Whither Magnetic Hyperthermia? A Tentative Roadmap.

The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia.

The enzyme-induced formation of iron hybrid nanostructures with different morphologies.

A new synthesis method for tailor-made iron-hybrid nanoparticles has been carried out for the first time using enzymes, which directly induce the formation of inorganic iron species. The role of the protein was critical for the formation and morphology of the iron nanostructures and, depending on the enzyme, by simple mixing with ammonium iron(ii) sulfate at room temperature and under air, it was possible to obtain, for the first time, well stabilized superparamagnetic iron and iron oxide nanorods, nanosheets and nanorings or even completely amorphous non-magnetic iron structures in the protein network. These iron nanostructure-enzyme hybrids showed excellent results as heterogeneous catalysts in organic chemistry (chemoselective hydrogenation and C-C bonding formation) and environmental remediation processes.

Tailor-made PEG coated iron oxide nanoparticles as contrast agents for long lasting magnetic resonance molecular imaging of solid cancers.

Magnetic resonance imaging (MRI) is the most powerful technique for non-invasive diagnosis of human diseases and disorders. Properly designed contrast agents can be accumulated in the damaged zone and be internalized by cells, becoming interesting cellular MRI probes for disease tracking and monitoring. However, this approach is sometimes limited by the relaxation rates of contrast agents currently in clinical use, which show neither optimal pharmacokinetic parameters nor toxicity. In this work, a suitable contrast agent candidate, based on iron oxide nanoparticles (IONPs) coated with polyethyleneglycol, was finely designed, prepared and fully characterized under a physical, chemical and biological point of view. To stand out the real potential of our study, all the experiments were performed in comparison with Ferumoxytol, a FDA approved IONPs. IONPs with a core size of 15 nm and coated with polyethyleneglycol of 5 kDa (OD15-P5) resulted the best ones, being able to be uptaken by both tumoral cells and macrophages and showing no toxicity for in vitro and in vivo experiments. In vitro and in vivo MRI results for OD15-P5 showed r2 relaxivity values higher than Ferumoxitol. Furthermore, the injected OD15-P5 were completely retained at the tumor site for up to 24 h showing high potential as MRI contrast agents for real time long-lasting monitoring of the tumor evolution.

Versatile Graphene-Based Platform for Robust Nanobiohybrid Interfaces.

Technologically useful and robust graphene-based interfaces for devices require the introduction of highly selective, stable, and covalently bonded functionalities on the graphene surface, whilst essentially retaining the electronic properties of the pristine layer. This work demonstrates that highly controlled, ultrahigh vacuum covalent chemical functionalization of graphene sheets with a thiol-terminated molecule provides a robust and tunable platform for the development of hybrid nanostructures in different environments. We employ this facile strategy to covalently couple two representative systems of broad interest: metal nanoparticles, via S-metal bonds, and thiol-modified DNA aptamers, via disulfide bridges. Both systems, which have been characterized by a multitechnique approach, remain firmly anchored to the graphene surface even after several washing cycles. Atomic force microscopy images demonstrate that the conjugated aptamer retains the functionality required to recognize a target protein. This methodology opens a new route to the integration of high-quality graphene layers into diverse technological platforms, including plasmonics, optoelectronics, or biosensing. With respect to the latter, the viability of a thiol-functionalized chemical vapor deposition graphene-based solution-gated field-effect transistor array was assessed.

Classification of Magnetic Nanoparticle Systems--Synthesis, Standardization and Analysis Methods in the NanoMag Project.

This study presents classification of different magnetic single- and multi-core particle systems using their measured dynamic magnetic properties together with their nanocrystal and particle sizes. The dynamic magnetic properties are measured with AC (dynamical) susceptometry and magnetorelaxometry and the size parameters are determined from electron microscopy and dynamic light scattering. Using these methods, we also show that the nanocrystal size and particle morphology determines the dynamic magnetic properties for both single- and multi-core particles. The presented results are obtained from the four year EU NMP FP7 project, NanoMag, which is focused on standardization of analysis methods for magnetic nanoparticles.

Degradation of magnetic nanoparticles mimicking lysosomal conditions followed by AC susceptibility.

BACKGROUND: A deeper knowledge on the effects of the degradation of magnetic nanoparticles on their magnetic properties is required to develop tools for the identification and quantification of magnetic nanoparticles in biological media by magnetic means. METHODS: Citric acid and phosphonoacetic acid-coated magnetic nanoparticles have been degraded in a medium that mimics lysosomal conditions. Magnetic measurements and transmission electron microscopy have been used to follow up the degradation process. RESULTS: Particle size is reduced significantly in 24 h at pH 4.5 and body temperature. These transformations affect the magnetic properties of the compounds. A reduction of the interparticle interactions is observed just 4 h after the beginning of the degradation process. A strong paramagnetic contribution coming from the degradation products appears with time. CONCLUSIONS: A model for the in vivo degradation of magnetic nanoparticles has been followed to gain insight on the changes of the magnetic properties of iron oxides during their degradation. The degradation kinetics is affected by the particle coating, in our case being the phosphonoacetic acid-coated particles degraded faster than the citric acid-coated ones.

