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 cancer stem cell potency of group 10‐Azadiphosphine metal complexes

Abstract: The cancer stem cell (CSC) potency of a series of structurally analogous Group 10‐azadiphosphine metal complexes is reported. The complexes comprise a Group 10 metal (Ni for 1, Pd for 2, or Pt for 3), an azadiphosphine ligand, and two chloride ligands. The complexes exhibit micromolar potency towards bulk breast cancer cells and breast CSCs cultured in monolayer systems. The cytotoxicity of the complexes is comparable to or better than clinically used metallopharmaceuticals, cisplatin and carboplatin, and the gold‐standard anti‐breast CSC agent, salinomycin. Notably, the breast CSC mammosphere inhibitory effect and potency of the complexes is dependent on the Group 10 metal present, increasing in the following order: 3<2<1. This study highlights the importance of the metal within a given series of structurally related compounds to their breast CSC mammosphere activity and reinforces the therapeutic potential of Group 10 coordination complexes as anti‐CSC agents

Crystal structure of tris(2,2′-bipyridine-κ2 N,N′)iron(II) triiodide – dichloromethane (2/1), C61H50Cl2Fe2I12N12

C61H50Cl2Fe2I12N12, orthorhombic, Pbcn (no. 60), a = 13.0247(4) Å, b = 17.0204(5) Å, c = 34.1475(9) Å, β = 90, V = 7570.0(4) Å3, Z = 4, Rgt (F) = 0.0694, wRref (F 2) = 0.1605, T = 293(2) K

On the Microcrystal Structure of Sputtered Cu Films Deposited on Si(100) Surfaces: Experiment and Integrated Multiscale Simulation

Sputtered Cu/Si thin films were experimentally prepared at different sputtering pressures and characterized using X-ray diffraction (XRD) and an atomic force microscope (AFM). Simultaneously, an application-oriented simulation approach for magnetron sputtering deposition was proposed in this work. In this integrated multiscale simulation, the sputtered atom transport was modeled using the Monte Carlo (MC) and molecular dynamics (MD) coupling method, and the deposition of sputtered atoms was simulated using the MD method. This application-oriented simulation approach was used to simulate the growth of Cu/Si(100) thin films at different sputtering pressures. The experimental results unveiled that, as the sputtering pressure decreased from 2 to 0.15 Pa, the surface roughness of Cu thin films gradually decreased; (111)-oriented grains were dominant in Cu thin films and the crystal quality of the Cu thin film was gradually improved. The simulation results were consistent with the experimental characterization results. The simulation results revealed that the transformation of the film growth mode from the Volmer–Weber growth mode to the two-dimensional layered growth mode resulted in a decrease in the surface roughness of Cu thin films; the increase in the amorphous compound CuSix and the hcp copper silicide with the decrease in the sputtering pressure was responsible for the improvement of the crystal quality of the Cu thin film. This work proposed a more realistic, integrated simulation scheme for magnetron sputtering deposition, providing theoretical guidance for the efficient preparation of high-quality sputtered films

Study on the Deposition Uniformity of Triple-Target Magnetron Co-Sputtering System: Numerical Simulation and Experiment

The uniformity of magnetron-sputtered films can be evaluated using an analytical model whose key parameters, such as included angle cosine and distance between infinitesimal elements, are so far calculated based on targets-substrate geometric relation. This existing computation scheme is not applicable in a triple-target magnetron co-sputtering system with complex targets-substrate geometric relation. In this work, a computation method was proposed to calculate the deposition uniformity of a triple-target magnetron co-sputtering system based on the analytical model. In this method, the coordinates of the infinitesimal elements on the substrate and targets were calibrated in an identical global coordinate system via coordinate transformation, such that the key parameters of the analytical formula can be evaluated by vector computation. The effects of the target-substrate angle and target-substrate distance on the deposition uniformity of a given triple-target magnetron co-sputtering system were investigated via numerical simulation and experiment, respectively. Simulation results were consistent with experimental results. Relevant evolution mechanisms of the deposition uniformity of the co-sputtering system with the variations of target-substrate parameters were discussed in detail based on the simulation results. It is expected that this computation approach can be employed to provide theoretical guidance for the fast and economical fabrication of high-quality, large-area film and composite films

