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Rising antimicrobial resistance (AMR) and lack of innovation in the antibiotic pipeline necessitate novel approaches to discovering new drugs. Metal complexes have proven to be promising antimicrobial compounds, but the number of studied compounds is still low compared to the millions of organic molecules investigated so far. Lately, machine learning (ML) has emerged as a valuable tool for guiding the design of small organic molecules, potentially even in low‐data scenarios. For the first time, we extend the application of ML to the discovery of metal‐based medicines. Utilising 288 modularly synthesized ruthenium arene Schiff‐base complexes and their antibacterial properties, a series of ML models were trained. The models perform well and are used to predict the activity of 54 new compounds. These displayed a 5.7x higher hit‐rate (53.7 %) against methicillin‐resistant Staphylococcus aureus (MRSA) compared to the original library (9.4 %), demonstrating that ML can be applied to improve the success‐rates in the search of new metalloantibiotics. This work paves the way for more ambitious applications of ML in the field of metal‐based drug discovery. [ABSTRACT FROM AUTHOR]

Interleukin‐2 (IL‐2) is one of the first FDA‐approved immunotherapeutics, but its use is limited by toxicity and low efficacy. In addition, all immunotherapies are limited by the immunosuppressive and desmoplastic microenvironment of "immunologically cold" tumors, such as pancreatic ductal adenocarcinoma (PDAC) or hepatocellular carcinoma (HCC) with advanced liver fibrosis. Here, a new chemoimmunotherapy nanogel (IL2‐Pt@Nanogel) for dual delivery of IL‐2 and the type II immunogenic cell death inducer Pt‐NHC that reduces the immunosuppressive phenotype of tumor‐associated macrophages and diminishes regulatory T cell infiltration by inducing the production of type I interferon (IFN) by cancer cells is reported. Combining the angiotensin II receptor blocker losartan with IL2‐Pt@Nanogel treatment reduces desmoplasia and reprogrammes the microenvironment of PDAC and HCC toward an immunostimulatory one. These effects result in potent anti‐tumor efficacy in models of primary and metastatic PDAC and HCC with underlying liver fibrosis. This study presents a strategy for IL‐2‐based chemoimmunotherapy with the potential for clinical translation to treat solid tumors. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance, caused by persistent adaptation and growing resistance of pathogenic bacteria to overprescribed antibiotics, poses one of the most serious and urgent threats to global public health. The limited pipeline of experimental antibiotics in development further exacerbates this looming crisis and new drugs with alternative modes of action are needed to tackle evolving pathogenic adaptation. Transition metal complexes can replenish this diminishing stockpile of drug candidates by providing compounds with unique properties that are not easily accessible using pure organic scaffolds. We spotlight four emerging strategies to harness these unique properties to develop new targeted antibacterial agents. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy‐disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000‐fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro‐survival responses to induce deadly metabolic catastrophe. [ABSTRACT FROM AUTHOR]

Mitochondria have emerged as important targets for cisplatin in cancer therapy. Apart from cisplatin, anticancer Pt complexes based on similar scaffolds have also been developed to target mitochondria. Yet cellular processing of cisplatin or these mitochondria‐targeting Pt analogues remained unexplored, largely due to a lack of tools capable of probing these Pt drugs within an intracellular environment. We developed the first mitochondria‐targeted fluorescent probe for real‐time monitoring of Pt accumulation in mitochondria. We applied the probe to investigate mitochondria as cellular targets for Pt drug complexes and uncovered two distinct pathways whereby these Pt complexes could be delivered to mitochondria after cell entry. [ABSTRACT FROM AUTHOR]

