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.

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.

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.

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).

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.

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.

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.

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.

An aluminum lining to the dark cloud of silver resistance: harnessing the power of potent antimicrobial activity of γ-alumina nanoparticles.

Although a biologically nonessential element in living organisms, aluminum is notably nontoxic to eukaryotic cells and has a venerable history of medicinal use. We demonstrate that polyethylene glycol-coated γ-alumina nanoparticles (Al2O3-NPs) with an average size of 15 nm prepared from a commercial bulk γ-alumina (γ-Al2O3) via the top-down sonication technique exhibit antibacterial activity that is comparable to that of AgNPs against both the Gram-negative drug-susceptible Pseudomonas aeruginosa (DSPA) and multidrug-resistant Pseudomonas aeruginosa (DRPA) bacteria, while the antibacterial activity of such Al2O3-NPs considerably surpasses that of AgNPs against both the Gram-positive methicillin-susceptible Staphylococcus aureus (DSSA) and methicillin-resistant Staphylococcus aureus (MRSA) bacteria. We also demonstrate that the DSPA bacteria sequentially exposed to Al2O3-NPs for 30 days show no indication of resistance development. Furthermore, such Al2O3-NPs can completely overcome the drug resistance developed in the conventional antibiotic ciprofloxacin-resistant and AgNP-resistant mutants without developing Al resistance.

K2 Mn3 [FeII (CN)6 ]2 NPs with High T1 -Relaxivity Attributable to Water Coordination on the Mn(II) Center for Gastrointestinal Tract MR Imaging.

The lack of acid stability in the stomach and of temporal stability when moving through the gastrointestinal (GI) tract has made the development of oral magnetic resonance imaging (MRI) contrast agents based on the platform of Gd3+ -complexes problematic.On the other hand, the negative contrast enhancement produced by the T2 -weighted magnetic metal oxide nanoparticles (NPs) often renders the image readout difficult. Biocompatible NPs of the manganese Prussian blue analog K2 Mn3 [FeII (CN)6 ]2 exhibit extremely high stability under the acidic conditions of the gastric juice. Additionally, the high r1 relaxivity, low toxicity, and high temporal stability of such NPs offer great potential for the development of a true T1 -weighted oral contrast agent for MRI of the entire GI tract.

Lipophilic Ga Complex with Broad-Spectrum Antimicrobial Activity and the Ability to Overcome Gallium Resistance in both Pseudomonas aeruginosa and Staphylococcus aureus.

Antibiotic resistance (AR) necessitates the discovery of new antimicrobials with alternative mechanisms of action to those employed by conventional antibiotics. One such strategy utilizes Ga3+ to target iron metabolism, a critical process for survival. Still, Ga-based therapies are generally ineffective against Gram-positive bacteria and promote Ga resistance. In response to these drawbacks, we report a lipophilic Ga complex, [Ga2L3(bpy)2] (L = 2,2'-bis(3-hydroxy-1,4-naphthoquinone; bpy = 2,2'-bipyridine)), effective against drug-resistant Pseudomonas aeruginosa (DRPA; minimum inhibitory concentration, MIC = 10 µM = 14.8 µg/mL) and methicillin-resistant Staphylococcus aureus (MRSA, MIC = 100 µM = 148 µg/mL) without iron-limited conditions. Importantly, [Ga2L3(bpy)2] shows noticeably delayed and decreased resistance in both MRSA and DRPA, with only 8× MIC in DRPA and none in MRSA after 30 passages. This is likely due to the dual mode of action afforded by Ga (disruption of iron metabolism) and the ligand (reactive oxygen species production). Overall, [Ga2L3(bpy)2] demonstrates the utility of lipophilic metal complexes with multiple modes of action in combatting AR in Gram-positive and Gram-negative bacteria.

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.

Naphthoquinone-derivative as a synthetic compound to overcome the antibiotic resistance of methicillin-resistant S. aureus.

