Accelerated size-focusing light activated synthesis of atomically precise fluorescent Au22(Lys-Cys-Lys)16 clusters.

Atomically precise metal nanoclusters are promising candidates for various biomedical applications, including their use as photosensitizers in photodynamic therapy (PDT). However, typical synthetic routes of clusters often result in complex mixtures, where isolating and characterizing pure samples becomes challenging. In this work, a new Au22(Lys-Cys-Lys)16 cluster is synthesized using photochemistry, followed by a new type of light activated, accelerated size-focusing. Fluorescence excitation-emission matrix spectroscopy (EEM) and parallel factor (PARAFAC) analysis have been applied to track the formation of fluorescent species, and to assess optical purity of the final product. Furthermore, excited state reactivity of Au22(Lys-Cys-Lys)16 clusters is studied, and formation of type-I reactive oxygen species (ROS) from the excited state of the clusters is observed. The proposed size-focusing procedure in this work can be easily adapted to conventional cluster synthetic methods, such as borohydride reduction, to provide atomically precise clusters.

Directing Intrinsic Chirality in Gold Nanoclusters: Preferential Formation of Stable Enantiopure Clusters in High Yield and Experimentally Unveiling the "Super" Chirality of Au144.

Chiral gold nanoclusters offer significant potential for exploring chirality at a fundamental level and for exploiting their applications in sensing and catalysis. However, their widespread use is impeded by low yields in synthesis, tedious separation procedures of their enantiomeric forms, and limited thermal stability. In this study, we investigated the direct synthesis of enantiopure chiral nanoclusters using the chiral ligand 2-MeBuSH in the fabrication of Au25, Au38, and Au144 nanoclusters. Notably, this approach leads to the unexpected formation of intrinsically chiral clusters with high yields for chiral Au38 and Au144 nanoclusters. Experimental evaluation of chiral activity by circular dichroism (CD) spectroscopy corroborates previous theoretical calculations, highlighting the stronger CD signal exhibited by Au144 compared to Au38 or Au25. Furthermore, the formation of a single enantiomeric form is experimentally confirmed by comparing it with intrinsically chiral Au38(2-PET)24 (2-PET: 2-phenylethanethiol) and is supported theoretically for both Au38 and Au144. Moreover, the prepared chiral clusters show stability against diastereoisomerization, up to temperatures of 80 °C. Thus, our findings not only demonstrate the selective preparation of enantiopure, intrinsically chiral, and highly stable thiolate-protected Au nanoclusters through careful ligand design but also support the predicted "super" chirality in the Au144 cluster, encompassing hierarchical chirality in ligands, staple configuration, and core structure.

What Contributes to the Measured Chiral Optical Response of the Glutathione-Protected Au25 Nanocluster?

The water-soluble glutathione-protected [Au25(GSH)18]-1 nanocluster was investigated by integrating several methodologies such as molecular dynamics simulations, essential dynamics analysis, and state-of-the-art time-dependent density functional theory calculations. Fundamental aspects such as conformational, weak interactions and solvent effects, especially hydrogen-bonds, were included and found to play a fundamental role in assessing the optical response of this system. Our analysis demonstrated not only that the electronic circular dichroism is extremely sensitive to the solvent presence but also that the solvent itself plays an active role in the optical activity of such system, forming a chiral solvation shell around the cluster. Our work demonstrates a successful strategy to investigate in detail chiral interfaces between metal nanoclusters and their environments, applicable, e.g., to chiral electronic interactions between clusters and biomolecules.

Atomistic View of the Energy Transfer in a Fluorophore-Functionalized Gold Nanocluster.

Understanding the dynamics of Förster resonance energy transfer (FRET) in fluorophore-functionalized nanomaterials is critical for developing and utilizing such materials in biomedical imaging and optical sensing applications. However, structural dynamics of noncovalently bound systems have a significant effect on the FRET properties affecting their applications in solutions. Here, we study the dynamics of the FRET in atomistic detail by disclosing the structural dynamics of the noncovalently bound azadioxotriangulenium dye (KU) and atomically precise gold nanocluster (Au25(p-MBA)18, p-MBA = para-mercaptobenzoic acid) with a combination of experimental and computational methods. Two distinct subpopulations involved in the energy transfer process between the KU dye and the Au25(p-MBA)18 nanoclusters were resolved by time-resolved fluorescence experiments. Molecular dynamics simulations revealed that KU is bound to the surface of Au25(p-MBA)18 by interacting with the p-MBA ligands as a monomer and as a π-π stacked dimer where the center-to-center distance of the monomers to Au25(p-MBA)18 is separated by ∼0.2 nm, thus explaining the experimental observations. The ratio of the observed energy transfer rates was in reasonably good agreement with the well-known 1/R6 distance dependence for FRET. This work discloses the structural dynamics of the noncovalently bound nanocluster-based system in water solution, providing new insight into the dynamics and energy transfer mechanism of the fluorophore-functionalized gold nanocluster at an atomistic level.

