Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

Hierarchical superstructure aerogels for in situ biofluid metabolomics.

High-throughput biofluid metabolomics analysis for screening life-threatening diseases is urgently needed. However, the high salt content of biofluid samples, which introduces severe interference, can greatly limit the analysis throughput. Here, a new 3-D interconnected hierarchical superstructure, namely a "plasmonic gold-on-silica (Au/SiO2) double-layered aerogel", integrating distinctive features of an upper plasmonic gold aerogel with a lower inert silica aerogel was successfully developed to achieve in situ separation and storage of inorganic salts in the silica aerogel, parallel enrichment of metabolites on the surface of the functionalized gold aerogel, and direct desorption/ionization of enriched metabolites by the photo-excited gold aerogel for rapid, sensitive, and comprehensive metabolomics analysis of human serum/urine samples. By integrating all these unique advantages into the hierarchical aerogel, multifunctional properties were introduced in the SALDI substrate to enable its effective utilization in clinical metabolomics for the discovery of reliable metabolic biomarkers to achieve unambiguous differentiation of early and advanced-stage lung cancer patients from healthy individuals. This study provides insight into the design and application of superstructured nanomaterials for in situ separation, storage, and photoexcitation of multi-components in complex biofluid samples for sensitive analysis.

Easy but Efficient: Facile Approach to Molecule with Theoretically Justified Donor-Acceptor Structure for Effective Photothermal Conversion and Intravenous Photothermal Therapy.

To accelerate the pace in the field of photothermal therapy (PTT), it is urged to develop easily accessible photothermal agents (PTAs) showing high photothermal conversion efficiency (PCE). As a proof-of-concept, hereby a conventional strategy is presented to prepare donor-acceptor (D-A) structured PTAs through cycloaddition-retroelectrocyclization (CA-RE) reaction, and the resultant PTAs give high PCE upon near-infrared (NIR) irradiation. By joint experimental-theoretical study, these PTAs exhibit prominent D-A structure with strong intramolecular charge transfer (ICT) characteristics and significantly twisting between D and A units which account for the high PCEs. Among them, the DMA-TCNQ exhibits the strongest absorption in NIR range as well as the highest PCE of 91.3% upon irradiation by 760-nm LED lamp (1.2 W cm-2). In vitro and in vivo experimental results revealed that DMA-TCNQ exhibits low dark toxicity and high phototoxicity after IR irradiation along with nude mice tumor inhibition up to 81.0% through intravenous therapy. The findings demonstrate CA-RE reaction as a convenient approach to obtain twisted D-A structured PTAs for effective PTT and probably promote the progress of cancer therapies.

Cycloplatinated (II) Complex Based on Isoquinoline Alkaloid Elicits Ferritinophagy-Dependent Ferroptosis in Triple-Negative Breast Cancer Cells.

The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.

Serum Lipidomic Fingerprints Encode Early Diagnosis and Staging of Lung Cancer on a Novel PbS/Au-Layered Substrate.

Lung cancer (LC) is a major cause of mortality among malignant tumors. Early diagnosis through lipidomic profiling can improve prognostic outcomes. In this study, a uniform PbS/Au-layered substrate that enhances the laser desorption/ionization process, an interfacial process triggered on the substrate surface upon laser excitation, was designed to efficiently characterize the lipidomic profiles of LC patient serum. By controlling the stacking arrangement and particle sizes of PbS QDs and AuNPs, the optimized substrate promotes the generation of excited electrons and creates an enhanced electric field that polarizes analyte molecules, facilitating ion adduction formation ([M + Na]+ and [M + K]+) and enhancing detection sensitivity down to the femtomole level. Combining multivariate statistics and machine learning, a distinct lipidomic biomarker panel is successfully identified for the early diagnosis and staging of LC, with an accurate prediction validated by an area under the curve of 0.9479 and 0.9034, respectively. We also found that 18 biomarkers were significantly correlated with six metabolic pathways associated with LC. These results demonstrate the potential of this innovative PbS/Au-layered substrate as a sensitive platform for accurate diagnosis of LC and facilitate the development of lipidomic-based diagnostic tools for other cancers.

Rapid detection of urine chloride enabled by ion exchange in hydrophilic lead halide perovskite nanocrystals.

The rapid and precise detection of chloride ions in biosystems is of great importance for clinical diagnosis. In this work, hydrophilic CsPbBr3 perovskite nanocrystals (PNCs) with a high photoluminescence (PL) quantum yield (QY) of 59% (0.5 g L-1) are successfully achieved through the passivation of micellar glycyrrhizic acid (GA), which enables good dispersion of PNCs in ethanol. Due to the ionic nature and halogen-dominated band edge, PNCs exhibit fast ion-exchange and halogen-dependent optical properties. As a result, colloidal GA-capped PNC ethanol solution shows a continuous PL shift once aqueous Cl- with different concentrations is added. This fluorescence sensor shows a wide linear detection range (2-200 mM) of Cl-, short response time (∼1 s), and low limit of detection (1.82 mM). Because of the encapsulation of GA, good water and pH stability, and anti-interference performance are observed for the GA-capped PNC-based fluorescence sensor. Our findings provide an insight into the biosensor applications of hydrophilic PNCs.

