Lipophilic Fe(III)-Complex with Potent Broad-Spectrum Anticancer Activity and Ability to Overcome Pt Resistance in A2780cis Cancer Cells.

Although iron is essential for all forms of life, it is also potentially toxic to cells as the increased and unregulated iron uptake can catalyze the Fenton reaction to produce reactive oxygen species (ROS), leading to lipid peroxidation of membranes, oxidation of proteins, cleavage of DNA and even activation of apoptotic cell death pathways. We demonstrate that Fe(hinok)3 (hinok = 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one), a neutral Fe(III) complex with high lipophilicity is capable of bypassing the regulation of iron trafficking to disrupt cellular iron homeostasis; thus, harnessing remarkable anticancer activity against a panel of five different cell lines, including Pt-sensitive ovarian cancer cells (A2780; IC50 = 2.05 ± 0.90 µM or 1.20 µg/mL), Pt-resistant ovarian cancer cells (A2780cis; IC50 = 0.92 ± 0.73 µM or 0.50 µg/mL), ovarian cancer cells (SKOV-3; IC50 = 1.23 ± 0.01 µM or 0.67 µg/mL), breast cancer cells (MDA-MB-231; IC50 = 3.83 ± 0.12 µM or 2.0 µg/mL) and lung cancer cells (A549; IC50 = 1.50 ± 0.32 µM or 0.82 µg/mL). Of great significance is that Fe(hinok)3 exhibits unusual selectivity toward the normal HEK293 cells and the ability to overcome the Pt resistance in the Pt-resistant mutant ovarian cancer cells of A2780cis.

Cyanide Bridged Platinum-Iron Complexes as Cisplatin Prodrug Systems: Design and Computational Study.

The potential role of cyanide-bridged platinum-iron complexes as an anti-cancer Pt(IV) prodrug is studied. We present design principles of a dual-function prodrug that can upon reduction dissociate and release concurrently six cisplatin units and a ferricyanide anion per prodrug unit. The prodrug molecule is a unique complex of hepta metal centers consisting of a ferricyanide core with six Pt(IV) centers each bonded to the Fe(III) core through a cyano ligand. The functionality of the prodrug is addressed through density functional theory (DFT) calculations.

KCa(H2 O)2 [FeIII (CN)6 ]⋠H2 O Nanoparticles as an Antimicrobial Agent against Staphylococcus aureus.

Biocompatible nanoparticles based on a calcium analogue of Prussian blue were designed and synthesized to take advantage of their ability to penetrate the cell membrane in Staphylococcus aureus and to undergo selective ion exchange with intracellular iron to disrupt iron metabolism in such pathogenic bacteria for antibacterial applications. KCa(H2 O)2 [FeIII (CN)6 ]⋅H2 O nanoparticles penetrate the bacterial cell membrane and sequester intracellular iron by ion exchange to form insoluble Prussian blue, thus inhibiting bacterial growth.

Nanoparticles of gadolinium-incorporated Prussian blue with PEG coating as an effective oral MRI contrast agent for gastrointestinal tract imaging.

Biocompatible nanoparticles of gadolinium-incorporated Prussian blue with the empirical formula K(0.94)Gd(0.02)Fe[Fe(CN)6] exhibit extremely high stability against the release of Gd(3+) and CN(-) ions under the acidic conditions similar to stomach juice. The high r1 relaxivity, low cytotoxicity and the ability of such nanoparticles to penetrate the cell membrane suggest that this coordination-polymer structural platform offers a unique opportunity for developing the next generation of T1-weighted oral cellular MRI probes for the early detection of tumors in the gastrointestinal tract.

Selective ion exchange governed by the Irving-Williams series in K2Zn3[Fe(CN)6]2 nanoparticles: toward a designer prodrug for Wilson's disease.

The principle of the Irving-Williams series is applied to the design of a novel prodrug based on K2Zn3[Fe(CN)6]2 nanoparticles (ZnPB NPs) for Wilson's disease (WD), a rare but fatal genetic disorder characterized by the accumulation of excess copper in the liver and other vital organs. The predetermined ion-exchange reaction rather than chelation between ZnPB NPs and copper ions leads to high selectivity of such NPs for copper in the presence of the other endogenous metal ions. Furthermore, ZnPB NPs are highly water-dispersible and noncytotoxic and can be readily internalized by cells to target intracellular copper ions for selective copper detoxification, suggesting their potential application as a new-generation treatment for WD.

