Taotao Zou

A Binuclear Gold(I) Complex with Mixed Bridging Diphosphine and Bis(N-Heterocyclic Carbene) Ligands Shows Favorable Thiol Reactivity and Inhibits Tumor Growth and Angiogenesis In Vivo†

In the design of anticancer gold(I) complexes with high in vivo efficacy, tuning the thiol reactivity to achieve stability towards blood thiols yet maintaining the thiol reactivity to target cellular thioredoxin reductase (TrxR) is of pivotal importance. Herein we describe a dinuclear gold(I) complex (1-PF6) utilizing a bridging bis(N-heterocyclic carbene) ligand to attain thiol stability and a diphosphine ligand to keep appropriate thiol reactivity. Complex 1-PF6 displays a favorable stability that allows it to inhibit TrxR activity without being attacked by blood thiols. In vivo studies reveal that 1-PF6 significantly inhibits tumor growth in mice bearing HeLa xenograft and mice bearing highly aggressive mouse B16-F10 melanoma. It inhibits angiogenesis in tumor models and inhibits sphere formation of cancer stem cells in vitro. Toxicology studies indicate that 1-PF6 does not show systemic anaphylaxis on guinea pigs and localized irritation on rabbits.

Luminescent organoplatinum(II) complexes containing bis(N-heterocyclic carbene) ligands selectively target the endoplasmic reticulum and induce potent photo-toxicity

A panel of luminescent platinum(II) complexes containing bidentate N-heterocyclic carbene ligands selectively localize to the endoplasmic reticulum (ER) domain, induce ER stress and cell apoptosis. Some of them show potent photo-toxicity to cancer cells.

A dinuclear cyclometalated gold(III)–phosphine complex targeting thioredoxin reductase inhibits hepatocellular carcinoma in vivo

A stable gold(III)–phosphine complex [(C⁁N⁁C)2Au2(μ-dppp)](CF3SO3)2 [Au3, HC⁁N⁁CH = 2,6-diphenylpyridine; dppp = bis(diphenylphosphino)propane] displays potent in vitro cytotoxicity towards various cancers with sub-micromolar range cytotoxic IC50 values, and is significantly more potent than its structural and iso-electronic platinum(II) analog [(C⁁N⁁N)2Pt2(μ-dppp)](CF3SO3)2 (HC⁁N⁁N = 6-phenyl-2,2′-bipyridine) and gold(III)–carbene complexes. Complex Au3 displays promising inhibition on tumor growth in animal models, and its acute and sub-chronic toxicities have been examined in mice and beagle dogs. Transcriptomic and connectivity map analyses have revealed that the transcriptional profile of Au3 is similar to those of inhibitors of thioredoxin reductase (TrxR) and inducers of endoplasmic reticulum (ER) stress. As we found that Au3 is also a nanomolar inhibitor of TrxR, a model of ER stress-induced cell death mediated by inhibition of TrxR is proposed. The transcriptomic analysis also leads to the identification of TRAIL, a ligand for death receptor 5 (DR5), as a synergistic agent of the anti-tumor activity of Au3. Collectively, our results demonstrate that the gold(III) complex Au3 effectively inhibits tumor growth in vivo, and displays promising cytotoxicity towards cancer cells in association with the inhibition of TrxR, induction of ER stress and also a death-receptor-dependent apoptotic pathway.

Controlled‐Release Systems for Metal‐Based Nanomedicine: Encapsulated/Self‐Assembled Nanoparticles of Anticancer Gold(III)/Platinum(II) Complexes and Antimicrobial Silver Nanoparticles

The therapeutic applications of many anticancer or antimicrobial metal complexes often suffer from low solubility and low stability in physiological conditions or from drug resistance. To circumvent these problems, nanoparticle systems that allow controlled release and specific accumulation in the targeted disease tissue are of advantage for efficient treatment with minimal toxicity. The focus of this Research News is metal-based nanomaterials comprising anticancer gold(III)/platinum(II) complexes or antimicrobial silver, highlighting the controlled-release properties of self-assembled metal systems.

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. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB-1, accompanied by expected downstream mechanisms of action. Additionally, PtII and PdII analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal-NHC scaffold in the design of anti-cancer metal medicines with multiple molecular targets.

Gold(III) complexes inhibit growth of cisplatin-resistant ovarian cancer in association with upregulation of proapoptotic PMS2 gene.

