Encapsulation and Delivery of an Osteosarcoma Stem Cell Active Gallium(III)-Diflunisal Complex Using Polymeric Micelles.

Here we report the encapsulation of an osteosarcoma stem cell (OSC) potent gallium(III)-diflunisal complex 1 into polymeric nanoparticles, and its delivery into osteosarcoma cells. At the optimum feed (20 %, 1 NP20 ), nanoparticle encapsulation of 1 enhances potency towards bulk osteosarcoma cells and OSCs (cultured in monolayer and three-dimensional systems). Strikingly, the nanoparticle formulation exhibits up to 5645-fold greater potency towards OSCs than frontline anti-osteosarcoma drugs, doxorubicin and cisplatin. The nanoparticle formulation evokes a similar mechanism of action as the payload, which bodes well for future translation. Specifically, the nanoparticle formulation induces nuclear DNA damage, cyclooxygenase-2 downregulation, and caspase-dependent apoptosis. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver an OSC-active metal complex into osteosarcoma cells.

Iron(0) tricarbonyl η4-1-azadiene complexes and their catalytic performance in the hydroboration of ketones, aldehydes and aldimines via a non-iron hydride pathway.

Six iron(0) tricarbonyl complexes (1a-f) with a η4-1-azadiene moiety were prepared and their performance in the hydroboration of unsaturated organic compounds was investigated. All the complexes exhibit catalytic activity towards hydroboration of ketones, aldehydes and aldimines with pinacolborane (HBpin) as a hydride source to lead to secondary alcohols, primary alcohols, and secondary amines, respectively, after hydrolysis of the hydroboration products. Of the iron(0) tricarbonyl complexes, complex 1e is the most robust one and was employed throughout the catalytic investigation. Its preference towards the three types of substrates is as follows: aldimines > aldehydes ≫ ketones. In total, 24 substrates were examined for the catalytic hydroboration reactivity and generally, isolation yields ranging from 40% to 95% were achieved. Mechanistic investigation suggests that the catalytic hydroboration of the substrates proceeds via intramolecular hydride transfer without going through an Fe-H intermediate. As indicated by 1H NMR spectroscopic monitoring, the substrates and the borane agent bind to the iron centre and the imine N atom, respectively, which facilitates the hydride transfer by activating the B-H bond and polarizing the double bond of the substrates.

Recent developments in electrochemical investigations into iron carbonyl complexes relevant to the iron centres of hydrogenases.

In this brief review mainly based on our own work, we summarised the electrochemical investigations into those iron carbonyl complexes relevant to the iron centres of [FeFe]-and [Fe]-hydrogenases in the following aspects: (i) electron transfer (E) coupled with a chemical reaction (C), EC process, (ii) two-electron process with potential inversion (ECisoE), and (iii) proton-coupled electron transfer (PCET) and the role of an internal base group in the non-coordination sphere. Through individual examples, these processes involved in the electrochemistry of the iron carbonyl complexes are discussed. In probing the complexes involving a two-electron process with potential inversion, the co-existence of one- and two-electron for a complex is demonstrated by incorporating intramolecularly a ferrocenyl group(s) into the complex. Our studies on proton reduction catalysed by three diiron complexes involving the PCET mechanism are also summarised. Finally, perspectives of the electrochemical study in iron carbonyl complexes inspired by the iron-containing enzymes are mentioned in the sense of developing mimics of low overpotentials for hydrogen evolution through exploiting the PCET effect.

Revealing the Intrinsic Nature of the Synergistic Effect Caused by the Formation of Heterojunctions in Cu-Cu2O/rGO-NH2 Nanomaterials in the Catalysis of Selective Aerobic Oxidation of Benzyl Alcohol.

Ternary nanomaterials Cu-Cu2O/rGO-NH2 (rGO = reduced graphene oxide) exhibited a synergistic effect in the quantitative catalysis of selective aerobic oxidation of benzyl alcohol. The synergistic effect is attributed to the heterojunctions among the three components and in intrinsic nature, the formation of the heterojunctions lowered the conduction band (CB) energy level and raised the valence band (VB) energy level of the main catalyst Cu2O, which eases electron transfer from the catalyst to O2 in its activation and from the substrate to the catalyst in the oxidation, respectively.

One high-nuclearity Eu18 nanoring with rapid ratiometric fluorescence response to dipicolinic acid (an anthrax biomarker).