Chloride Ligands on DNA-Stabilized Silver Nanoclusters.

DNA-stabilized silver nanoclusters (AgN-DNAs) are known to have one or two DNA oligomer ligands per nanocluster. Here, we present the first evidence that AgN-DNA species can possess additional chloride ligands that lead to increased stability in biologically relevant concentrations of chloride. Mass spectrometry of five chromatographically isolated near-infrared (NIR)-emissive AgN-DNA species with previously reported X-ray crystal structures determines their molecular formulas to be (DNA)2[Ag16Cl2]8+. Chloride ligands can be exchanged for bromides, which red-shift the optical spectra of these emitters. Density functional theory (DFT) calculations of the 6-electron nanocluster show that the two newly identified chloride ligands were previously assigned as low-occupancy silvers by X-ray crystallography. DFT also confirms the stability of chloride in the crystallographic structure, yields qualitative agreement between computed and measured UV-vis absorption spectra, and provides interpretation of the 35Cl-nuclear magnetic resonance spectrum of (DNA)2[Ag16Cl2]8+. A reanalysis of the X-ray crystal structure confirms that the two previously assigned low-occupancy silvers are, in fact, chlorides, yielding (DNA)2[Ag16Cl2]8+. Using the unusual stability of (DNA)2[Ag16Cl2]8+ in biologically relevant saline solutions as a possible indicator of other chloride-containing AgN-DNAs, we identified an additional AgN-DNA with a chloride ligand by high-throughput screening. Inclusion of chlorides on AgN-DNAs presents a promising new route to expand the diversity of AgN-DNA structure-property relationships and to imbue these emitters with favorable stability for biophotonics applications.

Supercrystal engineering of atomically precise gold nanoparticles promoted by surface dynamics.

The controllable packing of functional nanoparticles (NPs) into crystalline lattices is of interest in the development of NP-based materials. Here we demonstrate that the size, morphology and symmetry of such supercrystals can be tailored by adjusting the surface dynamics of their constituent NPs. In the presence of excess tetraethylammonium cations, atomically precise [Au25(SR)18]- NPs (where SR is a thiolate ligand) can be crystallized into micrometre-sized hexagonal rod-like supercrystals, rather than as face-centred-cubic superlattices otherwise. Experimental characterization supported by theoretical modelling shows that the rod-like crystals consist of polymeric chains in which Au25 NPs are held together by a linear SR-[Au(I)-SR]4 interparticle linker. This linker is formed by conjugation of two dynamically detached SR-[Au(I)-SR]2 protecting motifs from adjacent Au25 particles, and is stabilized by a combination of CH⋯π and ion-pairing interactions between tetraethylammonium cations and SR ligands. The symmetry, morphology and size of the resulting supercrystals can be systematically tuned by changing the concentration and type of the tetraalkylammonium cations.

Tailoring the interaction between a gold nanocluster and a fluorescent dye by cluster size: creating a toolbox of range-adjustable pH sensors.

We present a novel strategy for tailoring the fluorescent azadioxatriangulenium (KU) dye-based pH sensor to the target pH range by regulating the pK a value of the gold nanoclusters. Based on the correlation between the pK a and surface curvature of ligand-protected nanoparticles, the pK a value of the gold nanoclusters was controlled by size. In particular, three different-sized para-mercaptobenzoic acid (p-MBA) protected gold nanoclusters, Au25(p-MBA)18, Au102(p-MBA)44, and Au210-230(p-MBA)70-80 were used as the regulator for the pH range of the KU response. The negatively charged gold nanoclusters enabled the positively charged KU to bind to the surface, forming a complex and quenching the fluorescence of the KU by the energy transfer process. The fluorescence was restored after adjusting the surface charge of the gold nanocluster by controlling the solution pH. In addition, the KU exhibited a significantly different pH response behaviour for each gold nanocluster. Au210-230(p-MBA)70-80 showed a higher pH response range than Au102(p-MBA)44, which was intuitive. However, Au25(p-MBA)18 showed an unexpectedly high pH response behaviour. pK a titration measurement, molecular dynamics simulations, and essential dynamics analysis showed that small nanoclusters do not follow the scaling between the curvature and the pK a value. Instead, the behaviour is governed by the distribution and interaction of p-MBA ligands on the nanocluster surface. This work presents an effective design strategy for fabricating a range adjustable pH sensor by understanding the protonation behaviour of the ultrasmall gold nanoclusters in an atomic range.

