Nanocatalytic Medicine of Iron-Based Nanocatalysts

Introduction Ciclopirox olamine (CPO), a hydroxypyridone derivative, belongsto antifungal agents used for the treatment of superficial fungalinfections. Recently, it has been reported that CPO acts as apotential chelating agent and influences some cellular processesof the fungus by chelating metal irons.

Multifunctional nanosystems sequentially regulating intratumor Fenton chemistry by remodeling the tumor microenvironment to reinforce chemodynamic therapy.

Size-Tunable DNA-Based Micelles for Deep Tumor Penetration

Iron oxides such as hematite (α-Fe2O3) play an important role in diverse fields ranging from biogeochemistry to photocatalysis. In the majority of these cases their electrical properties are key because they facilitate electron transfer reactions occurring at their interfaces. The iron oxides tend to be wide band gap semiconductors with a narrow d band. Consequently, electron and hole charge carriers localize by self-trapping to form polarons, carriers whose mobilities are tied to the lattice distortions they create. Site-to-site polaron transport is thermally activated and the rate depends on the energy to reorganize the local structure into a suitable transition state, as well as the strength of the electronic coupling in that transient configuration. In turn, these depend on factors that determine the atomic and electronic structure, including crystallographic direction.Because the structure of polarons, the reorganization energy, and the electronic coupling matrix element are not readily experimentally accessible, quantum mechanical calculations have been extraordinarily useful. However, this also means that the accuracy of predicting polaronic charge carrier mobilities depends strongly on the computational method used. In the ~20 years since the first application of ab initio cluster model computations to this topic for hematite, both the methodological rigor and the supporting computational power have greatly advanced. After a brief historical overview, this talk will highlight current findings obtained with gap-optimized hybrid density functional theory with periodic boundary conditions performed on massively parallel supercomputers. Comparisons will be made to the original calculations for hematite published in 2003. The DFT-based predictions for other iron oxide phases will also be discussed.Specifically, we will present calculations of both the electron and hole polaron structures and associated reorganization energies for the bulk of hematite, lepidocrocite (γ-FeOOH), goethite (α-FeOOH) and white rust (Fe(OH)2).1 Through the use of gap-optimized hybrid functionals and large supercells under periodic boundary conditions, we remove some of the complications and uncertainties present in earlier cluster model calculations. It is found that while the hole polaron in these materials generally localizes onto a single iron site, the electron polaron delocalizes across two iron sites of the same spin layer as a consequence of the lower reorganization energy for electrons compared to holes. An exception to these trends is the hole of goethite, which according to our calculations does not form a localized polaron.For hematite,2 we find that upon ionization the hole relaxes from a delocalized band state to a polaron localized on a single iron atom with localization induced by tetragonal distortion of the six surrounding iron-oxygen bonds. This distortion is responsible for sluggish hopping transport in the Fe-bilayer, characterized by an activation energy of 70 meV and a hole mobility of 0.031 cm2/(V s). By contrast, the excess electron induces a smaller distortion of the iron-oxygen bonds resulting in delocalization over two neighboring Fe units. We find that 2-site delocalization is advantageous for charge transport due to the larger spatial displacements per transfer step. As a result, the electron mobility is predicted to be a factor of three higher than the hole mobility, 0.098 cm2/(V s), in qualitative agreement with experimental observations.The advances made on the theory and simulation front have provided increasing insight into the nature of polaronic transport in the iron oxides, and the methods have been widely duplicated successfully to a variety of materials. However, there is tremendous room for expansion of the work to treat the more challenging aspects governing iron oxide behavior in natural systems and in device application, including the role of interfaces, surface potential, and defects to name a few. Theoretical computations seem poised now more than ever to help unlock the fundamental insight into charge carrier transport in polaronic materials needed to understand and adapt their electrical transport properties. References Ahart C.S., Blumberger J., Rosso K.M. (2020) Polaronic structure of excess electrons and holes for a series of bulk iron oxides. Physical Chemistry Chemical Physics, 22, 10699-10709.Ahart C.S., Rosso K.M., Blumberger J. (2022) Electron and hole mobilities in bulk hematite from spin-constrained density functional theory. Journal of the American Chemical Society, 144, 4623-4632.