One 18-metal Eu(iii) nanoring (size: 1.0 × 2.7 × 2.7 nm) was constructed as a rapid ratiometric fluorescent probe for the detection of dipicolinic acid with high sensitivity and selectivity, by using two types of polydentate organic ligands.

Osteosarcoma Stem Cell Potent Gallium(III)-Polypyridyl Complexes Bearing Diflunisal.

We report the anti-osteosarcoma stem cell (OSC) properties of a series of gallium(III)-polypyridyl complexes (5-7) containing diflunisal, a non-steroidal anti-inflammatory drug. The most effective complex within the series, 6 (containing 3,4,7,8-tetramethyl-1,10-phenanthroline), displayed similar potency towards bulk osteosarcoma cells and OSCs, in the nanomolar range. Remarkably, 6 exhibited significantly higher monolayer and sarcosphere OSC potency (up to three orders of magnitude) than clinically approved drugs used in frontline (cisplatin and doxorubicin) and secondary (etoposide, ifosfamide, and carboplatin) osteosarcoma treatments. Mechanistic studies show that 6 downregulates cyclooxygenase-2 (COX-2) and kills osteosarcoma cells in a COX-2 dependent manner. Furthermore, 6 induces genomic DNA damage and caspase-dependent apoptosis. To the best of our knowledge, 6 is the first metal complex to kill osteosarcoma cells by simultaneously inhibiting COX-2 and damaging nuclear DNA.

The Discrete Breast Cancer Stem Cell Mammosphere Activity of Group 10-Bis(azadiphosphine) Metal Complexes.

We report the anti-breast cancer stem cell (CSC) properties of a series of Group 10-bis(azadiphosphine) complexes 1-3 under exclusively three-dimensional cell culture conditions. The breast CSC mammosphere potency of 1-3 is dependent on the Group 10 metal present, increasing in the following order: 1 (nickel complex) <2 (palladium complex) <3 (platinum complex). Notably, 3 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-active compound, or any reported anti-CSC metal complex tested under similar conditions. Mechanistic studies suggest that the most effective complexes 2 and 3 readily penetrate CSC mammospheres, enter CSC nuclei, induce genomic DNA damage, and trigger caspase-dependent apoptosis. To the best of our knowledge, this is the first study to systematically probe the anti-CSC activity of a series of structurally related Group 10 complexes and to be conducted entirely using three-dimensional CSC culture conditions.

Breast Cancer Stem Cell Potency of Nickel(II)-Polypyridyl Complexes Containing Non-steroidal Anti-inflammatory Drugs.

We report the breast cancer stem cell (CSC) potency of two nickel(II)-3,4,7,8-tetramethyl-1,10-phenanthroline complexes, 1 and 3, containing the non-steroidal anti-inflammatory drugs (NSAIDs), naproxen and indomethacin, respectively. The nickel(II) complexes, 1 and 3 kill breast CSCs and bulk breast cancer cells in the micromolar range. Notably, 1 and 3 display comparable or better potency towards breast CSCs than salinomycin, an established CSC-active agent. The complexes, 1 and 3 also display significantly lower toxicity towards non-cancerous epithelial breast cells than breast CSCs or bulk breast cancer cells (up to 4.6-fold). Mechanistic studies suggest that 1 and 3 downregulate cyclooxygenase-2 (COX-2) in breast CSCs and kill breast CSCs in a COX-2 dependent manner. Furthermore, the potency of 1 and 3 towards breast CSCs decreased upon co-treatment with necroptosis inhibitors (necrostatin-1 and dabrafenib), implying that 1 and 3 induce necroptosis, an ordered form of necrosis, in breast CSCs. As apoptosis resistance is a hallmark of CSCs, compounds like 1 and 3, which potentially provide access to alternative (non-apoptotic) cell death pathways could hold the key to overcoming hard-to-kill CSCs. To the best of our knowledge, 1 and 3 are the first compounds to be associated to COX-2 inhibition and necroptosis induction in CSCs.

The Bulk Osteosarcoma and Osteosarcoma Stem Cell Activity of a Necroptosis-Inducing Nickel(II)-Phenanthroline Complex.