Cytotoxic cis-ruthenium(III) bis(amidine) complexes.

In chemotherapy, the search for ruthenium compounds as alternatives to platinum compounds is proposed because of their unique properties. However, the geometry effect of ruthenium complexes is sparely investigated. In this paper, we report the synthesis of a series of bis(acetylacetonato)ruthenium(III) complexes bearing two amidines (1-) in a cis configuration. These complexes are highly cytotoxic against various cancer cell lines, including a cisplatin-resistant cell line. In vitro studies suggested that the representative complex can induce cell cycle G0/G1 phase arrest, decrease the mitochondrial membrane potential, elevate the intracellular reactive oxygen species level, and cause DNA damage and caspase-mediated mitochondrial pathway apoptosis in NCI-H460 cells. In vivo, it can effectively inhibit tumor xenograft growth in nude mouse models with no body weight loss. In combination with the reported trans-bis(amidine)ruthenium(III) complexes, we found that ruthenium(III) bis(amidine) complexes could be cytotoxic in both trans and cis geometries, which is in contrast to platinum-based compounds.

Integration of Non-targeted Proteomics Mass Spectrometry with Machine Learning for Screening Cooked Beef Adulterated Samples.

The degradation of ingredients in heat-processed meat products makes their authentication challenging. In this study, protein profiles of raw beef, chicken, duck, pork, and binary simulated adulterated beef samples (chicken-beef, duck-beef, and pork-beef) and their heat-processed samples were obtained by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Heat-stable characteristic proteins were found by screening the overlapping characteristic protein ion peaks of the raw and corresponding heat-processed samples, which were discovered by partial least-squares discriminant analysis. Based on the 36 heat-stable characteristic proteins, qualitative classification for the raw and heat-processed meats was achieved by extreme gradient boosting. Moreover, quantitative analysis via partial least squares regression was applied to determine the adulteration ratio of the simulated adulterated beef samples. The validity of the approach was confirmed by a blind test with the mean accuracy of 97.4%. The limit of detection and limit of quantification of this method were determined to be 5 and 8%, respectively, showing its practical aspect for the beef authentication.

Weakening Ligand-Liquid Affinity to Suppress the Desorption of Surface-Passivated Ligands from Perovskite Nanocrystals.

The interfacial migration of surface-bound ligands highly affects the colloidal stability and optical quality of semiconductor nanocrystals, of which the underlying mechanism is not fully understood. Herein, colloidal CsPbBr3 perovskite nanocrystals (PNCs) with fragile dynamic equilibrium of ligands are taken as the examples to reveal the important role of balancing ligand-solid/solvent affinity in suppressing the desorption of ligands. As a micellar surfactant, glycyrrhizic acid (GA) with bulky hydrophobic and hydrophilic groups exhibits a relatively smaller diffusion coefficient (∼440 µm2/s in methanol) and weaker ligand-liquid affinity than that of conventional alkyl amine and carboxy ligands. Consequently, hydrophilic GA-passivated PNCs (PNCs-GA) show excellent colloidal stability in various polar solvents with dielectric constant ranging from 2.2 to 32.6 and efficient photoluminescence with a quantum yield of 85.3%. Due to the suppressed desorption of GA, the morphological and optical properties of PNCs-GA are well maintained after five rounds purification and two months long-term storage. At last, hydrophilic PNCs-GA are successfully patterned through inkjet- and screen-printing technology. These findings offer deep insights into the interfacial chemistry of colloidal NCs and provide a universal strategy for preparing high-quality hydrophilic PNCs.

A Pyrazolate Osmium(VI) Nitride Exhibits Anticancer Activity through Modulating Protein Homeostasis in HepG2 Cells.

Interest in the third-row transition metal osmium and its compounds as potential anticancer agents has grown in recent years. Here, we synthesized the osmium(VI) nitrido complex Na[OsVI(N)(tpm)2] (tpm = [5-(Thien-2-yl)-1H-pyrazol-3-yl]methanol), which exhibited a greater inhibitory effect on the cell viabilities of the cervical, ovarian, and breast cancer cell lines compared with cisplatin. Proteomics analysis revealed that Na[OsVI(N)(tpm)2] modulates the expression of protein-transportation-associated, DNA-metabolism-associated, and oxidative-stress-associated proteins in HepG2 cells. Perturbation of protein expression activity by the complex in cancer cells affects the functions of the mitochondria, resulting in high levels of cellular oxidative stress and low rates of cell survival. Moreover, it caused G2/M phase cell cycle arrest and caspase-mediated apoptosis of HepG2 cells. This study reveals a new high-valent osmium complex as an anticancer agent candidate modulating protein homeostasis.

