Nitrodopamine modified MnO2 NS-MoS2QDs hybrid nanocomposite for the extracellular and intracellular detection of glutathione.

We have developed a highly sensitive and reliable fluorescence resonance energy transfer (FRET) probe using nitro-dopamine (ND) and dopamine (DA) coated MnO2 nanosheet (ND@MnO2 NS and DA@MnO2 NS) as an energy acceptor and MoS2 quantum dots (QDs) as an energy donor. By employing surface-modified MnO2 NS, we can effectively reduce the fluorescence intensity of MoS2 QDs through FRET. It can reduce MnO2 NS to Mn2+ and facilitate the fluorescence recovery of the MoS2 QDs. This ND@MnO2 NS@MoS2 QD-based nanoprobe demonstrates excellent sensitivity to GSH, achieving an LOD of 22.7 nM in an aqueous medium while exhibiting minimal cytotoxicity and good biocompatibility. Moreover, our sensing platform shows high selectivity to GSH towards various common biomolecules and electrolytes. Confocal fluorescence imaging revealed that the nanoprobe can image GSH in A549 cells. Interestingly, the ND@MnO2 NS nanoprobe demonstrates no cytotoxicity in living cancer cells, even at concentrations up to 100 µg mL-1. Moreover, the easy fabrication and eco-friendliness of ND@MnO2 NS make it a rapid and simple method for detecting GSH. We envision the developed nanoprobe as an incredible platform for real-time monitoring of GSH levels in both extracellular and intracellular mediums, proving valuable for biomedical research and clinical diagnostics.

Visible and NIR light photoactivatable o-hydroxycinnamate system for efficient drug release with fluorescence monitoring.

Photoactivatable protecting groups (PPGs) have become powerful materials for controlling the activity of biologically important molecules in the biomedical field. However, designing PPGs that can be efficiently activated by biologically benign visible and NIR light with fluorescence monitoring is still a great challenge. Herein, we report o-hydroxycinnamate-based PPGs that can be activated by both visible (one-photon) and NIR (two-photon) light for controlled drug release with real-time monitoring. Thus, a photoremovable 7-diethylamino o-hydroxycinnamate group is covalently attached to an anticancer drug, gemcitabine, to establish a photoactivatable prodrug system. Upon excitation by visible (400-700 nm) or NIR (800 nm) light, the prodrug efficiently releases drug which is quantified by monitoring the formation of a strongly fluorescent coumarin reporter. The prodrug is taken up by the cancer cells and interestingly accumulates within mitochondria as determined by FACS and fluorescence microscopy imaging. Further, the prodrug demonstrates photo-triggered, dose-dependent, and temporally controlled cell death upon irradiation with both visible and NIR light. This photoactivatable system could be useful and adapted in the future for the development of advanced therapies in biomedicine.

Multifunctional Iridium(III)-Platinum(IV) Conjugates as Potent Anticancer Theranostic Agents.

In this article, we report IriPlatins 1-3, a new class of heterobimetallic Ir(III)-Pt(IV) conjugates as multifunctional potent anticancer theranostic agents. In the designed construction, the octahedral Pt(IV) prodrug is tethered to the cancer cell targeting biotin ligand through one of the axial sites and the other axial site of Pt(IV) center is attached to multifunctional Ir(III) complexes that possess organelle-targeting capabilities with excellent anticancer and imaging properties. The conjugates preferentially accumulate within the mitochondria of cancer cells, and subsequently, Pt(IV) is reduced to Pt(II) species that concomitantly releases both the Ir(III) complex and biotin from its axial sites. The IriPlatin conjugates demonstrate potent anticancer activity in various 2D monolayer cancer cells, including the cisplatin-resistant cells in the nanomolar concentrations and 3D multicellular tumor spheroids. The mechanistic investigation of conjugates suggests that the loss of MMP, generation of ROS, and caspase-3-mediated apoptosis are responsible for cell death.

AIE-active cyclometalated iridium(III) complexes for the detection of lipopolysaccharides and wash-free imaging of bacteria.