We report the anti-osteosarcoma and anti-osteosarcoma stem cell (OSC) properties of a nickel(II) complex, 1. Complex 1 displays similar potency towards bulk osteosarcoma cells and OSCs, in the micromolar range. Notably, 1 displays similar or better OSC potency than the clinically approved platinum(II) anticancer drugs cisplatin and carboplatin in two- and three-dimensional osteosarcoma cell cultures. Mechanistic studies revealed that 1 induces osteosarcoma cell death by necroptosis, an ordered form of necrosis. The nickel(II) complex, 1 triggers necrosome-dependent mitrochondrial membrane depolarisation and propidium iodide uptake. Interestingly, 1 does not evoke necroptosis by elevating intracellular reactive oxygen species (ROS) or hyperactivation of poly ADP ribose polymerase (PARP-1). ROS elevation and PARP-1 activity are traits that have been observed for established necroptosis inducers such as shikonin, TRAIL and glutamate. Thus the necroptosis pathway evoked by 1 is distinct. To the best of our knowledge, this is the first report into the anti-osteosarcoma and anti-OSC properties of a nickel complex.

A 42-metal Yb(iii) nanowheel with NIR luminescent response to anions.

One Yb42 nanowheel [Yb42L14(OH)28(OAc)84] was constructed using a tridentate vanillin ligand. The external diameter of the wheel-like structure is about 3.6 nm, which allows direct visualization by TEM. It shows interesting NIR lanthanide luminescence sensing towards anions, especially to fluoride at the ppm level.

Diiron(ii) pentacarbonyl complexes as CO-releasing molecules: their synthesis, characterization, CO-releasing behaviour and biocompatibility.

Four diiron(ii) carbonyl complexes, [Fe2(µ-SR)3(CO)5X] (X- = Br-, I-; R = CH2CH3, CH2CH2CH3) were facilely synthesized by reacting [Fe(CO)4X2] with monothiolates. Their potential as carbon monoxide-releasing molecules (CORMs) was systematically investigated, revealing that their CO-releasing behaviour is highly solvent-dependent. Specifically, in dimethyl sulfoxide (DMSO), the CO-releasing kinetics were fast. Intermediates with a lower oxidation state might be involved in the reaction. By contrast, in less polar solvents such as methanol, acetonitrile and dichloromethane, intermediates featuring the triiron carbonyl cation, [Fe3(µ-SCH2CH3)6(CO)6]+, were isolated. The triiron intermediate underwent further decomposition to liberate CO. One of the iodo complexes was also examined for its CO-release in PBS solution when solubilised with DMSO in the presence of deoxy-Mb and the CO-release was found to be quantitative. Furthermore, kinetic analyses were performed and the CO-release in general obeyed a first-order kinetic model. Plausible CO-releasing pathways are proposed for the parent complexes and the triiron intermediate. Assessments in cytotoxicity indicated that the cytoxicity of the diiron(ii) complexes varied with both the halide and thiolate and those bearing bromide and the thiolate with longer chains were more biocompatible.

Degradable rhenium trioxide nanocubes with high localized surface plasmon resonance absorbance like gold for photothermal theranostics.

The applications of inorganic theranostic agents in clinical trials are generally limited to their innate non-biodegradability and potential long-term biotoxicity. To address this problem, herein via a straightforward and tailored space-confined on-substrate route, we obtained rhenium trioxide (ReO3) nanocubes (NCs) that display a good biocompatibility and biosafety. Importantly, their aqueous dispersion has high localized surface plasmon resonance (LSPR) absorbance in near-infrared (NIR) region different from previous report, which possibly associates with the charge transfer and structural distortion in hydrogen rhenium bronze (HxReO3), as well as ReO3's cubic shape. Such a high LSPR absorbance in the NIR region endows them with photoacoustic (PA)/infrared (IR) thermal imaging, and high photothermal conversion efficiency (∼57.0%) for efficient ablation of cancer cells. Also, ReO3 NCs show X-ray computed tomography (CT) imaging derived from the high-Z element Re. More attractively, those ReO3 NCs, with pH-dependent oxidized degradation behaviors, are revealed to be relatively stable in hypoxic and weakly acidic microenvironment of tumor for imaging and treatment whilst degradable in normal physiological environments of organs to enable effective clearance. In spite of their degradability, ReO3 NCs still possess tumor targeting capabilities. We thus develop a simple but powerful, safe and biodegradable inorganic theranostic platform to achieve PA/CT/IR imaging-guided cancer photothermal therapy (PTT) for improved therapeutic efficacy and decreased toxic side effects.