Covalent coupling of gum arabic onto superparamagnetic iron oxide nanoparticles for MRI cell labeling: physicochemical and in vitro characterization.

Gum arabic (GA) is a hydrophilic composite polysaccharide derived from exudates of Acacia senegal and Acacia seyal trees. It is biocompatible, possesses emulsifying and stabilizing properties and has been explored as coating agent of nanomaterials for biomedical applications, namely magnetic nanoparticles (MNPs). Previous studies focused on the adsorption of GA onto MNPs produced by co-precipitation methods. In this work, MNPs produced by a thermal decomposition method, known to produce uniform particles with better crystalline properties, were used for the covalent coupling of GA through its free amine groups, which increases the stability of the coating layer. The MNPs were produced by thermal decomposition of Fe(acac)3 in organic solvent and, after ligand-exchange with meso-2,3-dimercaptosuccinic acid (DMSA), GA coating was achieved by the establishment of a covalent bond between DMSA and GA moieties. Clusters of several magnetic cores entrapped in a shell of GA were obtained, with good colloidal stability and promising magnetic relaxation properties (r2 /r1 ratio of 350). HCT116 colorectal carcinoma cell line was used for in vitro cytotoxicity evaluation and cell-labeling efficiency studies. We show that, upon administration at the respective IC50 , GA coating enhances MNP cellular uptake by 19 times compared to particles bearing only DMSA moieties. Accordingly, in vitro MR images of cells incubated with increasing concentrations of GA-coated MNP present dose-dependent contrast enhancement. The obtained results suggest that the GA magnetic nanosystem could be used as a MRI contrast agent for cell-labeling applications.

The endocytic penetration mechanism of iron oxide magnetic nanoparticles with positively charged cover: a morphological approach.

In this study we present a morphological approach in observing the interaction of cationic magnetic nanoparticles with A-549 cells (human lung adenocarcinoma). Under our experimental conditions, nanoparticles easily penetrated cells and were observed in vivo, using bright light microscopy. In fixed cells, nanoparticles remained inside cells, showing quantity and distribution patterns similar to those in unfixed cells. The presence of nanoparticles did not affect cell viability or the morphologic parameters assessed. We determined the potential internalization mechanism of nanoparticles into cells using endocytosis inhibitors. The results suggest that nanoparticles used in this study penetrate A-549 cells mainly through a macropinocytosis process.

Gold nanoparticles generated in ethosome bilayers, as revealed by cryo-electron-tomography.

Gold nanoparticles have been synthesized inside ethosomes, vesicles composed of phospholipid, ethanol, and water, which could be very efficient not only in delivery probes to the skin but also as diagnostic and therapeutic multimodal agents. High efficiency encapsulation of gold nanoparticles is achieved by a simple strategy: the nanoparticles synthesis occurs simultaneously with the ethosomes formation in the absence of any undesirable reducing agents. A three-dimensional reconstruction of a gold-embedded ethosome generated by cryoelectron tomography reveals that the gold particle is localized inside the lipid bilayer, leaving the ethosome surface and core free for further functionalization. The resulting gold nanoparticles are homogeneous in size and shape and, depending on synthesis temperature, the size ranges from 10 to 20 nm, as revealed by TEM. The ethosome-nanoparticles hybrids' size has been investigated by means of dynamic light scattering and has been found to vary with temperature and gold salt concentration from 700 to 400 nm. Gold nanoparticles-encapsulated ethosomes offer a versatile platform for the enhancement of pharmacological efficacy in transdermal and dermal delivery systems.

Cytokine adsorption/release on uniform magnetic nanoparticles for localized drug delivery.

Attachment of cytokines to magnetic nanoparticles has been developed as a system for controlled local drug release in cancer therapy. We studied the adsorption/release of murine interferon gamma (IFN-gamma) on negatively charged magnetic nanoparticles prepared by three different methods, including coprecipitation, decomposition in organic media, and laser pyrolysis. To facilitate IFN-gamma adsorption, magnetic nanoparticles were surface modified by distinct molecules to achieve high negative charge at pH 7, maintaining small aggregate size and stability in biological media. We analyzed carboxylate-based coatings and studied the colloidal properties of the resulting dispersions. Finally, we incubated the magnetic dispersions with IFN-gamma and determined optimal conditions for protein adsorption onto the particles, as well as the release capacity at different pH and as a function of time. Particles prepared by decomposition in organic media and further modified with dimercaptosuccinic acid showed the most efficient adsorption/release capacity. IFN-gamma adsorbed on these nanoparticles would allow concentration of this protein or other biomolecules at specific sites for treatment of cancer or other diseases.