Infectious diseases caused by bacteria pose a major threat to human health and are currently one of the leading causes of mortality worldwide. Therefore, the development of probes for rapid detection of bacteria and their pathogenic components is highly essential. Aggregation-induced emission (AIE)-active compounds have shown great promise for the diagnosis of bacterial infections. In this study, we have synthesized three cationic AIE-active cyclometalated iridium(III) polypyridyl complexes viz., [Ir(C^N)2(N^N)]Cl2 (Ir1-Ir3), where C^N is a cyclometalating ligand such as pq = 2-phenylquinoline (in Ir1), pbt = 2-phenylbenzothiazole (in Ir2), and dfppy = 2-(2,4-difluorophenyl)pyridine (in Ir3), and N^N is a 2,2'-bipyridine derivative, for detection of lipopolysaccharide (LPS) in aqueous solution and wash-free imaging of bacteria. These complexes exhibit rapid sensing of LPS also known as endotoxin released by the bacteria, with a detection limit in the nanomolar range being determined by fluorescence spectroscopy within 5 min. Detection of both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus bacteria by the complexes is visible to the naked eye and was also observed by fluorescence microscopy imaging. The above features of the complexes make them a promising scaffold for the detection of bacterial contamination in aqueous samples.

COVID-19 detection using AIE-active iridium complexes.

The highly contagious COVID-19, caused by the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is commonly diagnosed using reverse transcription polymerase chain reaction (RT-PCR). However, despite being highly sensitive, RT-PCR is also time consuming and quite complex, which limits its use for point-of-care (POC) testing. We have developed a simple single-step fluorescence assay for SARS-CoV-2 RNA detection based on the principle of aggregation-induced emission (AIE) using iridium complexes. Our smartly designed iridium probes fluorescently "turn-on" in the presence of SARS-CoV-2 RNA and give specific results at room temperature within 10 min. The lower limit of detection (LOD) is 1.84 genome copies per reaction, and the sensitivity and specificity of the assay in 20 clinical samples are found to be 90% and 80%, respectively.

Development of Mitochondria Targeting AIE-Active Cyclometalated Iridium Complexes as Potent Antimalarial Agents.

The emergence of resistance to conventional antimalarial treatments remains a major cause for concern. New drugs that target the distinct development stages of Plasmodium parasites are required to address this risk. Herein, water-soluble aggregation-induced emission active cyclometalated iridium(III) polypyridyl complexes (Ir1-Ir12) are developed for the elimination of malaria parasites. Remarkably, these complexes show potent antimalarial activity in low nanomolar range against 3D7 (chloroquine and artemisinin sensitive strain), RKL9 (chloroquine resistant strain), and R539T (artemisinin resistant strains) strains of Plasmodium falciparum with faster killing rate of malaria parasites. Concomitantly, these complexes exhibit efficient in vivo antimalarial activity against both the asexual and gametocyte stages of Plasmodium berghei malaria parasite, suggesting promising transmission-blocking potential. The complexes tend to localize into mitochondria of P. falciparum determined by image and cell-based assay. The mechanistic studies reveal that these complexes exert their antimalarial activity by increasing reactive oxygen species levels and disrupting its mitochondrial membrane potential. Furthermore, the mitochondrial-dependent antimalarial activity of these complexes is confirmed in yeast model. Thus, this study for the first time highlights the potential role of targeting P. falciparum mitochondria by iridium complexes in discovering and developing the next-generation antimalarial agents for treating multidrug resistant malaria parasites.

Photoactivatable o-Hydroxycinnamic Platforms for Bioimaging and Therapeutic Release.

Photoactivatable or photoremovable protecting groups (PPGs) have become a powerful material and gained enormous interest in the field of biomedical applications. PPGs have been utilized for noninvasive, on-demand, spatio-temporal controlled release of biological effectors by irradiation with light to induce biochemical function. Over the past few years, o-hydroxycinnamate (oHC)-based PPGs have received considerable attention for the release of molecules of interest by either UV (one-photon) or near-IR (two-photon) irradiation. In this miniperspective, we have summarized the development of oHC PPGs for bioimaging and the controlled release of therapeutics, bioactive volatiles and other payloads with real-time monitoring. In addition, several future perspectives of oHC systems have been highlighted at the end of this miniperspective.

Mitochondria-Targeted Photoactivatable Real-Time Monitoring of a Controlled Drug Delivery Platform.