Biocompatible nanoparticles of KGd(H2O)2[Fe(CN)6]·H2O with extremely high T1-weighted relaxivity owing to two water molecules directly bound to the Gd(III) center.

A simple one-step method for preparing biocompatible nanoparticles of gadolinium ferrocyanide coordination polymer KGd(H2O)2[Fe(CN)6]·H2O is reported. The crystal structure of this coordination polymer is determined by X-ray powder diffraction using the bulk materials. The stability, cytotoxicity, cellular uptake, and MR phantom and cellular imaging studies suggest that this coordination-polymer structural platform offers a unique opportunity for developing the next generation of T1-weighted contrast agents with high relaxivity as cellular MR probes for biological receptors or markers. Such high-relaxivity MR probes may hold potential in the study of molecular events and may be used for in vivo MR imaging in biomedical research and clinical applications.

Synthesis, characterization, and X-ray attenuation properties of ultrasmall BiOI nanoparticles: toward renal clearable particulate CT contrast agents.

A unique decelerated hydrolytic procedure is developed and reported here for the preparation of ultrasmall nanoparticles (NPs) of PVP-coated BiOI with a narrow size distribution, i.e., 2.8 ± 0.5 nm. The crystal structure of this compound is determined by X-ray powder diffraction using the bulk materials. The stability, cytotoxicity, and potential use of the PVP-coated ultrasmall BiOI NPs as a CT contrast agent are investigated. Because of the combined X-ray attenuation effect of bismuth and iodine, such NPs exhibit a CT value that is among the best of those of the inorganic nanoparticle-based CT contrast agents reported in the literature.

Transferrin-inspired iron delivery across the cell membrane using [(L2Fe)2(µ-O)] (L = chlorquinaldol) to harness anticancer activity of ferroptosis.

Although iron is a bio-essential metal, dysregulated iron acquisition and metabolism result in production of reactive oxygen species (ROS) due to the Fenton catalytic reaction, which activates ferroptotic cell death pathways. The lipophilic Fe(III)-chelator chlorquinaldol (L; i.e., 5,7-dichloro-8-hydroxy-2-methylquinoline) strongly favors the formation of a highly stable binuclear Fe(III) complex [(L2Fe)2(µ-O)] (1) that can mimic the function of the Fe(III)-transferrin complex in terms of the strong binding to Fe(III) and facile release of Fe(II) when the metal center is reduced. It should be noted that the cellular uptake of 1 is not transferrin receptor-mediated but enhanced by the high lipophilicity of chlorquinaldol. Once 1 is transported across the cell membrane, Fe(III) can be reduced by ferric reductase or other cellular antioxidants to be released as Fe(II), which triggers the Fenton catalytic reaction, thus harnessing the anticancer activity of iron. As the result, this transferrin-inspired iron-delivery strategy significantly reduces the cytotoxicity of 1 in normal human embryonic kidney cells (HEK 293) and the hemolytic activity of 1 in human red blood cells (hRBCs), giving rise to the unique tumor-specific anticancer activity of this Fe(III) complex.

Energy calibration issues in nuclear resonant vibrational spectroscopy: observing small spectral shifts and making fast calibrations.

The conventional energy calibration for nuclear resonant vibrational spectroscopy (NRVS) is usually long. Meanwhile, taking NRVS samples out of the cryostat increases the chance of sample damage, which makes it impossible to carry out an energy calibration during one NRVS measurement. In this study, by manipulating the 14.4 keV beam through the main measurement chamber without moving out the NRVS sample, two alternative calibration procedures have been proposed and established: (i) an in situ calibration procedure, which measures the main NRVS sample at stage A and the calibration sample at stage B simultaneously, and calibrates the energies for observing extremely small spectral shifts; for example, the 0.3 meV energy shift between the 100%-(57)Fe-enriched [Fe4S4Cl4](=) and 10%-(57)Fe and 90%-(54)Fe labeled [Fe4S4Cl4](=) has been well resolved; (ii) a quick-switching energy calibration procedure, which reduces each calibration time from 3-4 h to about 30 min. Although the quick-switching calibration is not in situ, it is suitable for normal NRVS measurements.

Cysteine-assisted tailoring of adsorption properties and particle size of polymer and carbon spheres.

A series of cysteine-stabilized phenolic resin-based polymer and carbon spheres were prepared by the modified Stöber method. Cysteine plays a very important role in the proposed one-pot synthesis of the aforementioned spheres; namely, it acts as a particle stabilizer and a source of heteroatoms (nitrogen and sulfur) that can be introduced into these spheres. The diameter of these spheres can be tuned in the range of 70-610 nm by adjusting the cysteine amount and reaction temperature. Since polymer spheres obtained in the presence of cysteine contain sulfur and nitrogen heteroatoms, they were tested for adsorption of copper ions. It is shown that adsorption isotherms recorded for copper ions can be well fitted by Langmuir equation, giving unprecedented adsorption capacities up to ~65 mg/g.