Identifying Key Descriptors for the Single-Atom Catalyzed CO Oxidation

Homocytosine-templated gold nanoclusters as a label-free fluorescent probe: Ferrous ions and glucose detection based on Fenton and enzyme-Fenton reaction

Destruction of a dense nonaqueous phase liquid (DNAPL) by soluble iron (III)-catalyzed and pyrolusite (β-MnO 2 )-catalyzed Fenton's reactions (hydrogen peroxide and transition metal catalysts) was investigated using carbon tetrachloride (CT) as a model contaminant. In the system amended with 5 mM soluble iron (III), 24% of the CT DNAPL was destroyed after 3 h while CT dissolution in parallel fill-and-draw systems was minimal, indicating that CT was degraded more rapidly than it dissolved into the aqueous phase. Fenton's reactions catalyzed by the naturally occurring manganese oxide pyrolusite were even more effective in destroying CT DNAPLs, with 53% degradation after 3 h. Although Fenton's reactions are characterized by hydroxyl radical generation, carbon tetrachloride is unreactive with hydroxyl radicals; therefore, a transient oxygen species other than hydroxyl radicals formed through Fenton's propagation reactions was likely responsible for CT destruction. These results demonstrate that Fenton-like reactions in which nonhydroxyl radical species are generated may provide an effective method for the in situ treatment of DNAPLs.

Initiating localized catalytic chemical reactions in tumor microenvironment (TME) can achieve appealing tumor-therapeutic efficacy concurrently with high specificity and desirable biosafety, which is mainly dependent on the high performance of biomedical nanocatalysts. This report demonstrates that PEGylated single-atom Fe-containing nanocatalysts (PSAF NCs) could effectively trigger the in situ tumor-specific Fenton reaction to generate abundant toxic hydroxyl radicals (•OH) selectively under the acidic TME. Based on density functional theory, it has been theoretically uncovered that the nanocatalysts could specifically catalyze the heterogeneous Fenton reaction via a proton-mediated H2O2-homolytic pathway. These generated radicals could not only lead to the apoptotic cell death of malignant tumors, but also induce the accumulation of lipid peroxides, causing tumor cell ferroptosis, which synergistically lead to an impressive tumor suppression outcome. In the meantime, the favorable biodegradability and biocompatibility of PSAF NCs also guarantee their desirable biosafety both in vivo and in vitro.

Chemodynamic therapy based on Fe2+-catalyzed Fenton reaction holds great promise in cancer treatment. However, low-produced hydroxyl radicals in tumor cells constitute its severe challenges because of the fact that Fe2+ with high catalytic activity could be easily oxidized into Fe3+ with low catalytic activity, greatly lowering Fenton reaction efficacy. Here, we codeliver CuS with the iron-containing prodrug into tumor cells. In tumor cells, the overproduced esterase could cleave the phenolic ester bond in the prodrug to release Fe2+, activating Fenton reaction to produce the hydroxyl radical. Meanwhile, CuS could act as a nanocatalyst for continuously catalyzing the regeneration of high-active Fe2+ from low-active Fe3+ to produce enough hydroxyl radicals to efficiently kill tumor cells as well as a photothermal therapy agent for generating hyperthermia for thermal ablation of tumor cells upon NIR irradiation. The results have exhibited that the approach of photothermal therapy nanomaterials boosting transformation of Fe3+ into Fe2+ in tumor cells can highly improve Fenton reaction for efficient chemodynamic therapy. This strategy was demonstrated to have an excellent antitumor activity both in vitro and in vivo, which provides an innovative perspective to Fenton reaction-based chemodynamic therapy.

