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.

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.

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.

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.

CuS@mSiO2-PEG core-shell nanoparticles as a NIR light responsive drug delivery nanoplatform for efficient chemo-photothermal therapy.

We report a facile and low-cost approach to design a difunctional nanoplatform (CuS@mSiO2-PEG) as a near-infrared (NIR) light responsive drug delivery system for efficient chemo-photothermal therapy. The nanoplatform demonstrated good biocompatibility and colloidal stability, as well as high loading capacity for the anticancer drug (26.5 wt% for doxorubicin (DOX)). The CuS nanocrystals (core) within these CuS@mSiO2-PEG core-shell nanoparticles can effectively absorb and convert NIR light to fatal heat under NIR light irradiation for photothermal therapy, and the release of DOX from the mesoporous silica (shell) can be triggered by pH and NIR light for chemotherapy. When the CuS@mSiO2-PEG/DOX nanocomposites were irradiated by 980 nm light, both chemotherapy and photothermal therapy were simultaneously driven, resulting in a synergistic effect for killing cancer cells. Importantly, compared with chemotherapy or photothermal treatment alone, the combined therapy significantly improved the therapeutic efficacy.

Photothermal theragnosis synergistic therapy based on bimetal sulphide nanocrystals rather than nanocomposites.

A new generation of photothermal theranostic agents is developed based on Cu3BiS3 nanocrystals. A computed tomography imaging response and photothermal effect, as well as near-infrared fluorescence emission, can be simultaneously achieved through Cu3BiS3 nanocrystals rather than frequently used nanocomposites. These results provide some insight into the synergistic effect from bimetal sulphide semiconductor compounds for photothermal theragnosis therapy.

Na0.3WO3 nanorods: a multifunctional agent for in vivo dual-model imaging and photothermal therapy of cancer cells.

The combination of imaging diagnosis and photothermal ablation (PTA) therapy has become a potential treatment for cancer. In particular, tungsten bronzes have a number of unique properties such as broad near-infrared (NIR) absorption and a large X-ray attenuation coefficient. However, these materials have seldom been reported as an X-ray computed tomography (CT) contrast agent and a photothermal agent. Herein, we synthesized PEGylated Na(0.3)WO(3) nanorods (mean size ∼39 nm × 5 nm) by a simple one-pot solvothermal route. As we expected, the prepared PEGylated Na(0.3)WO(3) nanorods exhibit intense NIR absorption, derived from the outer d-electron of W(5+). These PEGylated Na(0.3)WO(3) nanorods also show an excellent CT imaging effect and a high HU value of 29.95 HU g L(-1) (much higher than the figure of iopamidol (19.35 HU g L(-1))), due to the intrinsic property of tungsten of large atomic number and X-ray attenuation coefficient. Furthermore, the temperature elevation and the in vivo photothermal experiment reveal that as-synthesized Na(0.3)WO(3) nanorods could be an effective photothermal agent, as they have low toxicity, high effectiveness and good photostability.

Folic acid-conjugated hollow mesoporous silica/CuS nanocomposites as a difunctional nanoplatform for targeted chemo-photothermal therapy of cancer cells.

In this work, we have developed a novel difunctional nanoplatform for targeted chemo-photothermal therapy. It is based on hollow mesoporous silica nanospheres as a carrier for anticancer drug-loading CuS nanoparticles attached on a silica nanosphere surface as a photothermal agent, and folic acid (FA) conjugated with a silica nanosphere as a cancer cell target. The nanoplatform has demonstrated a good photothermal effect and excellent doxorubicin (DOX) loading capacity (as high as 49.3 wt%). The photothermal agent and DOX can be targeted to deliver into cancer cells via a receptor mediated endocytosis pathway. Moreover, the release of DOX from the hollow mesoporous silica nanospheres can be triggered by pH and NIR light. Both chemotherapy and photothermal therapy can be simultaneously driven by irradiation with a 980 nm laser. More importantly, the combination of chemotherapy and photothermal therapy shows a better therapy effect than the individual therapies, thus demonstrating a synergistic action.

Water-soluble diiron hexacarbonyl complex as a CO-RM: controllable CO-releasing, releasing mechanism and biocompatibility.

A water soluble diiron hexacarbonyl complex, [Fe2{µ-SCH2CH(OH)CH2(OH)}2(CO)6] (1), was synthesised by reacting thioglycol with Fe3(CO)12 in THF. This diiron complex was employed as carbon monoxide releasing molecule (CO-RM). The CO-releasing was initiated via substitution of the bound CO by cysteamine (CysA, a clinic medicine). Further decomposition of the substituted products led to at least partially the formation of monoiron(II) dicarbonyl species via oxidative process while releasing more CO under inert atmosphere. Three intermediates generated in the CO-releasing process were spectroscopically identified. The kinetics of the decomposition of complex 1 was first-order process for both the complex and CysA, respectively. Under open atmosphere, the CO-releasing mechanism altered due to the involvement of oxygen in the decomposition of complex 1. The system showed minimal cytotoxicity in two selected arbitrarily cell lines, QSG-7701 and HepG2, with IC50 at the scale of 100 µmol L(-1).