The current anticancer therapies are limited by their lack of controlled spatiotemporal release at the target site of action. We report a novel drug delivery platform that provides on-demand, real-time, organelle-specific drug release and monitoring upon photoactivation. The system is comprised of a model anticancer drug doxorubicin, an alkyltriphenylphosphonium moiety to target mitochondria in cancer cells, and a hydroxycinnamate photoactivatable linker that is covalently attached to the drug and mitochondria-targeting moieties such that it can be phototriggered by either UV (one-photon) or NIR (two-photon) light to form a fluorescent coumarin product and facilitate the release of drug payload. The extent of drug release is quantified by the fluorescence intensity of the coumarin formed. Further, the photoactivatable prodrug accumulates in the mitochondria and shows light-triggered temporally controlled cell death. In the future, our platform can be tuned for any biological application of interest, offering immense value in biomedicine.

Iridium-Triggered Allylcarbamate Uncaging in Living Cells.

Designing a metal catalyst that addresses the major issues of solubility, stability, toxicity, cell uptake, and reactivity within complex biological milieu for bioorthogonal controlled transformation reactions is a highly formidable challenge. Herein, we report an organoiridium complex that is nontoxic and capable of the uncaging of allyloxycarbonyl-protected amines under biologically relevant conditions and within living cells. The potential applications of this uncaging chemistry have been demonstrated by the generation of diagnostic and therapeutic agents upon the activation of profluorophore and prodrug in a controlled fashion within HeLa cells, providing a valuable tool for numerous potential biological and therapeutic applications.

Correction: Aggregation-induced emission active metal complexes: a promising strategy to tackle bacterial infections.

Correction for 'Aggregation-induced emission active metal complexes: a promising strategy to tackle bacterial infections' by Puja Prasad et al., Chem. Commun., 2021, 57, 174-186, DOI: 10.1039/D0CC06037B.

Aggregation-induced emission active metal complexes: a promising strategy to tackle bacterial infections.

Bacterial infection is a major global threat to human health and currently one of the leading causes of death worldwide. The development of probes for rapid diagnosis of bacteria with desired sensitivity and selectivity along with antibacterial activity against multidrug-resistant (MDR) bacteria has remained a great challenge. Whilst the traditional methods such as cell culture and colony counting, polymerase chain reaction and immunoassays are used for bacterial infection detection, these are time consuming, laborious and require a skilled operator. On the other hand, the rapid emergence of MDR bacteria is also posing another serious public health threat. Hence, it is an utmost urgency to develop novel therapeutics and rapid diagnostic agents for tackling MDR bacteria. Over the last few years, significant progress has been made towards the development of metal-based aggregation-induced emission luminogens (AIEgens) for bacterial management. These AIEgen materials offer potential applications for simultaneous detection and image-guided elimination of bacteria for the treatment of bacterial infections. In this Feature Article, we have highlighted the recent progress in the development of metal-based AIEgens for detection, discrimination and decimation of bacteria. In addition, the potential challenges in developing antibacterial agents and several future perspectives of metal-based AIEgens in this field have also been discussed.

Simultaneous Ultrasensitive Detection and Elimination of Drug-Resistant Bacteria by Cyclometalated Iridium(III) Complexes.

Antimicrobial resistance has become a major threat to public health due to the rampant and empirical use of antibiotics. Rapid diagnosis of bacteria with the desired sensitivity and selectivity still, however, remains an open challenge. We report a special class of water-soluble metal-based aggregation-induced emission luminogens (AIEgens), namely, cyclometalated iridium(III) polypyridine complexes of the type [Ir(PQ)2(N^N)]Cl (1-3), where PQ = 2-phenylquinoline and N^N = 2,2'-bipyridine derivatives, that demonstrate dual capability for detection and elimination of drug-resistant bacteria in aqueous solutions. These AIEgens exhibit selective and rapid sensing of endotoxins, such as lipopolysaccharides (LPS) and lipoteichoic acid (LTA) released by the bacteria, with a detection limit in the lower nanomolar range. Targeting these naturally amplified biomarkers (approximately 1 million copies per cell) by iridium(III) complexes induces strong AIE in the presence of different Gram-negative and Gram-positive bacteria including carbapenem-resistant A. baumannii (CRAB) and methicillin-resistant S. aureus (MRSA) at concentrations as low as 1.2 CFU/mL within 5 min in spiked water samples. Detection of bacteria by the complexes is also visible to the naked eye at higher (108 CFU/mL) cell concentrations. More notably, complexes 1 and 2 show potent antibacterial activity against drug-resistant bacteria with low minimum inhibitory concentrations (MICs) ≤ 5 µg/mL (1-4 µM) via ROS generation and cell membrane disintegrity. To the best of our knowledge, this work is the "first-in-class" example of a metal-based theranostic system that integrates selective, sensitive, rapid, naked-eye, wash-free, and real-time detection of bacteria using broad-spectrum antibiotics into a single platform. This dual capability of AIEgens makes them ideal scaffolds for monitoring bacterial contamination in aqueous samples and pharmaceutical applications.