Gallium analogue of soluble Prussian blue KGa[Fe(CN)6]·nH2O: synthesis, characterization, and potential biomedical applications.

The gallium analogue of the soluble Prussian blue with the formula KGa[Fe(CN)6]·nH2O is synthesized and structurally characterized. A simple aqueous synthetic procedure for preparing nanoparticles of this novel coordination polymer is reported. The stability, in vitro ion exchange with ferrous ions, cytotoxicity, and cellular uptake of such nanoparticles coated with poly(vinylpyrrolidone) are investigated for potential applications of delivering Ga(3+) ions into cells or removing iron from cells.

Mechanochemical Synthesis of Nanoparticles for Potential Antimicrobial Applications.

There is an increased interest in porous materials due to their unique properties such as high surface area, enhanced catalytic properties, and biological applications. Various solvent-based approaches have been already used to synthesize porous materials. However, the use of large volume of solvents, their toxicity, and time-consuming synthesis make this process less effective, at least in terms of principles of green chemistry. Mechanochemical synthesis is one of the effective eco-friendly alternatives to the conventional synthesis. It adopts the efficient mixing of reactants using ball milling without or with a very small volume of solvents, gives smaller size nanoparticles (NPs) and larger surface area, and facilitates their functionalization, which is highly beneficial for antimicrobial applications. A large variety of nanomaterials for different applications have already been synthesized by this method. This review emphasizes the comparison between the solvent-based and mechanochemical methods for the synthesis of mainly inorganic NPs for potential antimicrobial applications, although some metal-organic framework NPs are briefly presented too.

Development of Biocompatible Ga2(HPO4)3 Nanoparticles as an Antimicrobial Agent with Improved Ga Resistance Development Profile against Pseudomonas aeruginosa.

Ga(III) can mimic Fe(III) in the biological system due to its similarities in charge and ionic radius to those of Fe(III) and can exhibit antimicrobial activity by disrupting the acquisition and metabolism of Fe in bacterial cells. For example, Ga(NO3)3 has been proven to be effective in treating chronic lung infections by Pseudomonas aeruginosa (P. aeruginosa) in cystic fibrosis patients in a recent phase II clinical trial. However, Ga(NO3)3 is an ionic compound that can hydrolyze to form insoluble hydroxides at physiological pH, which not only reduces its bioavailability but also causes potential renal toxicity when it is used as a systemic drug. Although complexion with suitable chelating agents has offered a varying degree of success in alleviating the hydrolysis of Ga(III), the use of nanotechnology to deliver this metallic ion should constitute an ultimate solution to all the above-mentioned problems. Thus far, the development of Ga-based nanomaterials as metalloantibiotics is an underexploited area of research. We have developed two different synthetic routes for the preparation of biocompatible Ga2(HPO4)3 NPs and shown that both the PVP- or PEG-coated Ga2(HPO4)3 NPs exhibit potent antimicrobial activity against P. aeruginosa. More importantly, such polymer-coated NPs do not show any sign of Ga-resistant phenotype development after 30 passes, in sharp contrast to Ga(NO3)3, which can rapidly develop Ga-resistant phenotypes of P. aeruginosa, indicating the potential of using Ga2(HPO4)3 NPs a new antimicrobial agent in place of Ga(NO3)3.

Harnessing the dual antimicrobial mode of action with a lipophilic Mn(II) complex using the principle of the Irving-Williams Series to completely eradicate Staphylococcus aurous.

The judicious selection of 5,7-dibromo-2-methy-8-quinolinol (BQ) as a Mn(II) ionophore results in the synthesis of Mn(BQ)2(DMSO)2·DMSO (1), a potent metalloantibiotic with a dual antimicrobial mode of action against four different strains of Staphylococcus aurous (SA) bacteria (MIC = 0.625 µg mL-1). Additionally, 1 can overcome ciprofloxacin-resistance in methicillin-resistant SA bacteria.

Broad-Spectrum Antimicrobial Activity of Ultrafine (BiO)2CO3 NPs Functionalized with PVP That Can Overcome the Resistance to Ciprofloxacin, AgNPs and Meropenem in Pseudomonas aeruginosa.

