Magnetic Nanoparticles in Human Health and Medicine

Various encapsulation methods have been employed for the synthesis of iron oxide clusters by using block copolymers, either bihydrophilic or amphiphilic and stabilizing agents. In general, these methods involve the formation of micelles. Ai et al. reported the clustering of monodisperse iron oxide particles inside the hydrophobic core of micelles made of PEG‐modified poly‐caprolactone polymer (Ai et al. 2005). These micelles were obtained by an oil‐in‐water approach performed via sonication; in detail, the nanoparticles and the polymer, dissolved in hexane, were dispersed in an aqueous polymer solution, and the resulting dispersion was sonicated, thus leading to the formation of the micelles, whose mean diameter was of 110 nm. Finally, the organic solvent was removed under reduced pressure. Following a similar approach, also block copolypeptide (Euliss et al. 2003) or copolymers of acrylic acid, styrenesulfonic acid, and vinylsulfonic acid have been studied (Ditsch et al. 2005). More recently, Schmidtke et al. reported a method for clustering colloidal nanoparticles by using a diblock copolymer system. The process was mainly described for magnetic nanoparticles, but a proof of clustering was also provided for semiconductor and plasmonic nanoparticles. First, the native ligand of nanoparticles was exchanged with polymer PI‐DETA; then the coated‐NPs were mixed with PI‐b‐PEG diblock copolymer and transferred in water by different injection approaches (manual, mechanical, and microfluidic). Finally, the polymer was thermally crosslinked by addition of a radical initiator. The resulting nanosphere was ultrastable and with a size ranging from 54 to 750 nm. The size was tuned by modifying the ratio polymer : NP, from 400 : 1 (smaller clusters) to 20 : 1 (larges ones). After magnetic characterizations (relaxometry, magnetization, and magneto‐rheological measurements), the authors observed that the cluster magnetic moment derived by the sum of entrapped NPs moments and that the dipolar interaction between the NPs as the cause of collective effect observer in magnetic clusters (Schmidtke et al. 2014). Another block copolymer, namely poly(aspartic acid)‐ b ‐poly( ε ‐caprolactone), was used for the clustering of 12 nm‐hydrophobic nanoparticles. The clusters showed an average diameter of 125 nm with good dispersion and an excellent r 2relaxivity (335 mM −1s −1at 1.5 T). In this study, the nanoclusters were exploited as a contrast agent for the labeling and the in vivo tracking of dendritic cell, achieving fine response for viability, proliferation, and differentiation capacity. The subcutaneous injection of labeled cells in mice footpad allowed to monitor the presence of cells and their migration in lymph nodes up to 72 hours without a significative loss of signal in MRI (Wu et al. 2015a). Recently, Vishwasrao et al. reported an extensive study on the clustering of hydrophobic magnetic nanoparticles by using a modified block copolymer. The clusters were obtained with nonmodified PLE‐b‐PEG block copolymer (via electrostatic binding of carboxylate groups of the PLE blocks and the nanoparticle surface) and with an alendronate sodium trihydrate (ALN)‐modified PLE‐b‐PEG polymer. In the latter, the alendronate acted as an anchor molecule due to the bisphosphonate groups of the molecule. In both cases, the cluster size remained quite small in the range between 40 and 70 nm. Moreover, the cluster was loaded with cisplatin and conjugated with luteinizing hormone‐releasing hormone (LHRH) to target corresponding overexpressed receptors on ovarian cancer cells membranes (Vishwasrao et al. 2016).

Peng et al. described the synthesis of PLGA‐coated nanoclusters for the delivery of siRNA. An aqueous suspension of presynthetized magnetic nanoparticles was mixed with a one‐pot precursor solution, composed of PLGA, siRNA, iron chloride, and citrate acid, and left to react for three hours at 60 °C. Dense clusters from 100 to 300 nm were obtained. The efficacy of these composite to deliver the siRNA was evaluated at 37 °C in a tube, achieving a full release of the payload after 12 days, and as inhibition of TNF‐ α expression in cocultured murine cancer cells RAW264.7 (Peng et al. 2012).

