al. 2009). The protocol was based on the controlled destabilization of a suspension of nanoparticles and polymer in tetrahydrofuran obtained with slow addition of acetonitrile. In the resulting clusters, nanoparticles were collapsed in the core, whereas the polymer enrolled the structure with a dense shell. The thickness of the coating was proportional to the polymer concentration, ranging from few to 30–40 nm. In this contribution, the polymer was functionalized with an organic dye for cell separation and detection, but actually, the structure offered many possibilities of modification. By the same group, colloidal quantum dots were introduced in the assembly, creating a magnetic‐fluorescent platform based on inorganic nanoparticles (Di Corato et al. 2011). CdSe@ZnS dots were dispersed in the nanoparticles suspension before the clustering, and the protocol was applied with no modification. Interestingly, the fluorescent nanoparticles were not collapsed in the core with the magnetic but were confined in the polymer shell, avoiding the fluorescent quenching of the resulting structure. This phenomenon was explained by a different grade of the insolubility of the nanoparticles in acetonitrile, due to the different surfactants on particles surface (TOPO and TOP on QDs, oleic acid, and oleylamine for magnetic nanoparticles). The functionalization with folic acid and the use of different QDs allowed performing a specific ligand separation and a multiplex analysis of sorted cells. As claimed before, this magnetic nanocluster was further modified with thermo‐responsive polymer (Deka et al. 2011) or with silver nanoparticles nucleated in situ on the polymeric surface (Di Corato et al. 2012). A variant of this clustering method involves the aggregation of the nanoparticles (dispersed in tetrahydrofuran) by adding a volume of acetonitrile in a 1 : 1 ratio. By this approach, very dense and organized, but unstable, clusters were obtained. Thus, immediately after the clustering, a polymeric shell was grafted on the surface of the ordered assemblies of nanoparticles, by condensation of a solution of poly(maleic anhydride alt‐1 octadecene) (Bigall et al. 2013). The separation of the two phases, clustering and polymer coating, was also investigated in a recent study, in which the hydrophobic nanoparticles were first collapsed in the above‐described tetrahydrofuran/acetonitrile mixture and subsequently coated with a thermo‐responsive hyaluronic acid derivative. By comparison with simultaneous one‐pot clustering, the two‐phases approach was considered more efficient to increase the concentration of nanoparticles in the structure core, with a consequence on the magnetic moment and magnetic responsiveness (Rippe et al. 2020).
In the last decade, magnetic nanocubes have aroused interest in the field of materials science as a heat mediator, due to different crystalline and shape anisotropies, compared to the most common spheres, resulting in higher heat capacity (Guardia et al. 2012; Noh et al. 2012). From clustering point of view, this class of nanomaterial is not straightforward to be managed because of the strong interparticle interaction. Materia et al. modified the previously reported procedure for spherical particles adjusting the solvent mixture and the injection rate of the polar solvent. When clustered, the nanocubes showed a lower SAR value, due to the suppression of Brownian contribution into the blocked polymeric superstructure. On the opposite, the relaxivities analysis resulted in a very low r1 value and a definite increase of the r2/r1 ratio, in comparison to the individual nanocubes (Materia et al. 2015). Recently, the same group investigated how the heat performance of the iron oxide nanocubes could be preserved or even enhanced by clustering. A possible answer is represented by nanoparticles assemblies with a 2D arrangement. Very small clusters composed of two and three nanocubes, namely dimers and trimers, showed a SAR valued almost doubled if compared to individual nanoparticles. When the nanocubes number overcame the threshold of four particles per cluster, an impressive fall of SAR value was observed (Niculaes et al. 2017). Nanocubes assembled with a 2D‐arrangement were also obtained by using an esterase‐sensitive biopolymer as an encapsulating agent. The enzyme activity resulted in the disassembly of the multiparticle cluster and, as confirmation of the above‐described study, in an enhanced SAR performance. In fact, the 2D‐clusters were split into smaller clusters composed of very few particles, in a chain‐like configuration (Avugadda et al. 2019).
Another modified‐amphiphilic polymer, poly(isobutylene‐alt‐maleic anhydride), was used for the fabrication of small nanocluster based on the assembly of hydrophobic nanoparticles. The maleic anhydrides of the polymer backbone acted as an anchor point for the addition of PEG (10%), dopamine (70%) and cystamine, a disulfide linker (20%). The three ligands ensured, respectively, high biocompatibility to the cluster, a high affinity to the nanoparticles surface and an amine for an additional functionalization. Therefore, chlorin e6, a photosensitive drug, was linked to the cystamine for the preparation of this multifunctional polymer. The cluster was prepared by a solvent exchange strategy, mixing the chloroform‐dispersed nanoparticles with a solution of the polymer in DMSO. After ultrasonication