Various gold complexes have been known to overcome cisplatin resistance in cancer cells. Yet, their in vivo anti-tumor efficacies and detailed action mechanisms in overcoming this resistance remain largely unexplored. In this work we have established a xenograft model simultaneously consisting of both cisplatin-sensitive and cisplatin-resistant tumors by inoculating human ovarian cancer cells A2780 and its cisplatin-resistant variant A2780cis into different flanks of the same nude mouse. Towards this model, a gold(III) porphyrin complex [AuIII(TPP)]Cl (gold-1a, wherein [TPP]2− = meso-tetraphenylporphyrinato ligand) was found to effectively inhibit the growth of both kinds of tumors, while cisplatin failed to suppress the growth of A2780cis tumors under similar conditions. In both A2780 and A2780cis cells, gold-1a was found to transcriptionally upregulate postmeiotic segregation increased 2 (PMS2) which has DNA mismatch repair and proapoptotic functions. Suppression of PMS2 by RNA interference in A2780cis cells partially rescued the gold-1a-induced death of the cells, indicating that gold-1a inhibited growth of cisplatin-resistant ovarian cancer in association with upregulation of this gene. Two other stable gold(III) analogues including gold(III) octaethylporphyrin (2) and gold(III)-NHC (3) complexes also displayed similar anti-cancer activities on A2780cis cells and capability in PMS2 regulation. In contrast, a gold(I) phosphine complex (4), a gold(I) thiourea complex (5), KAuIIICl4 and cisplatin all displayed a preferential cytotoxicity only towards the cisplatin-sensitive A2780 cells. Taken together, this work has demonstrated the prospect of gold(III) complexes for the treatment of cisplatin-resistant/relapsed ovarian cancers.

A Cancer-Targeted Nanosystem for Delivery of Gold(III) Complexes: Enhanced Selectivity and Apoptosis-Inducing Efficacy of a Gold(III) Porphyrin Complex

Construction of delivery systems for anticancer gold complexes to decrease their toxicity while maintaining efficacy is a key strategy to optimize and develop anticancer gold medicines. Herein, we describe cancer-targeted mesoporous silica nanoparticles (MSN) for delivery of a gold(III) porphyrin complex (Au-1 a@MSN(R)) to enhance its anticancer efficacy and selectivity between cancer and normal cells. Encapsulation of Au-1 a within mesoporous silica nanoparticles amplifies its inhibitory effects on thioredoxin reductase (TrxR), resulting in a loss of redox balance and overproduction of reactive oxygen species (ROS). Elevated cellular oxidative stress activates diversified downstream ROS-mediated signaling pathways, leading to enhanced apoptosis-inducing efficacy.

Light-induced catalytic and cytotoxic properties of phosphorescent transition metal compounds with a d8 electronic configuration

Transition metal compounds are well documented to have diverse applications such as in catalysis, light-emitting materials and therapeutics. In the areas of photocatalysis and photodynamic therapy, metal compounds of heavy transition metals are highly sought after because they can give rise to triplet excited states upon photoexcitation. The long lifetimes (more than 1 μs) of the triplet states of transition metal compounds allow for bimolecular reactions/processes such as energy transfer and/or electron transfer to occur. Reactions of triplet excited states of luminescent metal compounds with oxygen in cells may generate reactive oxygen species and/or induce damage to DNA, leading to cell death. This article recaps the recent findings on photochemical and phototoxic properties of luminescent platinum(II) and gold(III) compounds both from the literature and experimental results from our group.

Alkynyl gold(I) phosphane complexes: Evaluation of structure–activity-relationships for the phosphane ligands, effects on key signaling proteins and preliminary in-vivo studies with a nanoformulated complex

Gold alkynyl complexes with phosphane ligands of the type (alkynyl)Au(I)(phosphane) represent a group of bioorganometallics, which has only recently been evaluated biologically in more detail. Structure-activity-relationship studies regarding the residues of the phosphane ligand (P(Ph)3, P(2-furyl)3, P(DAPTA)3, P(PTA)3, P(Et)3, P(Me)3) of complexes with an 4-ethynylanisole alkyne ligand revealed no strong differences concerning cytotoxicity. However, a relevant preference for the heteroatom free alkyl/aryl residues concerning inhibition of the target enzyme thioredoxin reductase was evident. Complex 1 with the triphenylphosphane ligand was selected for further studies, in which clear effects on cell morphology were monitored by time-lapse microscopy. Effects on cellular signaling were determined by ELISA microarrays and showed a significant induction of the phosphorylation of ERK1 (extracellular signal related kinase 1), ERK2 and HSP27 (heat shock protein 27) in HT-29 cells. Application of 1 in-vivo in a mouse xenograft model was found to be challenging due to the low solubility of the complex and required a formulation strategy based on a peanut oil nanoemulsion.

Speciation of precious metal anti-cancer complexes by NMR spectroscopy

Understanding the mechanism of action of anti-cancer agents is of paramount importance for drug development. NMR spectroscopy can provide insights into the kinetics and thermodynamics of the binding of metallodrugs to biomolecules. NMR is most sensitive for highly abundant I=1/2 nuclei with large magnetic moments. Polarization transfer can enhance NMR signals of insensitive nuclei at physiologically-relevant concentrations. This paper reviews NMR methods for speciation of precious metal anti-cancer complexes, including platinum-group and gold-based anti-cancer agents. Examples of NMR studies involving interactions with DNA and proteins in particular are highlighted.