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 , which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations.

Integrative chemoproteomics reveals anticancer mechanisms of silver(i) targeting the proteasome regulatory complex.

Silver compounds have favorable properties as promising anticancer drug candidates, such as low side effects, anti-inflammatory properties, and high potential to overcome drug resistance. However, the exact mechanism by which Ag(i) confers anticancer activity remains unclear, which hinders further development of anticancer applications of silver compounds. Here, we combine thermal proteome profiling, cysteine profiling, and ubiquitome profiling to study the molecular mechanisms of silver(i) complexes supported by non-toxic thiourea (TU) ligands.

Silver nanoparticles promote osteogenic differentiation of mouse embryonic fibroblasts .

Objective: This study investigated if silver nanoparticles (AgNps) could promote the proliferation and osteogenic differentiation of mouse embryonic fibroblasts.

Methods: Mouse embryonic fibroblasts were divided into two groups: Group 1 cells were cultured in DMEM/F12 medium and Group 2 cells were cultured in osteogenic medium. Both groups were then treated with 16, 32, or 100 μM AgNps.

Dihydroartemisinin engages liver fatty acid binding protein and suppresses metastatic hepatocellular carcinoma growth.

Dihydroartemisinin non-covalently binds liver fatty acid binding protein (FABP1) with micromolar affinity, acts as a FABP1-dependent peroxisome proliferator-activated receptor alpha agonist and inhibits metastatic hepatocellular carcinoma growth.

Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8 T cell exhaustion and curtails anti-PD-1 efficacy.

Identifying signals that govern the differentiation of tumor-infiltrating CD8 T cells (CD8 TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8 T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8 T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy.

Dynamic supramolecular self-assembly of platinum(ii) complexes perturbs an autophagy-lysosomal system and triggers cancer cell death.

Self-assembly of platinum(ii) complexes to form supramolecular structures/nanostructures due to intermolecular ligand π-π stacking and metal-ligand dispersive interactions is widely used to develop functional molecular materials, but the application of such non-covalent molecular interactions has scarcely been explored in medical science. Herein is described the unprecedented biological properties of platinum(ii) complexes relevant to induction of cancer cell death manifesting such intermolecular interactions. With conjugation of a glucose moiety to the planar platinum(ii) terpyridyl scaffold, the water-soluble complex [Pt(tpy)(C[triple bond, length as m-dash]CArOGlu)](CFSO) (1a, tpy = 2,2':6',2''-terpyridine, Glu = glucose) is able to self-assemble into about 100 nm nanoparticles in physiological medium, be taken up by lung cancer cells energy-dependent endocytosis, and eventually transform into other superstructures distributed in endosomal/lysosomal and mitochondrial compartments apparently following cleavage of the glycosidic linkage.

Platinum(II) -heterocyclic carbene complexes arrest metastatic tumor growth.

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [Pt(C^N^N)(NHC)]PF (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= -heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.

Anticancer Gold(III) Compounds With Porphyrin or N-heterocyclic Carbene Ligands.

The use of gold in medicine has a long history. Recent clinical applications include anti-inflammatory agents for the treatment of rheumatoid arthritis (chrysotherapy), and is currently being developed as potential anticancer chemotherapeutics. Gold(III), being isoelectronic to platinum(II) as in cisplatin, is of great interest but it is inherently unstable and redox-reactive under physiological conditions.

Multifunctional Microparticles Incorporating Gold Compound Inhibit Human Lung Cancer Xenograft.

Purpose: Gold porphyrin (AuP) is a complex that has been shown to be potent against various tumors. A biocompatible interpenetrating network (IPN) system comprised of polyethyleneglycol diacrylate (PEGdA) and chemically-modified gelatin has been shown to be an effective implantable drug depot to deliver AuP locally. Here we designed IPN microparticles complexed with AuP to facilitate intravenous administration and to diminish systemic toxicity.

Surface optimization of gold nanoparticle mass tags for the sensitive detection of protein biomarkers 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.

Delayed application of silver nanoparticles reveals the role of early inflammation in burn wound healing.

Burn injury is common, and antimicrobial agents are often applied immediately to prevent wound infection and excessive inflammatory response. Although inflammation is essential for clearing bacteria and creating an environment conducive to the healing process, it is unclear what time-frame inflammation should be present for optimal wound healing. This study critically investigated the role of early inflammation in burn wound healing, and also revealed the molecular mechanisms underlying the pro-healing effects of silver nanoparticles (AgNPs).

An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols.

Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M-S bond formation, AuMesoIX is unique in that the -carbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols.

Anticancer auranofin engages 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as a target.

Auranofin (AuRF) has been reported to display anticancer activity and has entered several clinical trials; however, its mechanism of action remains largely unknown. In this work, the anticancer mechanism of auranofin was investigated using a proteomics strategy entailing subcellular fractionation prior to mass spectrometric analysis. Bioinformatics analysis of the nuclear sub-proteomes revealed that tumor suppressor p14 is a key regulator of transcription.

An Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target.

New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe a rare example of an antitumor Pt complex targeting a tumor-associated protein, rather than DNA, under cellular conditions. Complex [(bis-NHC)Pt(bt)]PF (1 a; Hbt=1-(3-hydroxybenzo[b]thiophen-2-yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin.

A Multifunctional Hydrogel Delivers Gold Compound and Inhibits Human Lung Cancer Xenograft.