Atomically Precise Gold Nanoclusters: Towards an Optimal Biocompatible System from a Theoretical-Experimental Strategy.

Potential biomedical applications of gold nanoparticles have increasingly been reported with great promise for diagnosis and therapy of several diseases. However, for such a versatile nanomaterial, the advantages and potential health risks need to be addressed carefully, as the available information about their toxicity is limited and inconsistent. Atomically precise gold nanoclusters (AuNCs) have emerged to overcome this challenge due to their unique features, such as superior stability, excellent biocompatibility, and efficient renal clearance. Remarkably, the elucidation of their structural and physicochemical properties provided by theory-experiment investigations offers exciting opportunities for site-specific biofunctionalization of the nanoparticle surface, which remains a significant concern for most of the materials in the biomedical field. This concept highlights the advantages conferred by atomically precise AuNCs for biomedical applications and the powerful strategy combining computational and experimental studies towards finding an optimal biocompatible AuNCs-based nanosystem.

Experimental Confirmation of a Topological Isomer of the Ubiquitous Au25(SR)18 Cluster in the Gas Phase.

High-resolution electrospray ionization ion mobility mass spectrometry has revealed a gas-phase isomer of the ubiquitous, extremely well-studied Au25(SR)18 cluster both in anionic and cationic form. The relative abundance of the isomeric structures can be controlled by in-source activation. The measured collision cross section of the new isomer agrees extremely well with a recent theoretical prediction (Matus, M. F.; et al. Chem. Commun. 2020, 56, 8087) corresponding to a Au25(SR)18- isomer that is energetically close and topologically connected to the known ground-state structure via a simple rotation of the gold core without breaking any Au-S bonds. The results imply that the structural dynamics leading to isomerization of thiolate-protected gold clusters may play an important role in their gas-phase reactions and that isomerization could be controlled by external stimuli.

Ligand Ratio Plays a Critical Role in the Design of Optimal Multifunctional Gold Nanoclusters for Targeted Gastric Cancer Therapy.

Nanodrug delivery systems (NDDSs) based on water-soluble and atomically precise gold nanoclusters (AuNCs) are under the spotlight due to their great potential in cancer theranostics. Gastric cancer (GC) is one of the most aggressive cancers with a low early diagnosis rate, with drug therapy being the primary means to overcome its increasing incidence. In this work, we designed and characterized a set of 28 targeted nanosystems based on Au144(p-MBA)60 (p-MBA = para-mercaptobenzoic acid) nanocluster to be potentially employed as combination therapy in GC treatment. The proposed multifunctional AuNCs are functionalized with cytotoxic drugs (5-fluorouracil and epirubicin) or inhibitors of different signaling pathways (phosphatidylinositol 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of the rapamycin (mTOR), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF)) and RGD peptides as targeting ligands, and we studied the role of ligand ratio in their optimal structural conformation using peptide-protein docking and all-atom molecular dynamics (MD) simulations. The results reveal that the peptide/drug ratio is a crucial factor influencing the potential targeting ability of the nanosystem. The most convenient features were observed when the peptide amount was favored over the drug in most cases; however, we demonstrated that the system composition and the intermolecular interactions on the ligand shell are crucial for achieving the desired effect. This approach helps guide the experimental stage, providing essential information on the size and composition of the nanosystem at the atomic level for ligand tuning in order to increase the desired properties.

A topological isomer of the Au25(SR)18- nanocluster.

Energetically low-lying structural isomers of the much-studied thiolate-protected gold cluster Au25(SR)18- are discovered from extensive (80 ns) molecular dynamics (MD) simulations using the reactive molecular force field ReaxFF and confirmed by density functional theory (DFT). A particularly interesting isomer is found, which is topologically connected to the known crystal structure by a low-barrier collective rotation of the icosahedral Au13 core. The isomerization takes place without breaking of any Au-S bonds. The predicted isomer is essentially iso-energetic with the known Au25(SR)18- structure, but has a distinctly different optical spectrum. It has a significantly larger collision cross-section as compared to that of the known structure, which suggests it could be detectable in gas phase ion-mobility mass spectrometry.

Atomic-level characterization and cilostazol affinity of poly(lactic acid) nanoparticles conjugated with differentially charged hydrophilic molecules.