Fluorescent dyes with a high photoluminescence quantum yield (PLQY) and photostability are favored in bioimaging as they offer better imaging signals at lower dye loading, circumventing issues of cytotoxicity and biological pathway interference. Quantum dots (QDs) are efficient emitters with narrow spectral line‐widths, but often employ toxic heavy‐metals, and show significantly diminished PLQY and poor stability after phase‐transfer into aqueous media. Here, the preparation of nontoxic, water‐dispersed giant‐shell In(Zn)As–In(Zn)P–GaP–ZnS QDs that emit in the near‐infrared (NIR) at 828 nm is demonstrated. The QDs exhibit a remarkable PLQY of 75% when initially synthesized in a hydrophobic medium, and retains a high PLQY of 60% after ligand‐exchange and phase‐transfer into water. The water‐dispersed QDs show robust photostability with negligible photoluminescence (PL) attenuation after 3 h of laser irradiation, suggesting that the giant shell is effective in reducing nonradiative recombination that may be caused by photoinduced defects. The water‐dispersed QDs also exhibit high aqueous colloidal stability, retaining a high PLQY of 53% without QD agglomeration after 14 months of storage at 4 °C at a high loading concentration of 20 mg mL−1. The QDs are also successfully incorporated into HeLa cells for confocal bioimaging with no practical signs of cytotoxicity. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo‐immunotherapeutic combination regimens through the establishment of a long‐term cancer immunity. None of the clinically used DNA‐binding PtII complexes is considered a Type II ICD inducer. We generated a series of PtII‐carbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt‐NHC and compared their efficiency in triggering ICD‐related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent PtII candidate with superior ICD properties. Crucially, the magnitude of ICD‐associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER‐localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers. [ABSTRACT FROM AUTHOR]

Fluorescence imaging using charge‐coupled device cameras has become the prevailing method for the investigation of cancer drug efficacy in in vivo preclinical trials involving animal models. The lack of imaging depth, however, limits the use of fluorescence techniques to small murine models, and compels large animal models to rely on more‐costly magnetic resonance imaging or positron emission tomography techniques. Here, a wide field‐of‐view fluorescence imaging technique that uses near‐infrared (NIR) laser‐scanning excitation and efficient quantum dot photoluminescence is developed to achieve deep imaging across thick animal tissues. The smaller excitation volume from the scanning laser beam minimizes undesired background fluorescence, and allows signals to be detected and resolved at large tissue depths exceeding 10 mm. By implementing an artificial neural network algorithm, a twofold enhancement in imaging resolution is further demonstrated, which paves a promising way forward for the use of machine intelligence to enhance imaging quality in highly scattering media. The superior contrast of the imaging method is further corroborated by the imaging of a human palm, where bone structures are, for the first time, distinguishable using a NIR technique. In combination, the laser‐scanning approach and the artificial neural network image‐processing can constitute a low‐cost, yet powerful methodology for performing noninvasive deep‐imaging in larger animal models or human tissues. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a highly aggressive disease which is treated by surgery and platinum chemotherapy. However, a significant proportion of treated patients develop resistance to platinum treatment resulting in tumor relapse. Acquired platinum resistance has been recently correlated with activation of pro-survival endoplasmic reticulum (ER) stress responses. We hypothesized that Au complexes that induce severe ER stress might counteract pro-survival cellular attempts leading to the ER stress-mediated apoptosis and reduced platinum resistance. In this work, we prepared a series of highly cytotoxic AuI-dialkyldithiocarbamate complexes and investigated their anticancer potential in ovarian cancer cells. Complexes demonstrated surprisingly low stability in chloroform, resulting in the formation of an Au chain polymer, which also displayed excellent cytotoxicity. Lead complex 2 induced oxidative stress and ER stress-mediated p53-independent apoptosis associated with PARP cleavage and cell cycle arrest at G2/M phase. Importantly, 2 caused the surface exposure of calreticulin (CRT), which is the first step in the activation of cellular immunogenic response. [ABSTRACT FROM AUTHOR]

The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination‐directed 3‐component assembly to prepare a library of 768 unique Ru–Arene Schiff‐base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites. [ABSTRACT FROM AUTHOR]

Fluorescence microscopy has emerged as an attractive technique to probe the intracellular processing of Pt‐based anticancer compounds. Herein, we reported the first through‐bond energy transfer (TBET) fluorescent probe NPR1 designed for sensitive detection and quantitation of PtII complexes. The novel TBET probe was successfully applied for ratiometric fluorescence imaging of anticancer PtII complexes such as cisplatin and JM118 in cells. Capitalizing on the ability of the probe to discriminate between PtII complexes and their PtIV derivatives, the probe was further applied to study the activation of PtIV prodrug complexes that are known to release active PtII species after intracellular reduction. [ABSTRACT FROM AUTHOR]

A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action PtIV prodrugs. The dual targeting was established by liposomal encapsulation of PtIV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the PtIV prodrug inside cancer cells, a second stage of targeting directed a portion of the PtIV prodrugs to the mitochondria. Upon intracellular reduction, these PtIV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our PtIV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform. [ABSTRACT FROM AUTHOR]