Photo-triggerable Hydrogel-Nanoparticle Hybrid Scaffolds for Remotely Controlled Drug Delivery.

Remotely-triggerable drug delivery systems enable the user to adjust dosing regimens on-demand based on a patient's physiological response and clinical needs. However, currently reported systems are limited by the non-specific leakage of drugs in the absence of triggering and the lack of repeatability over multiple cycles of release. To this end, we have designed a unique hydrogel-nanoparticle hybrid scaffold that provides a chemically-defined, remotely-triggerable and on-demand release of small molecule drugs. Our hybrid platform consists of three distinct components: 1) a photo-triggerable chemical compound, which serves to release a covalently-bound drug upon photo-irradiation, 2) a nanoparticle, which serves to covalently bind the photo-triggerable compound, and 3) a polymeric hydrogel, which serves to hold the drug-conjugated nanoparticle. Upon photo-irradiation, the activation of the photo-triggerable compound is designed to initiate a series of intramolecular chemical rearrangements, which would cleave the covalently-bound drug and release it from the hydrogel. The combination of these distinct components in a single scaffold proved to be an effective drug delivery system, as demonstrated by the delivery of a model drug to a malignant cancer line. Our hybrid scaffold can be easily tuned for practically any biological application of interest, thus offering immense potential for clinical therapies.

Single vehicular delivery of siRNA and small molecules to control stem cell differentiation.

Achieving a controlled and reproducible means to direct stem cell differentiation is the single most critical concern scientists have been trying to address since the discovery of stem cells. In this regard, the use of small molecules and RNA interference offers unique advantages by targeting different cellular mechanisms. Our cyclodextrin-modified dendritic polyamine construct (termed DexAM) combines the unique properties of two distinct chemical moieties in a single delivery vehicle. DexAM is a single vehicle that not only solubilizes hydrophobic small molecules in physiological solutions but also forms complexes with siRNA molecules, making it an attractive delivery system for controlling stem cell differentiation. Herein, we report the synthesis and application of DexAM to simultaneously deliver hydrophobic small molecules and siRNA into neural stem cells to significantly enhance their neuronal differentiation.

Planar triazinium cations from vanadyl-mediated ring cyclizations: the thiazole species for efficient nuclear staining and photocytotoxicity.

Planar triazinium cationic species from vanadyl-assisted cyclization of 1-(2-thiazolylazo)-2-naphthol (H-TAN, 1), 1-(2-pyridylazo)-2-naphthol (H-PAN, 2), 2-(2'-thiazolylazo)-p-cresol (H-TAC, 3) and 6-(2'-thiazolylazo)-resorcinol (H-TAR, 5) were prepared and characterized. A dioxovanadium(V) species [VO(2)(TAR)] (4) was also isolated. Compounds 1, 2 and 4 were structurally characterized. Both 1 and 2 have planar structures. Complex 4 has V(V)O(3)N(2) coordination geometry. The cyclised triazinium compound forms a radical species within -0.06 to -0.29 V vs. SCE in DMF-0.1 M tetrabutylammonium perchlorate with a second response due to formation of an anionic species. A confocal microscopic study showed higher nuclear uptake for 1 having a fused thiazole moiety than 2 with a fused pyridine ring. The compounds showed a partial intercalative mode of binding to calf thymus DNA. Compound 1 showed plasmid DNA photo-cleavage activity under argon and photocytotoxicity in HeLa and MCF-7 cells with IC(50) values of 15.1 and 3.4 µM respectively in visible light of 400-700 nm, while being essentially non-toxic in the dark with IC(50) values of 90.4 and 21.9 µM. A TDDFT study was done to rationalize the experimental data.

Metal complex catalysis in living biological systems.