Nanotherapeutics is a promising field for numerous diseases and represents the forefront of modern medicine. In the present work, full atomistic computer simulations were applied to study poly(lactic acid) (PLA) nanoparticles conjugated with polyethylene glycol (PEG). The formation of this complex system was simulated using the reactive polarizable force field (ReaxFF). A full picture of the morphology, charge and functional group distribution is given. We found that all terminal groups (carboxylic acid, methoxy and amino) are randomly distributed at the surface of the nanoparticles. The surface design of NPs requires that the charged groups must surround the surface region for an optimal functionalization/charge distribution, which is a key factor in determining physicochemical interactions with different biological molecules inside the organism. Another important point that was investigated was the encapsulation of drugs in these nanocarriers and the prediction of the polymer-drug interactions, which provided a better insight into structural features that could affect the effectiveness of drug loading. We employed blind docking to predict NP-drug affinity testing on an antiaggregant compound, cilostazol. The results suggest that the combination of molecular dynamics ReaxFF simulations and blind docking techniques can be used as an explorative tool prior to experiments, which is useful for rational design of new drug delivery systems.

Nanotechnology and primary hemostasis: Differential effects of nanoparticles on platelet responses.

Despite the numerous advantages offered by diverse platforms based on nanomedicine, several nanomaterials have shown significant cell toxicity that could induce chronic adverse effects on human health. Blood compatibility is one of the leading factors to consider for the design and development of nanosystems as therapeutics. Aforementioned is because systemic circulation is the gateway for most nano-drug therapeutic systems and its interactions with the blood components such as platelets could influence the maintenance of hemostasis and thrombus formation. Unfortunately, the thrombotoxicity of some nanomaterials regarding the activation/inhibition of platelets limits their biomedical applications. Additionally, the critical factors that drive those effects on platelet function are still not entirely elucidated. In this work, we describe the effect of different nanomaterials on the platelet function, its action mechanisms, and future potential as nanotherapeutics.

Anti-proliferative effect of terpenes on human prostate cancer cells: Natural sources and their potential role as chemopreventive agents / Efecto anti-proliferativo de los terpenos en células de cáncer de próstata humana: Fuentes naturales y su rol potencial como agentes quimiopreventivos

ABSTRACT Prostate cancer is one of the neoplastic diseases with the highest morbidity and mortality in the world. The diversity of available treatments and side effects related to therapeutic treatments are severe and affect a patient's quality of life. Thus, to creating new therapeutic alternatives to reduce morbidity and creating safe and effective therapies is a constant challenge. Recently, the use of traditional medicine and chemoprevention has gained importance. Several clinical and epidemiological studies suggest that a high-terpenoid compound-based diet is associated with a reduced risk of prostate cancer. This review is focused on the anti-proliferative effects of different terpenoids isolated from natural sources on human prostate cancer cells, with the aim of setting the basis to use these compounds as phytotherapeutic, nutraceutical and functional ingredients.

RESUMEN El cáncer de próstata es una de las neoplasias que produce gran morbilidad y mortalidad en el mundo. Los tratamientos y los efectos secundarios de la terapia son severos y afectan la calidad de vida del paciente. Por esto, es necesario crear nuevas alternativas terapéuticas para reducir la morbilidad y generar terapias seguras y efectivas es un desafío permanente. En los últimos años, el uso de la medicina tradicional y agentes quimiopreventivos han adquirido importancia. Estudios clínicos y epidemiológicos sugieren que una dieta basada en altas dosis de terpenoides se asocia a una reducción en el riesgo de presentar cáncer de próstata. Esta revisión se centra en los efectos anti-proliferativos sobre las células de cáncer de próstata en humanos de diferentes terpenoides aislados de fuentes naturales, con el objetivo de establecer las bases para utilizar estos compuestos como ingredientes fitoterapéuticos, nutracéuticos y funcionales.

Isoxazoles: synthesis, evaluation and bioinformatic design as acetylcholinesterase inhibitors.

OBJECTIVES: Inhibition of acetylcholinesterase (AChE) is a common treatment for early stages of Alzheimer's disease. In this study, nine isoxazoles derivatives were tested for their in-vitro AChE activity. The molecular docking showed the interaction of the compounds with the active site. METHODS: The isoxazoles were synthesized using 1,3-dipolar cycloaddition in the presence of sodium hypochlorite. They were also isolated and characterized by spectroscopic methods. The in-vitro activity was measured by an adapted version of Ellman's assay. KEY FINDINGS: The isoxazoles are described as inhibitors of AChE. The most potent compound in the series exhibited a moderate inhibitory activity (50% inhibitory concentration = 134.87 µm). The design of new compounds was created by using the RACHEL module of the SYBYL software. CONCLUSIONS: Our research provided enough evidence of the efficacy of isoxazoles as AChE inhibitors. The isoxazoles were synthesized and evaluated as inhibitors of AChE. The docking study based on a novel series of complexes isoxazole with AChE from Electroporus electricus has demonstrated that the ligand bind is similar to the compounds used as reference. To find new candidates with the isoxazole core that act as inhibitors of AChE, part of the structure of the compound 9 was used for de-novo design. Molecular docking models of the ligand-AChE complexes suggest that the compound 10 is located on the periphery of the AChE active site.