Iron-Based Magnetic Nanosystems for Diagnostic Imaging and Drug Delivery: Towards Transformative Biomedical Applications.

The advancement of biomedicine in a socioeconomically sustainable manner while achieving efficient patient-care is imperative to the health and well-being of society. Magnetic systems consisting of iron based nanosized components have gained prominence among researchers in a multitude of biomedical applications. This review focuses on recent trends in the areas of diagnostic imaging and drug delivery that have benefited from iron-incorporated nanosystems, especially in cancer treatment, diagnosis and wound care applications. Discussion on imaging will emphasise on developments in MRI technology and hyperthermia based diagnosis, while advanced material synthesis and targeted, triggered transport will be the focus for drug delivery. Insights onto the challenges in transforming these technologies into day-to-day applications will also be explored with perceptions onto potential for patient-centred healthcare.

Magnetic cryogels as a shape-selective and customizable platform for hyperthermia-mediated drug delivery.

Cryogels consisting of polyvinyl alcohol and iron (II, III) oxide magnetic nanoparticles coated with a model drug-acetaminophen, were developed as a tunable platform for thermally triggered drug release, based on shape-selective heat transfer. Two different shapes of cryogels; discs and spherical caps, were formed via adding polymer-nanoparticle-drug mixtures into 3D printed molds, followed by freeze-thawing five times. No additional chemical crosslinking agents were used for gel formation and the iron oxide nanoparticles were coated with acetaminophen using only citric acid as a hydrogen-bonding linker. The two gel shapes displayed varying levels of acetaminophen release within 42-50 °C, which are ideal temperatures for hyperthermia induced drug delivery. The amount and time of drug-release were shown to be tunable by changing the temperature of the medium and the shape of the gels, while keeping all other factors (ex. gel volume, surface area, polymer/nanoparticle concentrations and drug-loading) constant. The discs displayed higher drug release at all temperatures while being particularly effective at lower temperatures (42-46 °C), in contrast to the spherical caps, which were more effective at higher temperatures (48-50 °C). Magnetic hyperthermia-mediated thermal imaging and temperature profiling studies revealed starkly different heat transfer behavior from the two shapes of gels. The disc gels retained their structural integrity up to 51 °C, while the spherical caps were stable up to 59 °C, demonstrating shape-dependent robustness. The highly customizable physicochemical features, facile synthesis, biocompatibility and tunable drug release ability of these cryogels offer potential for their application as a low cost, safe and effective platform for hyperthermia-mediated drug delivery, for external applications such as wound care/muscle repair or internal applications such as melanoma treatment.

Re-designing materials for biomedical applications: from biomimicry to nature-inspired chemical engineering.

Gathering inspiration from nature for the design of new materials, products and processes is a topic gaining rapid interest among scientists and engineers. In this review, we introduce the concept of nature-inspired chemical engineering (NICE). We critically examine how this approach offers advantages over straightforward biomimicry and distinguishes itself from bio-integrated design, as a systematic methodology to present innovative solutions to challenging problems. The scope of application of the nature-inspired approach is demonstrated via examples from the field of biomedicine, where much of the inspiration is still more narrowly focused on imitation or bio-integration. We conclude with an outlook on prospective future applications, offered by the more systematic and mechanistically based NICE approach, complemented by rapid progress in manufacturing, computation and robotics. This article is part of the theme issue 'Bioinspired materials and surfaces for green science and technology'.

Titanium(IV)-induced cristobalite formation in titanosilicates and its potential impact on catalysis.

Cristobalite, a crystalline form of silica, is shown to be formed within an amorphous titanosilicate, at previously unknown conditions. Mesoporous titanosilicate microspheres (MTSM) were synthesized as efficient catalysts for the epoxidation of cyclohexene with tert-butyl hydroperoxide. High-resolution transmission electron microscopy revealed the presence of crystals in this predominantly amorphous material, after calcination at 750 °C. When calcined at 800 °C, the crystals were identified via PXRD as predominantly cristobalite, which possibly marks its first observation in titanosilicates at such a low temperature, without adding any alkali metals during synthesis. Catalytic experiments conducted with MTSM materials calcined at temperatures varying from 650 to 950 °C, reveal that the amount of cristobalite formed increases with temperature, and that it has a significant impact on the pore structure, and, remarkably, correlates with the catalytic activity of titanosilicates.

Polymer-Magnetic Composite Fibers for Remote-Controlled Drug Release.

An efficient method is reported, for the fabrication of composite microfibers that can be magnetically actuated and are biocompatible, targeting controlled drug release. Aqueous solutions of polyvinyl alcohol, incorporated with citric acid-coated Fe3O4 magnetic nanoparticles (MNPs), are subject to infusion gyration to generate 100-300 nm diameter composite fibers, with controllable MNP loading. The fibers are stable in polar solvents, such as ethanol, and do not show any leaching of MNPs for over 4 weeks. Using acetaminophen as an example, we demonstrate that this material is effective in immobilization and triggered release of drugs, which is achieved by a moving external magnetic field. The remote actuation ability, coupled with biocompatibility and lightweight property, renders enormous potential for these fibers to be used as a smart drug release agent.