Evolution Mechanism of Sputtered Film Uniformity with the Erosion Groove Size: Integrated Simulation and Experiment

In this work, Cu thin films were experimentally fabricated at different target–substrate distances by 2-inch and 4-inch circular planar magnetron targets. Meanwhile, the sputtering deposition of Cu thin films was investigated via an integrated multiscale simulation, where the magnetron sputtering discharge was modeled using the Monte Carlo (MC) method, and the sputtered particle transport was simulated using a coupled Monte Carlo (MC) and molecular dynamics (MD) method. Experimental results indicated that, as the target–substrate distance increased from 30 to 120 mm, the film thickness distribution of the 2-inch target sputtering changed from a bell-shaped curve to a line-shaped curve, while that of the 4-inch target sputtering varied from a saddle-shaped curve to a line-shaped curve. The simulation results were accordant with the experimental results. The simulation results revealed that, at a target–substrate distance of 30 mm, the sputtering particle flow from the 2-inch target overlapped strongly near the substrate center, leading to a bell-shaped film thickness distribution, while the increased diameter of the erosion groove on the 4-inch target reduced the superposition effect of the sputtering particle flow near the substrate center, resulting in a saddle-shaped film thickness distribution. In addition, when the target–substrate distance ranged from 30 to 120 mm, the film thickness uniformity of 4-inch target sputtering was superior to that of 2-inch target sputtering, and the underlying mechanism was discussed in detail

Influence of Sputtering Pressure on the Micro-Topography of Sputtered Cu/Si Films: Integrated Multiscale Simulation

In this work, an integrated multiscale simulation of magnetron sputtering epitaxy was conducted to study the effect of sputtering pressure on the surface micro-topography of sputtered Cu/Si films. Simulation results indicated that, as the sputtering pressure increased from 0.15 to 2 Pa, the peak energy of the incident energy distribution gradually decreased from 2 to 0.2 eV, which might be mainly due to the gradual decrease in the proportion of deposited Cu atoms whose energy ranged from 2 to 30 eV; the peak angle of the incident polar angle distribution increased from 25° to 35°, which might be attributed to the gradual thermalization of deposited Cu atoms; the growth mode of Cu film transformed from the two-dimensional layered mode to the Volmer-Weber mode. The transformation mechanism of growth mode was analyzed in detail. A comprehensive analysis of the simulation results indicated that incident energy ranging from 2 to 30 eV and incident angle between 10° and 35° might be conducive to the two-dimensional layered growth of sputtered Cu films. This work proposes an application-oriented modeling approach for magnetron sputtering epitaxy

Influence of Target-Substrate Distance on the Transport Process of Sputtered Atoms: MC-MD Multiscale Coupling Simulation

A Monte Carlo (MC) and molecular dynamics (MD) coupling simulation scheme for sputtered particle transport was first proposed in this work. In this scheme, the MC method was utilized to model the free-flight process of sputtered atoms, while the MD model was adopted to simulate the collision between the sputtered atom and background gas atom so as to self-consistently calculate the post-collision velocity of the sputtered atom. The reliability of the MD collision model has been verified by comparing the computation results of the MD model and of an analytical model. This MC-MD coupling simulation scheme was used to investigate the influence of target-substrate distance on the transport characteristic parameters of sputtered Cu atoms during magnetron sputtering discharge. As the target-substrate distance increased from 30 to 150 mm, the peak energy of the incident energy distribution of deposited Cu atoms decreased from 2 to 1 eV due to the gradual thermalization of sputtered atoms. The distribution of differential deposition rate in unit solid angle firstly became more forward-peaked and then reversely approached the cosine distribution, which was agreed with the existing experimental observations. This work is expected to provide a more realistic simulation scheme for sputtered particle transport, which can be further combined with the MD simulation of sputtered film growth to explore the influence mechanism of process parameters on the properties of sputtered film

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. The nickel(II) 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 intracellular reactive oxygen species (ROS) elevation or poly ADP ribose polymerase (PARP-1) hyperactivation. ROS elevation and PARP-1 activity are traits that have been observed for established necroptosis-inducers such as shikinon, TRAIL, and glutamate. Thus the necroptosis pathway evoked by 1 is distinct. To the best of our awareness this is the first report into the anti-osteosarcoma and anti-OSC properties of a nickel complex