CuCo2S4 nanocrystals: a new platform for multimodal imaging guided photothermal therapy.

Multifunctional nanomaterials open an avenue for the integration of cancer treatment and diagnosis, trending towards the clinical application of nanomedicines in future. Herein, we synthesized biocompatible CuCo2S4 nanocrystals (NCs) via a simple reflux method and unitized them as a new theranostic platform, where an intense near-infrared (NIR) absorption offers the CuCo2S4 NCs a perfect photothermal performance and photoacoustic (PA) imaging ability; the magnetic characteristic of Co allows them to serve as an enhanced magnetic resonance (MR) contrast agent. The in vitro and in vivo experiments demonstrated their good biocompatibility, non-toxicity and perfect photothermal conversion performance and further confirmed that HeLa tumors could be effectively thermal-ablated upon the assistance of the CuCo2S4 NCs. This work introduces the first bioapplication of the CuCo2S4 NCs and promotes theranostics based on other ternary compounds.

Enhancement in catalytic proton reduction by an internal base in a diiron pentacarbonyl complex: its synthesis, characterisation, inter-conversion and electrochemical investigation.

The reaction of a tripodal ligand (H2L) with a {S2N} donor-set with tri-iron dodecacarbonyl in toluene leads to the isolation of a diiron pentacarbonyl complex 1 as a model for the sub-site of the [FeFe]-hydrogenase. Protonation of this complex under CO (1 atm.) forms quantitatively the hexacarbonyl complex 2H+ with a pendant pyridinium group. Infrared spectroscopic investigations indicate that its pendant pyridinium group dissociates to give hexacarbonyl complex 2 which forms subsequently the pentacarbonyl complex 1. The electrochemistry of these complexes has been investigated. Complex 2H+ exhibits electrocatalysis on proton reduction at a potential more positive by over 200 mV compared to that for other neutral diiron hexacarbonyl complexes. This catalysis is enhanced under a CO atmosphere by freeing the bound base group which acts as a proton relay in the catalysis.

Core-shell materials bearing iron(ii) carbonyl units and their CO-release via an upconversion process.

CO-release induced by near infrared (NIR) light, to which body tissues are relatively transparent, from photoactive CO-releasing molecules (PhotoCORMs) has great significance in exploring the clinical potential of CO. In this work, a novel upconversion nanoparticle-based nanoplatform, UCNPs@SiO2-CORMs, has been developed using a one-pot reaction. The materials liberate CO under the irradiation of NIR light. TEM images of the materials showed that this nanoplatform consisted of a core-shell structure. On the surface were incorporated thiol groups through which mono-iron(ii) carbonyl units, "Fe(η5-Cp)(CO)2" were successfully anchored by a ligand exchange reaction between [Fe(η5-Cp)(CO)2I] (1) and the thiol groups. The core of the materials consists of ß-NaYF4:Yb3+/Er3+ upconversion nanoparticles (UCNPs). Strong emission bands around 530 and 550 nm from the materials upon irradiation by NIR fall into the broad band of the electronic spectrum of the materials. Consequently, the constructed nanoplatform steadily released CO upon irradiation with a 980 nm laser (1 W cm-2). Kinetic analysis suggests that CO-release from UCNPs@SiO2-CORMs in DMSO/D2O media fits a zero-order reaction model. Assessment of the cytotoxicity of UCNPs@SiO2-CORMs indicated that they showed excellent biocompatibility and no significant photo-toxicity.

Synthesis of WS2 Nanowires as Efficient 808 nm-Laser-Driven Photothermal Nanoagents.

A prerequisite for the development of photothermal ablation therapy for cancer is to obtain efficient photothermal nanoagents that can be irradiated by near-infrared (NIR) laser. Herein, we have reported the synthesis of WS2 nanowires as photothermal nanoagents by the reaction of WCl6 with CS2 in oleylamine at 280 degrees C. WS2 nanowires have the thickness of -2 nm and length of -100 nm. Importantly, the chloroform dispersion of WS2 nanowires exhibits strong photoabsorption in NIR region. The temperature of the dispersion (0.10-0.50 mg/mL) can increase by 12.8-23.9 degrees C in 5 min under the irradiation of 808 nm laser with a power density of 0.80 W/cm2. Therefore, WS2 nanowires have a great superiority as a new nanoagent for NIR-induced photothermal ablation of cancer, due to their small size and excellent photothermal performance.

