Nanoparticle-Catalyzed Transamination under Tumor Microenvironment Conditions: A Novel Tool to Disrupt the Pool of Amino Acids and GSSG in Cancer Cells.

Catalytic cancer therapy targets cancer cells by exploiting the specific characteristics of the tumor microenvironment (TME). TME-based catalytic strategies rely on the use of molecules already present in the TME. Amino groups seem to be a suitable target, given the abundance of proteins and peptides in biological environments. Here we show that catalytic CuFe2O4 nanoparticles are able to foster transaminations with different amino acids and pyruvate, another key molecule present in the TME. We observed a significant in cellulo decrease in glutamine and alanine levels up to 48 h after treatment. In addition, we found that di- and tripeptides also undergo catalytic transamination, thereby extending the range of the effects to other molecules such as glutathione disulfide (GSSG). Mechanistic calculations for GSSG transamination revealed the formation of an imine between the oxo group of pyruvate and the free -NH2 group of GSSG. Our results highlight transamination as alternative to the existing toolbox of catalytic therapies.

Platinum-based nanodendrites as glucose oxidase-mimicking surrogates.

Catalytic conversion of glucose represents an interesting field of research with multiple applications. From the biotechnology point of view, glucose conversion leads to the fabrication of different added-value by-products. In the field of nanocatalytic medicine, the reduction of glucose levels within the tumor microenvironment (TME) represents an appealing approach based on the starvation of cancer cells. Glucose typically achieves high conversion rates with the aid of glucose oxidase (GOx) enzymes or by fermentation. GOx is subjected to degradation, possesses poor recyclability and operates under very specific reaction conditions. Gold-based materials have been typically explored as inorganic catalytic alternatives to GOx in order to convert glucose into building block chemicals of interest. Still, the lack of sufficient selectivity towards certain products such as gluconolactone, the requirement of high fluxes of oxygen or the critical size dependency hinder their full potential, especially in liquid phase reactions. The present work describes the synthesis of platinum-based nanodendrites as novel enzyme-mimicking inorganic surrogates able to convert glucose into gluconolactone with outstanding selectivity values above 85%. We have also studied the enzymatic behavior of these Pt-based nanozymes using the Michaelis-Menten and Lineweaver-Burk models and used the main calculation approaches available in the literature to determine highly competitive glucose turnover rates for Pt or Pt-Au nanodendrites.

Heterogeneous-Driven Glutathione Oxidation: Defining the Catalytic Role of Chalcopyrite Nanoparticles.

Transition-metal nanocatalysis represents a novel alternative currently experiencing flourishing progress to tackle the tumor microenvironment (TME) in cancer therapy. These nanomaterials aim at attacking tumor cells using the intrinsic selectivity of inorganic catalysts. In addition, special attention to tune and control the release of these transition metals is also required. Understanding the chemical reactions behind the catalytic action of the transition-metal nanocatalysts and preventing potential undesired side reactions caused by acute cytotoxicity of the released ionic species represent another important field of research. Specifically, copper-based oxides may suffer from acute leaching that potentially may induce toxicity not only to target cancer cells but also to nearby cells and tissues. In this work, we propose the synthesis of chalcopyrite (CuFeS2) nanostructures capable of triggering two key reactions for an effective chemodynamic therapy (CDT) in the heterogeneous phase: (i) glutathione (GSH) oxidation and (ii) oxidation of organic substrates using H2O2, with negligible leaching of metals under TME-like conditions. This represents an appealing alternative toward the development of safer copper-iron-based nanocatalytic materials with an active catalytic response without incurring leaching side phenomena.

Unveiling the interplay between homogeneous and heterogeneous catalytic mechanisms in copper-iron nanoparticles working under chemically relevant tumour conditions.