Novel water-soluble and pH-responsive anticancer drug nanocarriers: Doxorubicin–PAMAM dendrimer conjugates attached to superparamagnetic iron oxide nanoparticles (IONPs)

Nanoscale zero-valent iron particles (nZVI), with sizes smaller than 100 nm, are promising for environmental remediation of polluted water, soil and sediments. nZVI particles have high potential for migration in the environment and are likely to interact not only with pollutant chemicals but also with living organisms. For these reasons, an environmental concern is rising with respect to unintended effects that need to be weighed against the benefits of remediation. The nZVI particles have a tendency to release electrons and Fe(2+). The Fe(2+) can convert less reactive hydrogen peroxide to more reactive oxygen species, particularly hydroxyl radicals, via the Fenton reaction. Hydroxyl radicals show strong biochemical activity and can react directly with membrane lipids, proteins and DNA. Reactive oxygen species are normally scavenged by antioxidants and various enzymes; however, elevated concentrations of ROS in microbial cells can result in oxidative stress. Cells under severe oxidative stress show various dysfunctions of membrane lipids, proteins and DNA. This review focuses on the processes resulting in oxidative stress and on up-to-date studies of nZVI-induced intracellular changes leading to such stress in microorganisms.

Rationale: Magnetic resonance imaging (MRI) is one of the most widely used diagnostic tools in the clinic. In this setting, real-time monitoring of therapy and tumor site would give the clinicians a handle to observe therapeutic response and to quantify drug amount to optimize the treatment. In this work, we developed a liposome-based cargo (cancer drugs) delivery strategy that could simultaneously monitor the real-time alternating magnetic field-induced cargo release from the change in MRI relaxation parameter R1 and the location and condition of liposome from the change in R2. The tumor site can then be monitored during the cargo release because liposomes would passively target the tumor site through the enhanced permeability and retention (EPR) effect. Physical insights from the experimental results and corresponding Monte Carlo spin dynamics simulations were also discussed.Methods: Superparamagnetic iron oxide (SPIO) nanoparticles, diethylenetriaminepentaacetic acid gadolinium(III) (Gd(III)-DTPA), and a model cancer drug (fluorescein) were co-loaded in PEGylated thermosensitive liposomes. The liposomes were characterized by transmission electron cryo-microscopy (cryoTEM), dynamic light scattering (DLS), and inductively coupled plasma optical emission spectrometry (ICP-OES). Alternating magnetic field (AMF) was used to create controlled mild hyperthermia (39-42°C) and facilitate controlled cargo (fluorescein) release from the thermosensitive liposomes. MRI relaxation parameters, R1 and R2, were measured at room temperature. The temporal variation in R1 was used to obtain the temporal profile of cargo release. Due to their similar sizes, both the gadolinium and cargo (model cancer drug fluorescein) would come out of the liposomes together as a result of heating. The temporal variation in R2 was used to monitor SPIO nanoparticles to enhance the tumor contrast. Monte Carlo spin dynamics simulations were performed by solving the Bloch equations and modeling SPIO nanoparticles as magnetized impenetrable spheres.Results: TEM images and DLS measurements showed the diameter of the liposome nanoparticle ~ 200 nm. AMF heating showed effective release of the model drug. It was found that R1 increased linearly by about 70% and then saturated as the cargo release process was completed, while R2 remained approximately constant with an initial 7%-drop and then recovered. The linear increase in R1 is consistent with the expected linear cargo release with time upon AMF heating. Monte Carlo spin dynamics simulations suggest that the initial temporal fluctuation of R2 is due to the plausible changes of SPIO aggregation and the slow non-recoverable degradation of liposomal membrane that increases water permeability with time by the heating process. The simulations show an order of magnitude increase in R2 at higher water permeability.Conclusion: We have performed MR parameter study of the release of a cargo (model cancer drug, fluorescein) by magnetic heating from thermosensitive multifunctional liposomes loaded with dual contrast agents. The size of the liposome nanoparticles loaded with model cancer drug (fluorescein), gadolinium chelate, and SPIO nanoparticles was appropriate for a variety of cancer therapies. A careful and detailed analysis with theoretical explanation and simulation was carried out to investigate the correlation between MRI relaxation parameters, R1 and R2, and different cargo release fractions. We have quantified the cargo release using R1, which shows a linear relation between each other. This result provides a strong basis for the dosage control of drug delivered. On the other hand, the fairly stable R2 with almost constant value suggests that it could be used to monitor the position and condition of the liposomal site, as SPIO nanoparticles mostly remained in the aqueous core of the liposome. Because our synthesized SPIO-encapsulated liposomes could be targeted to tumor site passively by the EPR effect, or actively through magnetofection, this study provides a solid ground for developing MR cancer theranostics in combination of this nanostructure and AMF heating strategy. Furthermore, our simulation results predict a sharp increase in R2 during the AMF heating, which opens up the exciting possibility of high-resolution, high-contrast real-time imaging of the liposomal site during the drug release process, provided AMF heating could be incorporated into an MRI setup. Our use of the clinically approved materials, along with confirmation by theoretical simulations, make this technique a promising candidate for translational MR cancer theranostics.