Polypyrrole-encapsulated iron tungstate nanocomposites: a versatile platform for multimodal tumor imaging and photothermal therapy.

A versatile nanoplatform of FeWO4@Polypyrrole (PPy) core/shell nanocomposites, which was facilely fabricated by first hydrothermal synthesis of FeWO4 nanoparticles and subsequent surface-coating of polypyrrole shell, was developed as an effective nanotheranostic agent of cancer. The as-prepared nanocomposites demonstrated excellent dispersion in saline, long-term colloidal storage, outstanding photo-stability and high photothermal efficiency in solution. In particular, FeWO4@PPy exhibited efficient performance for hyperthermia-killing of cancer cells under the irradiation of an 808 nm laser, accompanied with multimodal contrast capabilities for magnetic resonance imaging, X-ray computed tomography and infrared thermal imaging in vitro and in vivo. Furthermore, the nanocomposites presented impactful tumor growth inhibition and good biocompability in animal experiments. Blood circulation and biodistribution of the nanocomposites were also investigated to understand their in vivo behaviours. Our results verified the platform of FeWO4@PPy nanocomposites as a promising photothermal agent for imaging-guided cancer theranostics.

NaYF4:Yb/Er@PPy core-shell nanoplates: an imaging-guided multimodal platform for photothermal therapy of cancers.

Imaging guided photothermal agents have attracted great attention for accurate diagnosis and treatment of tumors. Herein, multifunctional NaYF4:Yb/Er@polypyrrole (PPy) core-shell nanoplates are developed by combining a thermal decomposition reaction and a chemical oxidative polymerization reaction. Within such a composite nanomaterial, the core of the NaYF4:Yb/Er nanoplate can serve as an efficient nanoprobe for upconversion luminescence (UCL)/X-ray computed tomography (CT) dual-modal imaging, the shell of the PPy shows strong near infrared (NIR) region absorption and makes it effective in photothermal ablation of cancer cells and infrared thermal imaging in vivo. Thus, this platform can be simultaneously used for cancer diagnosis and photothermal therapy, and compensates for the deficiencies of individual imaging modalities and satisfies the higher requirements on the efficiency and accuracy for diagnosis and therapy of cancer. The results further provide some insight into the exploration of multifunctional nanocomposites in the photothermal theragnosis therapy of cancers.

Photoinduced Carbon Monoxide Release from Half-Sandwich Iron(II) Carbonyl Complexes by Visible Irradiation: Kinetic Analysis and Mechanistic Investigation.

Three half-sandwich iron(II) complexes, [Fe(η(5) -Cp)(cis-CO)2 X] (X(-) =Cl(-) , Br(-) , I(-) ), were synthesized and characterized. The kinetics of the CO-releasing behaviour of these complexes upon illumination by visible irradiation in various media was investigated. Our results indicated that the CO release was significantly affected by the auxiliary ligands. Of the three light sources used (blue, green, and red), blue light exhibited the highest efficiency. In the photoinduced CO release, the solvents and exogenous nucleophiles in the media were involved, which allowed their CO-releasing reaction to comply with pseudo first-order model rather than the characteristic zero-order model for a photochemical reaction. In aqueous media (D2 O), an intermediate bearing the core of {Fe(II) (cis-CO)2 } involving cleavage of cyclopentadiene was detected. Despite the non-absorption of the red light, its illumination combined with nucleophilic substitution did cause considerable CO release. Assessment of the cytotoxicity of the three complexes indicated that they showed good biocompatibility.

Hydrous RuO2 nanoparticles as an efficient NIR-light induced photothermal agent for ablation of cancer cells in vitro and in vivo.

Metal oxides are receiving an incremental attention in recent years for their potential applications in ablation of cancer cells due to their efficient photothermal conversion and good biocompatibility, but the large sizes and poor photo-stability will seriously limit their practical application. Herein, hydrous RuO2 nanoparticles were synthesized by a facile hydrothermal treatment and surface-modified with polyvinylpyrrolidone (PVP) coating. PVP-coated RuO2 nanoparticles exhibit a well dispertion in saline solution, strong characteristic plasmonic absorption in NIR region, enhanced photothermal conversion efficiency of 54.8% and remarkable photo-stability under the irridation of an 808 nm laser. The nanoparticles were further employed as a new photothermal ablation agent for cancer cells which led rapidly to cellular deaths both in vitro and in vivo.