Peptide nanosponges designed for rapid uptake by leukocytes and neural stem cells.

The structure of novel binary nanosponges consisting of (cholesterol-(K/D) n DEVDGC)3-trimaleimide units possessing a trigonal maleimide linker, to which either lysine (K)20 or aspartic acid (D)20 are tethered, has been elucidated by means of TEM. A high degree of agreement between these findings and structure predictions through explicit solvent and then coarse-grained molecular dynamics (MD) simulations has been found. Based on the nanosponges' structure and dynamics, caspase-6 mediated release of the model drug 5(6)-carboxyfluorescein has been demonstrated. Furthermore, the binary (DK20) nanosponges have been found to be virtually non-toxic in cultures of neural progenitor cells. It is of a special importance for the future development of cell-based therapies that DK20 nanosponges were taken up efficiently by leucocytes (WBC) in peripheral blood within 3 h of exposure. The percentage of live cells among the WBC was not significantly decreased by the DK20 nanosponges. In contrast to stem cell or leucocyte cell cultures, which have to be matched to the patient, autologous cells are optimal for cell-mediated therapy. Therefore, the nanosponges hold great promise for effective cell-based tumor targeting.

Nanoscopic surfactant behavior of the porin MspA in aqueous media.

The mycobacterial porin MspA is one of the most stable channel proteins known to date. MspA forms vesicles at low concentrations in aqueous buffers. Evidence from dynamic light scattering, transmission electron microscopy and zeta-potential measurements by electrophoretic light scattering indicate that MspA behaves like a nanoscale surfactant. The extreme thermostability of MspA allows these investigations to be carried out at temperatures as high as 343 K, at which most other proteins would quickly denature. The principles of vesicle formation of MspA as a function of temperature and the underlying thermodynamic factors are discussed here. The results obtained provide crucial evidence in support of the hypothesis that, during vesicle formation, nanoscopic surfactant molecules, such as MspA, deviate from the principles underlined in classical surface chemistry.

Adaptation of Mycobacterium smegmatis to an Industrial Scale Medium and Isolation of the Mycobacterial PorinMspA.

The adaptation of the organism to a simple and cost-effective growth medium is mandatory in developing a process for large scale production of the octamericporinMspA, which is isolated from Mycobacterium smegmatis. A fermentation optimization with the minimal nutrients required for growth has been performed. During the fermentation, the iron- and ammonium chloride concentrations in the medium were varied to determine their impact on the observed growth rates and cell mass yields. Common antibiotics to control contamination were eliminated in favor of copper sulfate to reduce costs. MspA has been successfully isolated from the harvested M. smegmatisusing aqueous nOPOE (n-octyloligooxyethylene) at 65°C. Because of the extraordinary stability of MspA, it is possible to denature and precipitate virtually all other proteins and contaminants by following this approach. To further purify the product, acetone is used for precipitation. Gel electrophoresis confirmed the presence and purity of MspA. A maximum of 840µg (via Bradford assay) of pure MspA per liter of the optimized simple growth medium has been obtained. This is a 40% increase with respect to the previously reported culture medium for MspA.

A hybrid soft solar cell based on the mycobacterial porin MspA linked to a sensitizer-viologen Diad.

A prototype of a nano solar cell containing the mycobacterial channel protein MspA has been successfully designed. MspA, an octameric transmembrane channel protein from Mycobacterium smegmatis, is one of the most stable proteins known to date. Eight Ruthenium(II) aminophenanthroline-viologen maleimide Diads (Ru-Diads) have been successfully bound to the MspA mutant MspAA96C via cysteine-maleimide bonds. MspA is known to form double layers in which it acts as nanoscopic surfactant. The nanostructured layer that is formed by (Ru-Diad)8MspA at the TiO2 electrode is photochemically active. The resulting "protein nano solar cell" features an incident photon conversion efficiency of 1% at 400 nm. This can be regarded as a proof-of-principle that stable proteins can be successfully integrated into the design of solar cells.

Channel blocking of MspA revisited.

Porin A from Mycobacterium smegmatis (MspA) is a highly stable, octameric channel protein, which acts as the main transporter of electrolytes across the cell membrane. MspA features a narrow, negatively charged constriction zone, allowing stable binding of various analytes thereby blocking the channel. Investigation of channel blocking of mycobacterial porins is of significance in developing alternate treatment methods for tuberculosis. The concept that ruthenium(II)quaterpyridinium complexes have the capability to act as efficient channel blockers for MspA and related porins, emerged after very high binding constants were measured by high-performance liquid chromatography and steady-state luminescence studies. Consequently, the interactions between the ruthenium(II) complex RuC2 molecules and MspA, leading to RuC2@MspA assemblies, have been studied utilizing time-resolved absorption/emission, atomic force microscopy, dynamic light scattering, ζ potential measurements, and isothermal titration calorimetry. The results obtained provide evidence for the formation of clusters/large aggregates of RuC2 and MspA. The results are of interest with respect to utilizing prospective channel blockers in porins. The combination of results from conceptually different techniques shed some light onto the chemical nature of MspA-channel blocker interactions thus contributing to the development of a paradigm for channel blocking.