The treatment of Staphylococcus aureus (S. aureus) infections has become more difficult due to the emergence of multidrug resistance in the bacteria. Here, we report the synthesis of a lawsone (2-hydroxy-1,4-naphthoquinone)-based compound as an antimicrobial agent against methicillin-resistant S. aureus (MRSA). A series of lawsone-derivative compounds were synthesized by means of tuning the lipophilicity of lawsone and screened for minimum inhibitory concentrations against MRSA to identify a candidate compound that possesses a potent antibacterial activity. The identified lawsone-derivative compound exhibited significantly improved drug resistance profiles against MRSA compared to conventional antibiotics. The therapeutic efficacy of the compound was validated using murine models of wound infection as well as non-lethal systemic infection induced by MRSA. Our study further revealed the multifaceted modes of action of the compound, mediated by three distinctive mechanisms: (1) cell membrane damage, (2) chelation of intracellular iron ions, and (3) generation of intracellular reactive oxygen species.

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.

Dielectric and ferroelectric sensing based on molecular recognition in Cu(1,10-phenlothroline)2SeO4·(diol) systems.

The process of molecular recognition is the assembly of two or more molecules through weak interactions. Information in the process of molecular recognition can be transmitted to us via physical signals, which may find applications in sensing and switching. The conventional signals are mainly limited to light signal. Here, we describe the recognition of diols with Cu(1,10-phenlothroline)2SeO4 and the transduction of discrete recognition events into dielectric and/or ferroelectric signals. We observe that systems of Cu(1,10-phenlothroline)2SeO4·(diol) exhibit significant dielectric and/or ferroelectric dependence on different diol molecules. The compounds including ethane-1,2-diol or propane-1,2-diol just show small temperature-dependent dielectric anomalies and no reversible polarization, while the compound including ethane-1,3-diol shows giant temperature-dependent dielectric anomalies as well as ferroelectric reversible spontaneous polarization. This finding shows that dielectricity and/or ferroelectricity has the potential to be used for signalling molecular recognition.

Incorporation of gallium-68 into the crystal structure of Prussian blue to form K(68)GaxFe1-x[Fe(CN)6] nanoparticles: toward a novel bimodal PET/MRI imaging agent.

Similarity between the Ga(+) ion and the Fe(3+) ion allows for partial replacement of Fe(3+) ions with Ga(3+) ions in the Fe(iii) crystallographic positions in Prussian blue (PB) to form various solid solutions KGaxFe1-x[Fe(CN)6] (0 < x < 1). Such solid solutions possess very high thermodynamic stability as expected from the parent PB structure. Consequently, a simple one-step (68)Ga-labeling method was developed for preparing a single-phase nanoparticulate bimodal PET/MRI imaging agent based on the PB structural platform. Unlike the typical (68)Ga-labelling reaction based on metal complexation, this novel chelator-free (68)Ga-labeling reaction was shown to be kinetically fast under the acidic conditions. The Ga(3+) ion does not hydrolyze, and affords the (68)Ga-labelled PB nanoparticles, which are easy to purify and have extremely high stability against radionuclidic leaching in aqueous solution.

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.

Adsorption of Lead Ions from Aqueous Phase on Mesoporous Silica with P-Containing Pendant Groups.

Mesoporous silica materials with hydroxyphosphatoethyl pendant groups (POH-MS) were obtained by a two-step process: (1) block copolymer Pluronic P123-templated synthesis of mesoporous silica with diethylphosphatoethyl groups (DP-MS) by co-condensation of diethylphosphatoethyl triethoxysilane (DPTS) and tetraethylorthosilicate (TEOS) under acidic conditions and (2) conversion of diethylphosphatoethyl into hydroxyphosphatoethyl groups upon suitable treatment with concentrated hydrochloric acid. The DP-MS samples obtained by using up to 20% of DPTS featured hexagonally ordered mesopores, narrow pore size distribution and high specific surface area. Conversion of DP-MS to mesoporous silica with hydroxyphosphatoethyl groups (POH-MS) resulted in the enlargement of the specific surface area, total porosity, and microporosity. High affinity of hydroxyphosphatoethyl groups toward lead ions (Pb(2+)) makes the POH-MS materials attractive sorbents for lead ions, which is reflected by high lead uptake reaching 272 mg of Pb(2+) per gram of POH-MS. This study shows that the simple and effective co-condensation strategy assures high loading of P-containing groups showing high affinity toward lead ions, which is of great importance for removal of highly toxic lead ions from contaminated water.