Using ESR spin-trapping techniques with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), we confirmed the 1:1 stoichiometry for the formation of hydroxyl radicals with Fe2+ in the Fenton reaction under experimental conditions wherein [H2O2] is 90 microM and [Fe2+] is very low, 1 microM or less. The stoichiometry decreased markedly as the Fe2+ concentration was increased. The efficiency of hydroxyl radical generation varied with the nature of the iron chelators used and increased in the order of phosphate alone approximately ADP less than EDTA less than diethylenetriaminepentaacetic acid (DETAPAC). The second order rate constant for the Fenton reaction was measured to be 2.0 x 10(4) M-1 s-1 for phosphate alone, 8.2 x 10(3) M-1 s-1 for ADP, 1.4 x 10(4) M-1 s-1 for EDTA, and 4.1 x 10(2) M-1 s-1 for DETAPAC. Measuring the radicals formed as spins trapped in the presence of ethanol, we estimated the amount of total oxidizing intermediates formed in the Fenton reaction, which we concluded consists of hydroxyl radicals and an iron species. The oxidizing species of iron which might be assigned as ferryl, FeO2+, or Fe(IV) = O was generated effectively in the presence of ADP even at low Fe2+ concentrations. In general, as the Fe2+ concentration was increased, the ferryl species predominated over the hydroxyl radical except for the case of Fe(II)-DETAPAC, which generated only hydroxyl radicals as the oxidizing species. Three possible pathways are proposed for the Fenton reaction, the dominant ones depending very much on the nature of the iron chelator being used.

Boosting oxygen reduction of single atomic iron sites by charge redistribution

Iron oxide nanoparticles (IONPs) have garnered significant attention as a promising platform for reactive oxygen species (ROS)-dependent disease treatment, owing to their remarkable biocompatibility and Fenton catalytic activity. However, the low catalytic activity of IONPs is a major hurdle in their clinical translation. To overcome this challenge, IONPs of different compositions are examined for their Fenton reaction under pharmacologically relevant conditions. The results show that wüstite (FeO) nanoparticles exhibit higher catalytic activity than magnetite (Fe3 O4 ) or maghemite (γ-Fe2 O3 ) of matched size and coating, despite having a similar surface oxidation state. Further analyses suggest that the high catalytic activity of wüstite nanoparticles can be attributed to the presence of internal low-valence iron (Fe0 and Fe2+ ), which accelerates the recycling of surface Fe3+ to Fe2+ through intraparticle electron transport. Additionally, ultrasmall wüstite nanoparticles are generated by tuning the thermodecomposition-based nanocrystal synthesis, resulting in a Fenton reaction rate 5.3 times higher than that of ferumoxytol, an FDA-approved IONP. Compared with ferumoxytol, wüstite nanoparticles substantially increase the level of intracellular ROS in mouse mammary carcinoma cells. This study presents a novel mechanism and pivotal improvement for the development of highly efficient ROS-inducing nanozymes, thereby expanding the horizons for their therapeutic applications.