Purpose: Interpenetrating network system (IPN), consisting of polyethylene glycol (PEG) -diacrylate (PEGdA) and modified gelatin, is a biocompatible and biodegradable hydrogel and has been studied for the local delivery of bioactive molecules and drugs. Gold(III) porphyrin(AuP) is a stable metal compound in the development for anticancer application when administered systemically. The aim of this work is to develop a novel formulation for AuP based on IPN for local delivery.

Plasmonic metal nanoparticles as efficient mass tags for ion signal amplification and ultrasensitive detection of protein markers.

The development of sensitive and specific analytical methods is critical for the discovery of molecular biomarkers, which assists disease diagnosis and understanding biological processes. Herein, a highly sensitive method is developed using antibody-conjugated plasmonic metal nanoparticles for the detection of targeted biomarkers down to low attomole level via coupling of immunoassay techniques with laser ionization mass spectrometry (LI-MS). The conjugated antibodies target specific antigens, while the metal nanoparticles act as mass tags and ion reservoirs for the signal amplification.

Plasmonic gold nanoparticles as multifaceted probe for tissue imaging.

The localized surface plasmon resonance property of gold nanoparticles enables their application as a versatile and sensitive imaging probe, with intense colour, enhanced fluorescence and strong MS ion intensity for biological tissue imaging.

Luminescent ruffled iridium(iii) porphyrin complexes containing N-heterocyclic carbene ligands: structures, spectroscopies and potent antitumor activities under dark and light irradiation conditions.

A panel of iridium(iii) porphyrin complexes containing axial N-heterocyclic carbene (NHC) ligand(s) were synthesized and characterized. X-ray crystal structures of the bis-NHC complexes [Ir(ttp)(IMe)] (), [Ir(oep)(BIMe)] (), [Ir(oep)(I Pr)] () and [Ir(Ftpp)(IMe)] () display ruffled porphyrin rings with mesocarbon displacements of 0.483-0.

Chemical Printing of Biological Tissue by Gold Nanoparticle-Assisted Laser Ablation.

A chemical printing method based on gold nanoparticle (AuNP)-assisted laser ablation has been developed. By rastering a thin layer of AuNPs coated on a rat kidney tissue section with a UV laser, biomolecules are extracted and immediately transferred/printed onto a supporting glass substrate. The integrity of the printed sample is preserved, as revealed by imaging mass spectrometric analysis.

Shotgun Proteomics and Quantitative Pathway Analysis of the Mechanisms of Action of Dehydroeffusol, a Bioactive Phytochemical with Anticancer Activity from Juncus effusus.

Dehydroeffusol (DHE) is a phenanthrene isolated from the Chinese medicinal plant Juncus effusus. Biological evaluation of DHE reveals in vitro and in vivo anticancer effects. We performed a shotgun proteomic analysis using liquid chromatography-tandem mass spectrometry to investigate the changes in the protein profiles in cancer cells upon DHE treatment.

Anticancer metal-N-heterocyclic carbene complexes of gold, platinum and palladium.

Transition metal compounds are a rich source for anticancer drug development. Judicious application of coordination ligands is a critical success factor in the design of effective anti-tumor compounds. N-heterocyclic carbenes (NHC) are stable ligands that have strong donor strengths in stabilizing metal ions and versatility in structural modifications to provide diverse scaffolds for biological molecular targeting.

A multi-functional PEGylated gold(iii) compound: potent anti-cancer properties and self-assembly into nanostructures for drug co-delivery.

Gold(iii) porphyrin-PEG conjugates [Au(TPP-COO-PEG-OCH)]Cl () and [Au(TPP-CONH-PEG-OCH)]Cl () have been synthesized and characterized. Based on the amphiphilic character of the conjugates, they were found to undergo self-assembly into nanostructures with size 120-200 nm and this did not require the presence of other surfactants or components for nano-assembly, unlike most conventional drug nano-formulations. With a readily hydrolyzable ester linkage, chemotherapeutic [Au(TPP-COOH)] exhibited triggered release from the conjugate in acidic buffer solution as well as and without the formation of toxic side products.

Cyclometalated Gold(III) Complexes Containing N-Heterocyclic Carbene Ligands Engage Multiple Anti-Cancer Molecular Targets.

Metal N-heterocyclic carbene (NHC) complexes are a promising class of anti-cancer agents displaying potent in vitro and in vivo activities. Taking a multi-faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti-cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti-tumor activities in mice bearing xenografts of human cervical and lung cancers.

Silver nanoparticle treatment ameliorates biliary atresia syndrome in rhesus rotavirus inoculated mice.

Biliary atresia (BA) is a neonatal biliary system disease closely associated with viral infection and bile duct inflammation. Silver nanoparticles (AgNps) have previously revealed antiviral and anti-inflammatory properties. In this study, we have investigated the effects of AgNps in the treatment of the Rhesus rotavirus inoculation induced BA in mice.

A macromolecular cyclometalated gold(iii) amphiphile displays long-lived emissive excited state in water: self-assembly and in vitro photo-toxicity.

We report an amphiphilic macromolecule containing a cyclometalated gold(iii) complex that self-assembles into nano-sized micelles and also displays a long-lived emissive triplet excited state with a lifetime of 84 μs in degassed water. This amphiphilic Au complex exhibits good biocompatibility and activity towards in vitro photo-toxicity, as well as enhanced permeability and retention effects in vivo.