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Bioorthogonal catalysis employing transition metal catalysts is a promising strategy for the in situ synthesis of imaging and therapeutic agents in biological environments. The transition metal Pd has been widely used as a bioorthogonal catalyst, but bare Pd poses challenges in water solubility and catalyst stability in cellular environments. In this work, Pd(0) loaded amphiphilic polymeric nanoparticles are applied to shield Pd in the presence of living cells for the in situ generation of a fluorescent dye and anticancer drugs. Pd(0) loaded polymeric nanoparticles prepared by the reduction of the corresponding Pd(II)-polymeric nanoparticles are highly active in the deprotection of pro-rhodamine dye and anticancer prodrugs, giving significant fluorescence enhancement and toxigenic effects, respectively, in HepG2 cells. In addition, we show that the microstructure of the polymeric nanoparticles for scaffolding Pd plays a critical role in tuning the catalytic efficiency, with the use of the ligand triphenylphosphine as a key factor for improving the catalyst stability in biological environments.

Bioorthogonal catalysis employing transition metal catalysts is a promising strategy for the in situ synthesis of imaging and therapeutic agents in biological environments. The transition metal Pd has been widely used as a bioorthogonal catalyst, but bare Pd poses challenges in water solubility and catalyst stability in cellular environments. In this work, Pd(0) loaded amphiphilic polymeric nanoparticles are applied to shield Pd in the presence of living cells for the in situ generation of a fluorescent dye and anticancer drugs. Pd(0) loaded polymeric nanoparticles prepared by the reduction of the corresponding Pd(II)-polymeric nanoparticles are highly active in the deprotection of pro-rhodamine dye and anticancer prodrugs, giving significant fluorescence enhancement and toxigenic effects, respectively, in HepG2 cells. In addition, we show that the microstructure of the polymeric nanoparticles for scaffolding Pd plays a critical role in tuning the catalytic efficiency, with the use of the ligand triphenylphosphine as a key factor for improving the catalyst stability in biological environments.

Several studies have reported the successful use of bio-orthogonal catalyst nanoparticles (NPs) for cancer therapy. However, the delivery of the catalysts to the target tissues in vivo remains an unsolved challenge. The combination of catalytic NPs with extracellular vesicles (EVs) has been proposed as a promising approach to improve the delivery of therapeutic nanomaterials to the desired organs. In this study, we have developed a nanoscale bio-hybrid vector using a CO-mediated reduction at low temperature to generate ultrathin catalytic Pd nanosheets (PdNSs) as catalysts directly inside cancer-derived EVs. We have also compared their biodistribution with that of PEGylated PdNSs delivered by the EPR effect. Our results indicate that the accumulation of PdNSs in the tumour tissue was significantly higher when they were administered within the EVs compared to the PEGylated PdNSs. Conversely, the amount of Pd found in non-target organs (i.e., liver) was lowered. Once the Pd-based catalytic EVs were accumulated in the tumours, they enabled the activation of a paclitaxel prodrug demonstrating their ability to carry out bio-orthogonal uncaging chemistries in vivo for cancer therapy.

Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin and oleandrin in human cell lines under various modalities of senescence. The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives. Our approach led to several hundred-fold reduction in drug screening costs and demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data, paving the way for new open science approaches to early-stage drug discovery.

Bioorthogonal metallocatalysis has opened up a xenobiotic route to perform nonenzymatic catalytic transformations in living settings. Despite their promising features, most metals are deactivated inside cells by a myriad of reactive biomolecules, including biogenic thiols, thereby limiting the catalytic functioning of these abiotic reagents. Here we report the development of cytocompatible alloyed AuPd nanoparticles with the capacity to elicit bioorthogonal depropargylations with high efficiency in biological media. We also show that the intracellular catalytic performance of these nanoalloys is significantly enhanced by protecting them following two different encapsulation methods. Encapsulation in mesoporous silica nanorods resulted in augmented catalyst reactivity, whereas the use of a biodegradable PLGA matrix increased nanoalloy delivery across the cell membrane. The functional potential of encapsulated AuPd was demonstrated by releasing the potent chemotherapy drug paclitaxel inside cancer cells. Nanoalloy encapsulation provides a novel methodology to develop nanoreactors capable of mediating new-to-life reactions in cells.

Preparation and characterization of NPs, prodye, and prodrug; methods and experimental procedures; biological assays; and Figures S1–S8.

Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.

One of the major issues of anti-cancer drugs is their toxicity and side effects duc to their low tissue-specificity. lnnovative methods to localize drug aclivity at the tumour site are needed to improve chemotherapy treatments. In recent years, transition metals not found in living beings (e.g., Au. Pd, Rh) have been employed as bioorthogonal catalysts able to spatially control the uncaging of anti-cancer prodrugs in tumour sites. The localization of catalytic activity has been achieved creating devices containing the calalyst which are implanted directly in the tumour. These devices are normally nonbiodegradable so they remain at the affected tissue alter the treatment. In this work, we present the development of novel high-performance biocompatible and biodegradable crystal-based, devices which entrap bioorthogonal organomctallic catalysts. These composite materials have proven to be highly effective catalysing the uncaging of profluorophores and prodrugs in a selective manner. We employed biomacromolecules based crystals as matrices, so only small molecules (such as prodrugs and pro-dyes) can reach thc catalyst avoiding any interaction with surrounding proteins. Additionally, their biological composition allows these devices eventually to be biodegraded thus disappearing from the tissue alter the treatment, which represents an important advance in the field.

Novel approaches to targeted cancer therapy that combine improved efficacy of current chemotherapies while minimising side effects are highly sought after. The development of single-chain polymeric nanoparticles (SCPNs) as bio-orthogonal catalysts for targeted site-specific pro-drug activation is a promising avenue to achieve this. Currently, the application of SCPNs as bio-orthogonal catalysts is in its early stages due to reduced performance when increasing the medium's complexity. Herein, we present a systematic approach to identify the various aspects of SCPN-based catalytic systems, to improve their efficiency in future in vitro/in vivo studies. We developed amphiphilic polymers with a polyacrylamide backbone and functionalised with the Pd(ii)-binding ligands triphenylphosphine and bipyridine. The resulting polymers collapse into small-sized nanoparticles (5-6 nm) with an inner hydrophobic domain that comprises the Pd(ii) catalyst. We systematically evaluated the effect of polymer microstructure, ligand-metal complex, and substrate hydrophobicity on the catalytic activity of the nanoparticles for depropargylation reactions in water, PBS or DMEM. The results show that the catalytic activity of nanoparticles is primarily impacted by the ligand-metal complex while polymer microstructure has a minor influence. Moreover, the rate of reaction is increased for hydrophobic substrates. In addition, Pd(ii) leaching studies confirmed little to no loss of Pd(ii) from the hydrophobic interior which can reduce off-target toxicities in future applications. Careful deconstruction of the catalytic system revealed that covalent attachment of the ligand to the polymer backbone is necessary to retain its catalytic activity in cell culture medium while not in water. Finally, we activated anti-cancer pro-drugs based on 5-FU, paclitaxel, and doxorubicin using the best-performing catalytic SCPNs. We found that the rate of pro-drug activation in water was accelerated efficiently by