An unusual precursor, the iron(III) 3‐allylacetylacetonate, was used for the synthesis, and assembly, of magnetic nanoparticles. The obtained particles that resulted grafted on the surface with allyl groups, suitable for thiol‐ene click (TEC) reaction. Usually, this chemistry approach has been used for the bioconjugation of specific ligands on the particles; in this work, the allyl groups acted as a platform for the TEC reaction with thiol‐functionalized PEG (SH‐PEG), resulting in the formation of pegylated nanoclusters with a size of 60–100 nm. The use of SH‐PEG modified with folic acid resulted in nanocluster functionalized with the vitamin, without any interference on the clustering process. The obtained nanocomposite was injected intravenously into mice for testing its capability in MRI and hyperthermia treatment. After 24 hours, the clusters accumulated mainly in the grafted tumor, in liver and spleen. The magnetic particles that reached the tumor were sufficient to enhance an evident contrast in MRI and a reduction of tumor growth of 90% in comparison to control mice (Hayashi et al. 2013).

Li et al. investigated the role of cationic electrolytes in the assembly of poly(acrylic acid)‐coated magnetic nanoparticles. Interestingly, the interaction between these building blocks, that is fast and wild, was simply controlled by tuning the ionic strength of the polymers. In this case, the NPs suspension and the polymer solution were mixed, and the assembly was monitored over time: in a first step (40 minutes) the magnetic particles were clustered in dense and regular assemblies of 250 nm. Afterward, the preformed clusters started to overassembly in noncontrolled structures, that the authors defined as coral‐like aggregates, with micrometer‐range size. By repeating the entire experiment in the presence of an external magnetic field, well‐defined and regular 2 μm, cylindrical bundles were obtained. These large aggregates also occurred in this configuration as a second overassembly, since during the first 40 minutes seeding step spherical magnetic cluster were formed (Li et al. 2017).

The preparation of hybrid nanoparticles, composed of a donor–acceptor‐type conjugated polymer (PCPDTBT), hydrophobic magnetite nanoparticles and a phospholipid, was recently described. The nanoparticles were obtained first drying an organic suspension of the three main components, followed by hydration of the obtained film. The resulting particles, with a nonregular shape and a size between 100 and 150 nm, were further functionalized and stabilized with PEG molecules via NHS chemistry. The hybrid composite showed a 22‐fold photoacoustic intensity increase in the optical window (NIR‐I) as well as a shortening of T 2relaxation time, with a r 2relaxivity of 309.3 mM −1s −1at 7 T for the best nanocomposite (Pham et al. 2019).

Another class of molecules extensively used for the coating of magnetic nanocluster is represented by polysaccharides. These molecules are highly biocompatible and, in a certain case, of natural derivation. It is noteworthy that the first FDA‐approved formulations based on magnetic nanoparticles were obtained by assisted nucleation of magnetite, or maghemite, in the presence of dextran‐derivative (e.g. ferucarbotran and ferumoxide).

Kim et al. set a method for the preparation of nanoclusters based on the self‐assembly of magnetic nanoparticles in a modified‐dextran. First, the polysaccharide was modified with the introduction of different oleic acid amount; after that, the NPs, dispersed in the organic phase, was mixed with modified‐dextran and a nanoemulsion was inducted by ultrasonication step. After solvent evaporation, the clusters were resuspended in water. The substitution grade of dextran and the polymer amount used during clustering were selected as main parameters to govern the overall size of the nano‐object (below 100 nm) and the T 2relaxivities response. Moreover, the dextran‐modified surface properties exhibited sufficient affinity to macrophages, and therefore, the nanocluster was tested for the diagnosis, by MRI, of atherosclerotic plaques in vitro and in vivo (Kim et al. 2014).