Although it has no known biochemical role in living organisms, bismuth has been used to treat syphilis, diarrhea, gastritis and colitis for almost a century due to its nontoxic nature to mammalian cells. When prepared via a top-down sonication route from a bulk sample, bismuth subcarbonate (BiO)2CO3 nanoparticles (NPs) with an average size of 5.35 ± 0.82 nm exhibit broad-spectrum potent antibacterial activity against both the gram-positive and gram-negative bacteria including methicillin-susceptible Staphylococcus aureus (DSSA), methicillin-resistant Staphylococcus aureus (MRSA), drug-susceptible Pseudomonas aeruginosa (DSPA) and multidrug-resistant Pseudomonas aeruginosa (DRPA). Specifically, the minimum inhibitory concentrations (MICs) are 2.0 µg/mL against DSSA and MRSA and 0.75 µg/mL against DSPA and DRPA. In sharp contrast to ciprofloxacin, AgNPs and meropenem, (BiO)2CO3 NPs show no sign of developing Bi-resistant phenotypes after 30 consecutive passages. On the other hand, such NPs can readily overcome the resistance to ciprofloxacin, AgNPs and meropenem in DSPA. Finally, the combination of (BiO)2CO3 NPs and meropenem shows a synergistic effect with the fractional inhibitory concentration (FIC) index of 0.45.

Harnessing the Dual Antimicrobial Mechanism of Action with Fe(8-Hydroxyquinoline)3 to Develop a Topical Ointment for Mupirocin-Resistant MRSA Infections.

8-Hydroxyquinoline (8-hq) exhibits potent antimicrobial activity against Staphylococcus aureus (SA) bacteria with MIC = 16.0-32.0 µM owing to its ability to chelate metal ions such as Mn2+, Zn2+, and Cu2+ to disrupt metal homeostasis in bacterial cells. We demonstrate that Fe(8-hq)3, the 1:3 complex formed between Fe(III) and 8-hq, can readily transport Fe(III) across the bacterial cell membrane and deliver iron into the bacterial cell, thus, harnessing a dual antimicrobial mechanism of action that combines the bactericidal activity of iron with the metal chelating effect of 8-hq to kill bacteria. As a result, the antimicrobial potency of Fe(8-hq)3 is significantly enhanced in comparison with 8-hq. Resistance development by SA toward Fe(8-hq)3 is considerably delayed as compared with ciprofloxacin and 8-hq. Fe(8-hq)3 can also overcome the 8-hq and mupirocin resistance developed in the SA mutant and MRSA mutant bacteria, respectively. Fe(8-hq)3 can stimulate M1-like macrophage polarization of RAW 264.7 cells to kill the SA internalized in such macrophages. Fe(8-hq)3 exhibits a synergistic effect with both ciprofloxacin and imipenem, showing potential for combination therapies with topical and systemic antibiotics for more serious MRSA infections. The in vivo antimicrobial efficacy of a 2% Fe(8-hq)3 topical ointment is confirmed by the use of a murine model with skin wound infection by bioluminescent SA with a reduction of the bacterial burden by 99 ± 0.5%, indicating that this non-antibiotic iron complex has therapeutic potential for skin and soft tissue infections (SSTIs).

Ferroelectricity induced by ordering of twisting motion in a molecular rotor.

A novel mononuclear metal-organic compound, [Cu(Hdabco)(H(2)O)Cl(3)] (1, dabco = 1,4-diazabicyclo[2.2.2]octane) in which the Cu(II) cation adopts a slightly distorted bipyramidal geometry where the three Cl anions constitute the equatorial plane and the Hdabco cation and H(2)O molecule occupy the two axial positions, was synthesized. Its paraelectric-to-ferroelectric phase transition at 235 K (T(c)) and dynamic behaviors were characterized by single crystal X-ray diffraction analysis, thermal analysis, dielectric and ferroelectric measurements, second harmonic generation experiments, and solid-state nuclear magnetic resonance measurements. Compound 1 behaves as a molecular rotor above room temperature in which the (Hdabco) part rotates around the N···N axis as a rotator and the [Cu(H(2)O)Cl(3)] part acts as a stator. In the temperature range 235-301 K, a twisting motion of the rotator is confirmed. Below the T(c), the motions of the rotor are frozen and the molecules become ordered, corresponding to a ferroelectric phase. Origin of the ferroelectricity was ascribed to relative movements of the anions and cations from the equilibrium position, which is induced by the order-disorder transformation of the twisting motion of the molecule between the ferroelectric and paraelectric phases. Study of the deuterated analogue [Cu(Ddabco)(D(2)O)Cl(3)] (2) excludes the possibility of proton ordering as the origin of the ferroelectricity in 1.