Platinum(iv) carboxylate scaffolds have garnered considerable research interest because they can be engineered to function as prodrugs of clinical platinum(ii) anticancer drugs. These platinum(iv) prodrug complexes are stable and tunable, and activated by reduction to release their cytotoxic platinum(ii) cargo. Here we propose new platinum(iv) prodrug complexes designed to release cisplatin via photoreduction upon UV irradiation. The central strategy is to utilise aryl carboxylate ligands on the axial positions of that platinum(iv) scaffold that confer significant UV absorption and would stabilise carboxyl radical formation, thus favouring homolytic Pt–O bond cleavage. We isolated and identified aryl carboxyl radicals via spin-trapping and showed that the photoreduced platinum species mirror cisplatin reactivity toward DNA bases, thereby validating the efficacy of this approach. [ABSTRACT FROM AUTHOR]

The PtIV prodrug strategy has emerged as an excellent alternative to tackle the problems associated with conventional PtII drug therapy. However, there is a lack of tools to study how this new class of PtIV drugs are processed at the cellular level. Herein, we report the first ratiometric probe for cisplatin detection and use it to investigate PtIV anticancer complexes in biological systems. The probe was able to distinguish between cisplatin and its PtIV derivatives, allowing us to probe the intracellular reduction of PtIV prodrug complexes. The correlation between the amount of active PtII species available after intracellular reduction of PtIV complexes and their cytotoxicity and the role glutathione plays in the reduction of PtIV complexes were investigated. Watching closely: A ratiometric fluorescent probe was engineered to detect the clinically relevant platinum drug cisplatin. The ability to distinguish platinum(II) species from their parental platinum(IV) complexes allowed the application of the probe to the study of the activation of platinum(IV) carboxylate prodrug complexes within a complex intracellular environment. [ABSTRACT FROM AUTHOR]

Abstract: The development of new methods to synthesize nanometric metal catalysts has always been an important and prerequisite step in advanced catalysis. Herein, we design a stable nitrogen ligated Pt complex for the straightforward synthesis by carbonization of uniformly sized atomic and sub‐nanometric Pt catalysts supported on mesoporous silica. During the carbonization of the Pt precursor into active Pt species, the nitrogen‐containing ligand directed the decomposition in a controlled fashion to maintain uniform sizes of the Pt species. The nitrogen ligand had a key role to stabilize the single Pt atoms on a weak anchoring support like silica. The Pt catalysts exhibited remarkable activities in the hydrogenation of common organic functional groups with turnover frequencies higher than in previous studies. By a simple post‐synthetic treatment, we could selectively remove the Pt nanoparticles to obtain a mixture of single atoms and nanoclusters, extending the applicability of the present method. [ABSTRACT FROM AUTHOR]

Abstract: A new pre‐assembled ratiometric sensing platform was constructed from a coumarin donor and a rhodamine acceptor designed for through‐bond energy transfer (TBET). A phenylacetylene linker was installed to disrupt the planarity of the extended conjugated system but retaining the efficient energy transfer between the donor and acceptor motifs. To demonstrate its versatility as a sensing platform, we conjugated recognition motifs through amide coupling reactions to yield two TBET chemosensors capable of sensing either endogenously produced NO and ClO−. Both probes possessed high selectivity for their analytes, exhibited good stability under physiological conditions, and performed well as bioimaging probes in living cells. [ABSTRACT FROM AUTHOR]

A series of water-soluble sodium salts of 3-formyl-4-hydroxybenzenesulfonic acid thiosemicarbazones (or sodium 5-sulfonate-salicylaldehyde thiosemicarbazones) containing different substituents at the terminal nitrogen atom (H, Me, Et, Ph) and their copper(ii) complexes have been prepared and characterised by elemental analysis, spectroscopic techniques (IR, UV-vis, 1H NMR), ESI mass spectrometry, X-ray crystallography and cyclic voltammetry. The proligands and their copper(ii) complexes exhibit moderate water solubility and good stability in aqueous environment, determined by investigating their proton dissociation and complex formation equilibria. The copper(ii) complexes showed moderate anticancer activity in established human cancer cell lines, while the proligands were devoid of cytotoxicity. The anticancer activity of the copper(ii) complexes correlates with their ability to induce ROS accumulation in cells, consistent with their redox potentials within the biological window, triggering the activation of antioxidation defense mechanisms in response to the ROS insult. These studies pave the way for the investigation of ROS-inducing copper(ii) complexes as prospective antiproliferative agents in cancer chemotherapy. [ABSTRACT FROM AUTHOR]