The present work sheds light on a generally overlooked issue in the emerging field of bio-orthogonal catalysis within tumour microenvironments (TMEs): the interplay between homogeneous and heterogeneous catalytic processes. In most cases, previous works dealing with nanoparticle-based catalysis in the TME focus on the effects obtained (e.g. tumour cell death) and attribute the results to heterogeneous processes alone. The specific mechanisms are rarely substantiated and, furthermore, the possibility of a significant contribution of homogeneous processes by leached species - and the complexes that they may form with biomolecules - is neither contemplated nor pursued. Herein, we have designed a bimetallic catalyst nanoparticle containing Cu and Fe species and we have been able to describe the whole picture in a more complex scenario where both homogeneous and heterogeneous processes are coupled and fostered under TME relevant chemical conditions. We investigate the preferential leaching of Cu ions in the presence of a TME overexpressed biomolecule such as glutathione (GSH). We demonstrate that these homogeneous processes initiated by the released by Cu-GSH interactions are in fact responsible for the greater part of the cell death effects found (GSH, a scavenger of reactive oxygen species, is depleted and highly active superoxide anions are generated in the same catalytic cycle). The remaining solid CuFe nanoparticle becomes an active catalyst to supply oxygen from oxygen reduced species, such as superoxide anions (by-product from GSH oxidation) and hydrogen peroxide, another species that is enriched in the TME. This activity is essential to sustain the homogeneous catalytic cycle in the oxygen-deprived tumour microenvironment. The combined heterogeneous-homogeneous mechanisms revealed themselves as highly efficient in selectively killing cancer cells, due to their higher GSH levels compared to healthy cell lines.

Platinum nanoplatforms: classic catalysts claiming a prominent role in cancer therapy.

Platinum nanoparticles (Pt NPs) have a well-established role as a classic heterogeneous catalyst. Also, Pt has traditionally been employed as a component of organometallic drug formulations for chemotherapy. However, a new role in cancer therapy is emerging thanks to its outstanding catalytic properties, enabling novel approaches that are surveyed in this review. Herein, we critically discuss results already obtained and attempt to ascertain future perspectives for Pt NPs as catalysts able to modify key processes taking place in the tumour microenvironment (TME). In addition, we explore relevant parameters affecting the cytotoxicity, biodistribution and clearance of Pt nanosystems. We also analyze pros and cons in terms of biocompatibility and potential synergies that emerge from combining the catalytic capabilities of Pt with other agents such as co-catalysts, external energy sources (near-infrared light, X-ray, electric currents) and conventional therapies.

Gold-Platinum Nanoparticles with Core-Shell Configuration as Efficient Oxidase-like Nanosensors for Glutathione Detection.

Nanozymes, defined as nanomaterials that can mimic the catalytic activity of natural enzymes, have been widely used to develop analytical tools for biosensing. In this regard, the monitoring of glutathione (GSH), a key antioxidant biomolecule intervening in the regulation of the oxidative stress level of cells or related with Parkinson's or mitochondrial diseases can be of great interest from the biomedical point of view. In this work, we have synthetized a gold-platinum Au@Pt nanoparticle with core-shell configuration exhibiting a remarkable oxidase-like mimicking activity towards the substrates 3,3',5,5'-tetramethylbenzidine (TMB) and o-phenylenediamine (OPD). The presence of a thiol group (-SH) in the chemical structure of GSH can bind to the Au@Pt nanozyme surface to hamper the activation of O2 and reducing its oxidase-like activity as a function of the concentration of GSH. Herein, we exploit the loss of activity to develop an analytical methodology able to detect and quantify GSH up to µM levels. The system composed by Au@Pt and TMB demonstrates a good linear range between 0.1-1.0 µM to detect GSH levels with a limit of detection (LoD) of 34 nM.

Glutathione-Triggered catalytic response of Copper-Iron mixed oxide Nanoparticles. Leveraging tumor microenvironment conditions for chemodynamic therapy.

Heterogeneous catalysis has emerged as a promising alternative for the development of new cancer therapies. In addition, regarding the tumor microenvironment as a reactor with very specific chemical features has provided a new perspective in the search for catalytic nanoarchitectures with specific action against chemical species playing a key role in tumor metabolism. One of these species is glutathione (GSH), whose depletion is the cornerstone of emerging strategies in oncology, since this metabolite plays a pivotal regulatory role as antioxidant agent, dampening the harmful effects of intracellular reactive oxidative species (ROS). Herein, we present copper-iron oxide spinel nanoparticles that exhibit a versatile and selective catalytic response to reduce GSH levels while generating ROS in a cascade reaction. We demonstrate a clear correlation between GSH depletion and apoptotic cell death in tumor cells in the presence of the copper-iron nanocatalyst. Furthermore, we also provide a novel analytical protocol, alternative to state-of-the-art commercial kits, to accurately monitoring the concentration of GSH intracellular levels in both tumor and healthy cells. We observe a selective action of the nanoparticles, with lower toxicity in healthy cell lines, whose intrinsic GSH levels are lower, and intense apoptosis in tumor cells accompanied by a fast reduction of GSH levels.