Bi2O3 nanoparticles exhibit potent broad-spectrum antimicrobial activity and the ability to overcome Ag-, ciprofloxacin- and meropenem-resistance in P. aeruginosa: the next silver bullet of metal antimicrobials?

Antimicrobial resistance is a persistent threat to global public health. In order to combat the spread of pathogenic bacteria, numerous antimicrobial materials have been incorporated into wound dressings and medical devices such as implants and catheters. The most frequently utilized of these materials are Ag-salts and Ag-nanoparticles (AgNPs) due to their low minimum inhibitory concentrations (MICs) against common Gram-negative pathogenic bacteria such as P. aeruginosa. However, such Ag-based materials are limited to treating Gram-negative bacteria and prone to generating Ag-resistant phenotypes after only 7 consecutive exposures to these materials at a sub-inhibitory concentration. Here, we demonstrate α-Bi2O3 NPs as potential replacements for such materials, i.e., α-Bi2O3 NPs that exhibit potent broad-spectrum antibacterial activity (MIC = 0.75 µg mL-1 against P. aeruginosa; MIC = 2.5 µg mL-1 against S. aureus). Furthermore, these NPs are effective against Ag-resistant and carbapenem-resistant bacteria (MICs = 1.0 µg mL-1 and 1.25 µg mL-1, respectively) and also show a synergistic effect with meropenem (mero) in P. aeruginosa bacteria, allowing for the use of meropenem with smaller therapeutic doses (fractional inhibitory concentration = 0.45). Finally, unlike other materials that have been explored as effective antimicrobials, α-Bi2O3 NPs do not contribute to the development of Bi-resistant phenotypes after 30 passages of consecutive exposure to a sub-lethal dose of such NPs. Our results demonstrate that Bi-based materials represent a critical tool against multidrug resistant bacteria and require greater attention within the community. We anticipate this study to inspire broader investigation into the use of other metal oxides as antimicrobial materials, particularly those that limit the development of resistant phenotypes.

Harnessing the toxicity of dysregulated iron uptake for killing Staphylococcus aureus: reality or mirage?

Iron is essential for all forms of life including pathogenic bacteria. However, iron is also a double-edged sword in biology, as increase of iron uptake can result in reactive oxygen species (ROS)-triggered cell death from the iron-catalyzed Fenton reaction. In this study, we demonstrate that iron-hinokitiol, Fe(hinok)3, a neutral Fe(III) complex formed with the naturally occurring metal chelator hinokitiol; (2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one) can harness the clear ability, due to its high lipophilicity and the nonpolar nature, to penetrate the cell membrane of Staphylococcus aureus (SA) and exhibit potent antimicrobial activity that is enhanced by approximately 10 000 times as compared with hinokitiol itself. Additionally, this Fe(III) complex shows a strong ability to inhibit biofilm formation. More importantly, the development of resistance in SA toward this complex is considerably hampered in comparison with that toward ciprofloxacin. The in vivo evaluation of antimicrobial efficacy in the murine model of skin wound infection by SA confirms that the treatment with a single dose of this complex can reduce the bacterial burden by 83%, demonstrating the therapeutic potential of Fe(hinok)3 in treating skin and soft tissue infections.

Europium-151 and iron-57 nuclear resonant vibrational spectroscopy of naturally abundant KEu(III)Fe(II)(CN)6 and Eu(III)Fe(III)(CN)6 complexes.

We have performed and analyzed the first combined 151Eu and 57Fe nuclear resonant vibrational spectroscopy (NRVS) for naturally abundant KEu(III)[Fe(II)(CN)6] and Eu(III)[Fe(III)(CN)6] complexes. Comparison of the observed 151Eu vs.57Fe NRVS spectroscopic features confirms that Eu(III) in both KEu(III)[Fe(II)(CN)6] and Eu(III)[Fe(III)(CN)6] occupies a position outside the [Fe(CN)6] core and coordinates to the N atoms of the CN- ions, whereas Fe(III) or Fe(II) occupies the site inside the [Fe(CN)6]4- core and coordinates to the C atoms of the CN- ions. In addition to the spectroscopic interest, the results from this study provide invaluable insights for the design and evaluation of the nanoparticles of such complexes as potential cellular contrast agents for their use in magnetic resonance imaging. The combined 151Eu and 57Fe NRVS measurements are also among the first few explorations of bi-isotopic NRVS experiments.