Covalent Bonding and Coulomb Repulsion-Guided AuNP Array: A Tunable and Reusable Substrate for Metabolomic Characterization of Lung Cancer Patient Sera.

Surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) has gained increased attention in the metabolic characterization of human biofluids. However, the stability and reproducibility of nanoparticle-based substrates remain two of the biggest challenges in high-salt environments. Here, by controlling the extent of Coulomb repulsion of 26 nm positively charged AuNPs, a homogeneous layer of covalently bonded AuNPs on a coverslip with tunable interparticle distances down to 16 nm has been successfully fabricated to analyze small biomolecules in human serum. Compared with the self-assembled AuNP array, the covalently bonded AuNP array showed superior performances on stability, reproducibility, and sensitivity in high-salt environments. The stable attachment of AuNPs maintained a detection reproducibility with a RSD less than 12% and enabled the reusability of the array for 10 experiments without significant signal deterioration (<15%) and carryover effects. Moreover, the closely positioned AuNPs allowed the coupling of photoinduced plasmons to generate an enhanced electric field, which promotes the generation of excited electrons to facilitate the desorption/ionization processes instead of the heat dissipation, thus enhancing the detection sensitivity with detection limits down to the femtomole level. Combined with machine learning methods, the AuNP array has been successfully applied to discover seven biomarkers for differentiating early-stage lung cancer patients from healthy controls. It is anticipated that this simple approach of developing robust AuNP arrays can also be extended to other types of NP arrays for wider applications of SALDI-MS technology.

Osmium(VI) nitride triggers mitochondria-induced oncosis and apoptosis.

We report a new osmium(VI) nitrido complex bearing a nonplanar tetradentate ligand with potent anticancer activity. This complex causes mitochondrial damage, which induces liver cancer cell death via oncosis and apoptosis. This is the first osmium-based anticancer candidate that induces oncosis.

Combining MALDI-MS with machine learning for metabolomic characterization of lung cancer patient sera.

An increasing amount of evidence has proven that serum metabolites can instantly reflect disease states. Therefore, sensitive and reproducible detection of serum metabolites in a high-throughput manner is urgently needed for clinical diagnosis. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is a high-throughput platform for metabolite detection, but it is hindered by significant signal fluctuations because of the "sweet spot" effect of organic matrices. Here, by screening two transformation methods and four normalization techniques to reduce the significant signal fluctuations of the DHB matrix, an integrated MALDI-MS data processing approach combined with machine learning methods was established to reveal metabolic biomarkers of lung cancer. In our study, 13 distinctive features with statistically significant differences (p < 0.001) between 34 lung cancer patients and 26 healthy controls were selected as significant potential biomarkers of lung cancer. 6 out of the 13 distinctive features were identified as intact metabolites. Our results demonstrate the potential for clinical application of MALDI-MS in serum metabolomics for biomarker screening in lung cancer.

Correction: Aggregation-induced phosphorescence sensitization in two heptanuclear and decanuclear gold-silver sandwich clusters.

[This corrects the article DOI: 10.1039/D0SC05095D.].

A cytotoxic nitrido-osmium(VI) complex induces caspase-mediated apoptosis in HepG2 cancer cells.

The osmium(vi) nitrido complex [OsVI(N)(sap)(py)Cl] is a potential anti-cancer drug with promising in vitro antiproliferative activities toward a panel of cancer cell lines, including cisplatin-resistant cells (IC50 values of 2.8-13.8 µM). This drug targets DNA and changes its conformation via covalent binding and insertion. In vitro studies indicate that the drug induces HepG2 cells G2/M phase arrest, disrupts the mitochondrial membrane potential and causes caspase-mediated apoptosis. Further in vivo studies using HepG2-bearing nude mice reveal that this drug not only shows good antitumor efficacy of inhibiting tumor growth, but also does not show the side effect of weight loss.

Surface optimization of gold nanoparticle mass tags for the sensitive detection of protein biomarkers via immuno-capture LI-MS.

HPV-induced cervical cancer is one of the most lethal cancers. Therefore, the development of a reliable and accurate method for the early diagnosis of HPV infections is highly important. Here, gold nanoparticles (AuNPs) were utilized as mass tags in an immuno-capture LI-MS assay for the detection of HPV marker proteins. Through the optimization of the amount of antibodies and surface charges on AuNPs, high antigen detection efficiency with minimal non-specific binding was achieved. With optimized antibody-conjugated AuNPs, low attomole amount of HPV proteins in HeLa cell lysate was quantified.