This feature article discusses synthetic metal complexes that are capable of catalyzing chemical transformations in living organisms. Photodynamic therapy exemplifies what is probably the most established artificial catalytic process exploited in medicine, namely the photosensitized catalytic generation of cell-damaging singlet oxygen. Different redox catalysts have been designed over the last two decades to target a variety of redox alterations in cancer and other diseases. For example, pentaazamacrocyclic manganese(ii) complexes catalyze the dismutation of superoxide to O(2) and H(2)O(2)in vivo and thus reduce oxidative stress in analogy to the native enzyme superoxide dismutase. Recently, piano-stool ruthenium and iridium complexes were reported to influence cellular redox homeostasis indirectly by catalytic glutathione oxidation and catalytic transfer hydrogenation using the coenzyme NADH, respectively. Over the last few years, significant progress has been made towards the application of non-biological reactions in living systems, ranging from the organoruthenium-catalyzed cleavage of allylcarbamates and a gold-catalyzed intramolecular hydroarylation to palladium-catalyzed Suzuki-Miyaura and Sonogashira cross-couplings within the cytoplasm or on the surface of living cells. The design of bioorthogonal catalyst/substrate pairs, which can passively diffuse into cells, combines the advantages of small molecules with catalysis and promises to provide exciting new tools for future chemical biology studies.

Hydrolytically stable octahedral silicon complexes as bioactive scaffolds: application to the design of DNA intercalators.

We here introduce octahedral silicon serving as a structural center for the design of hydrolytically stable bioactive complexes as demonstrated with the generation of silicon-based high affinity DNA binders. This proof-of-principle study suggests that octahedral silicon complexes are falsely neglected, promising structural templates for widespread applications in chemical biology and medicinal chemistry.

Catalytic azide reduction in biological environments.

In the quest for the identification of catalytic transformations to be used in chemical biology and medicinal chemistry, we identified iron(III) meso-tetraarylporphines as efficient catalysts for the reduction of aromatic azides to their amines. The reaction uses thiols as reducing agents and tolerates water, air, and other biological components. A caged fluorophore was employed to demonstrate that the reduction can be performed even in living mammalian cells. However, in vivo experiments in nematodes (Caenorhabditis elegans) and zebrafish (Danio rerio) revealed a limitation to this method: the metabolic reduction of aromatic azides.

Planar triazinium cations from VO(2+)-assisted ring cyclizations: a remarkably efficient thiazole species for nuclear staining, PDT and anaerobic photocleavage of DNA.

Planar triazinium cationic species, from VO(2+)-assisted cyclization of 1-(2-thiazolylazo)-2-naphthol, shows efficient DNA intercalative binding, visible light-induced anaerobic plasmid DNA photocleavage activity and photocytotoxicity in HeLa and MCF-7 cancer cells by an apoptotic pathway with selective localization of the compound in the nucleus as evidenced from the nuclear staining and confocal imaging.

Photocytotoxicity and DNA cleavage activity of L-arg and L-lys Schiff base oxovanadium(IV) complexes having phenanthroline bases.

Oxovanadium(IV) complexes [VO(sal-argH)(B)]Cl (1-3) and [VO(sal-lysH)(B)]Cl (4-6), where sal-argH2 and sal-lysH2 are N-salicylidene-L-arginine and N-salicylidene-L-lysine Schiff bases and B is a phenanthroline base, viz. 1,10-phenanthroline (phen in 1 and 4); dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 2 and 5) and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 3 and 6), have been prepared, characterized and their DNA photocleavage activity studied. Complex 1, characterized by X-ray crystallography, shows the presence of a vanadyl group in V(IV)O3N3 coordination geometry with a tridentate Schiff base having a pendant guanidinium moiety and bidentate phen ligand. The complexes exhibit a d-d band at 715 nm in 20% DMF-Tris-HCl buffer. The complexes are redox active showing cathodic and anodic responses near -1.0 V and 0.85 V (vs. SCE) for the V(IV)-V(III) and V(V)-V(IV) couples, respectively, in DMF-Tris-HCl buffer. The complexes bind to calf thymus DNA giving Kb values in the range of 3.8 x 10(4) to 1.6 x 10(5) M(-1). Thermal denaturation and viscosity data suggest DNA groove binding nature of the complexes. The complexes do not show any "chemical nuclease" activity in dark in the presence of 3-mercaptopropionic acid or H2O2. The dpq and dppz complexes are efficient photocleavers of plasmid DNA in UV-A (365 nm) and red light (676 nm) via singlet oxygen pathway. The dppz complexes exhibit photocytotoxicity in HeLa cancer cells giving IC50 values of 15.4 microM for 3 and 17.5 microM for 6 in visible light while being non-toxic in dark giving IC50 values of >100 microM.