Aggregation-induced phosphorescence sensitization in two heptanuclear and decanuclear gold-silver sandwich clusters.

The strategy of aggregation-induced emission enhancement (AIEE) has been proven to be efficient in wide areas and has recently been adopted in the field of metal nanoclusters. However, the relationship between atomically precise clusters and AIEE is still unclear. Herein, we have successfully obtained two few-atom heterometallic gold-silver hepta-/decanuclear clusters, denoted Au6Ag and Au9Ag, and determined their structures by X-ray diffraction and mass spectrometry. The nature of the AuI⋯AgI interactions thereof is demonstrated through energy decomposition analysis to be far-beyond typical closed-shell metal-metal interaction dominated by dispersion interaction. Furthermore, a positive correlation has been established between the particle size of the nanoaggregates and the photoluminescence quantum yield for Au6Ag, manifesting AIEE control upon varying the stoichiometric ratio of Au : Ag in atomically-precise clusters.

A New Series of Cytotoxic Pyrazoline Derivatives as Potential Anticancer Agents that Induce Cell Cycle Arrest and Apoptosis.

A new series of pyrazoline derivatives 1b-12b was designed, synthesized and evaluated for antiproliferative activity against three cancer cell lines (HepG-2, Hela and A549). Additionally, NIH/3T3 cell cytotoxicity were tested and the structure activity relationships (SARs) were also determined. Among these new derivatives, the compounds 3-(4-fluorophenyl)-5-(3,4,5-trimethoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (1b) and 3-(4-chlorophenyl)-5-(3,4,5-trimethoxythiphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (2b) showed the best activity against HepG-2 cells, with IC50 values of 6.78 µM and 16.02 µM, respectively. They also displayed potent activity against Hela cells; meanwhile, 3-(4-chlorophenyl)-5-(3-bromo-4-hydroxy-5-methoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (5b) and 3-(4-bromo-phenyl)-5-(3-bromo-4-hydroxy-5-methoxythiophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (6b) were also identified as promising anticancer agents against A549 cells owing to their notable inhibitory effect, compared with cisplatin (IC50 = 29.48 µM). Furthermore, it was also found that compounds 1b and 2b had low cytotoxicity against NIH/3T3 cells and further mechanistic studies revealed that 1b arrested HepG-2 cells cycle at the G2/M phase at high concentrations and induced apoptosis in HepG-2 cells. Moreover, 1b upregulated protein expression level of cleaved caspase-3, cleaved PARP, Bax and p53 and downregulated protein expression level of Bcl-2 in dose-dependent way in HepG-2 cells. Thus, this study indicates that compound 1b might be a promising antitumor drug candidate.

Selective Chlorination of Toluene to p-Chlorotoluene Catalyzed by Nanosized Zeolite K-L Catalysts.

Nanosized zeolite K-L catalysts were synthesized by the hydrothermal method starting from silica sol and potassium aluminate. The crystallinities of the zeolite K-L catalysts increased with increasing the SiO2/Al2O3 mole ratio of reaction solution and prolonging the autoclaving time. Nanosized and well-dispersed zeolite K-L catalysts were synthesized when the SiO2/Al2O3 mole ratio was more than 26:1. Well-crystallized and nanosized zeolite K-L catalysts showed high catalytic activity for the chlorination of toluene to p-chlorotoluene. When the nanosized zeolite K-L catalyst was synthesized with the SiO2/Al2O3 mole ratio of 31:1 at the autoclaving temperature of 150 °C for 96 h, the selectivities of p-chlorotoluene and o-chlorotoluene were 76.2% and 20.0%, respectively, at the complete conversion of toluene.

Metallophilicity-driven dynamic aggregation of a phosphorescent gold(I)-silver(I) cluster prepared by solution-based and mechanochemical approaches.

We observed an unusual reversible aggregation process showing stimuli-responsive structural dynamics and optical changes attributed to the formation of a sandwich-like Au3-Ag-Au3 cluster, which can be synthesized through both solution and mechanochemical methods. Unlike many other heteronuclear gold-silver clusters, the affinity of two cyclic Au3 complexes and a Ag(I) ion is solely bound by ligand unsupported Au-Ag bonding. The assembly/disassembly behavior, further forming nanoaggregates, is controllable by adjusting the concentration of the solution. In the solid state, the insertion of Ag(I) ion can be implemented through a mechanochemical approach, accompanied by visual color changes and reversible luminochromism. Furthermore, an uncommon solid-liquid extraction is demonstrated, showing the uniqueness of this labile Au-Ag metallophilicity and hinting at the possibility of manipulating a bonding process through a heterogeneous route.