David Tai Leong

From Aggregation-Induced Emission of Au(I)–Thiolate Complexes to Ultrabright Au(0)@Au(I)–Thiolate Core–Shell Nanoclusters

A fundamental understanding of the luminescence of Au-thiolate nanoclusters (NCs), such as the origin of emission and the size effect in luminescence, is pivotal to the development of efficient synthesis routes for highly luminescent Au NCs. This paper reports an interesting finding of Au(I)-thiolate complexes: strong luminescence emission by the mechanism of aggregation-induced emission (AIE). The AIE property of the complexes was then used to develop a simple one-pot synthesis of highly luminescent Au-thiolate NCs with a quantum yield of ~15%. Our key strategy was to induce the controlled aggregation of Au(I)-thiolate complexes on in situ generated Au(0) cores to form Au(0)@Au(I)-thiolate core-shell NCs where strong luminescence was generated by the AIE of Au(I)-thiolate complexes on the NC surface. We were able to extend the synthetic strategy to other thiolate ligands with added functionalities (in the form of custom-designed peptides). The discovery (e.g., identifying the source of emission and the size effect in luminescence) and the synthesis protocols in this study can contribute significantly to better understanding of these new luminescence probes and the development of new synthetic routes.

Identification of a Highly Luminescent Au22(SG)18 Nanocluster

The luminescence property of thiolated gold nanoclusters (Au NCs) is thought to involve the Au(I)-thiolate motifs on the NC surface; however, this hypothesis remains largely unexplored because of the lack of precise molecular composition and structural information of highly luminescent Au NCs. Here we report a new red-emitting thiolated Au NC, which has a precise molecular formula of Au22(SR)18 and exhibits intense luminescence. Interestingly, this new Au22(SR)18 species shows distinctively different absorption and emission features from the previously reported Au22(SR)16, Au22(SR)17, and Au25(SR)18. In stark contrast, Au22(SR)18 luminesces intensely at ∼665 nm with a high quantum yield of ∼8%, while the other three Au NCs show very weak luminescence. Our results indicate that the luminescence of Au22(SR)18 originates from the long Au(I)-thiolate motifs on the NC surface via the aggregation-induced emission pathway. Structure prediction by density functional theory suggests that Au22(SR)18 has two RS-[Au-SR]3 and two RS-[Au-SR]4 motifs, interlocked and capping on a prolate Au8 core. This predicted structure is further verified experimentally by Au L3-edge X-ray absorption fine structure analysis.

Nanotheranostics ˗ Application and Further Development of Nanomedicine Strategies for Advanced Theranostics

Nanotheranostics is to apply and further develop nanomedicine strategies for advanced theranostics. This review summarizes the various nanocarriers developed so far in the literature for nanotheranostics, which include polymer conjugations, dendrimers, micelles, liposomes, metal and inorganic nanoparticles, carbon nanotubes, and nanoparticles of biodegradable polymers for sustained, controlled and targeted co-delivery of diagnostic and therapeutic agents for better theranostic effects with fewer side effects. The theranostic nanomedicine can achieve systemic circulation, evade host defenses and deliver the drug and diagnostic agents at the targeted site to diagnose and treat the disease at cellular and molecular level. The therapeutic and diagnostic agents are formulated in nanomedicine as a single theranostic platform, which can then be further conjugated to biological ligand for targeting. Nanotheranostics can also promote stimuli-responsive release, synergetic and combinatory therapy, siRNA co-delivery, multimodality therapies, oral delivery, delivery across the blood-brain barrier as well as escape from intracellular autophagy. The fruition of nanotheranostics will be able to provide personalized therapy with bright prognosis, which makes even the fatal diseases curable or at least treatable at the earliest stage.

Glutathione-protected silver nanoclusters as cysteine-selective fluorometric and colorimetric probe.

The integration of the unique thiol-Ag chemistry and the specific steric hindrance from the organic layer of fluorescent Ag nanoclusters (AgNCs) was first developed in this work to achieve a simple detection of cysteine (Cys) with high selectivity and sensitivity. The key design is a strongly red-emitting AgNC protected by the interference biothiol, glutathione, or GSH (hereafter referred to as GSH-AgNCs), where both the physicochemical properties (Ag surface chemistry and fluorescence) of the NC core and the physical properties (e.g., steric hindrance) of the organic shell were fully utilized for Cys detection with three major features. First, owing to the specific thiol-Ag interaction, the fluorescent GSH-AgNCs showed superior selectivity for Cys over the other 19 natural amino acids (nonthiol-containing). Second, the GSH protecting layer on the NC surface made possible the differentiation of Cys from GSH (or other large-sized thiol molecules) simply by their size. Third, the ultrasmall size of GSH-AgNCs and the high affinity of the thiol-Ag interaction provided high sensitivity for Cys detection with a detection limit of <3 nM. The assay developed in this study is of interest not only because it provides a simple Cys sensor with high selectivity and sensitivity but also because it exemplifies the utilization of the physical properties of organic ligands on the nanomaterial surface to further improve the sensor performance, which could open a new design strategy for other sensor development.

Ultrasmall Au(10-12)(SG)(10-12) nanomolecules for high tumor specificity and cancer radiotherapy.

Radiosensitizers can increase local treatment efficacy under a relatively low and safe radiation dose, thereby facilitating tumor eradication and minimizing side effects. Here, a new class of radiosensitizers is reported, which contain several gold (Au) atoms embedded inside a peptide shell (e.g., Au10-12 (SG)10-12 ) and can achieve ultrahigh tumor uptake (10.86 SUV at 24 h post injection) and targeting specificity, efficient renal clearance, and high radiotherapy enhancement.

Toward Understanding the Growth Mechanism: Tracing All Stable Intermediate Species from Reduction of Au(I)–Thiolate Complexes to Evolution of Au25 Nanoclusters

Despite 20 years of progress in synthesizing thiolated gold nanoclusters (Au NCs), the knowledge of their growth mechanism still lags behind. Herein the detailed process from reduction of Au(I)-thiolate complex precursors to the eventual evolution of and focusing to the atomically precise Au25 NCs was revealed for the first time by monitoring the time evolution of Au(I) precursor and Au NC intermediate species with ESI-MS. A two-stage, bottom-up formation and growth process was proposed: a fast stage of reduction-growth mechanism, followed by a slow stage of intercluster conversion and focusing. Balanced reactions of formation for each identified NC were suggested, backed by theoretical calculations of the thermodynamic driving force. This work advances one step further toward understanding the mechanism of formation and growth of thiolated Au NCs.

Balancing the rate of cluster growth and etching for gram-scale synthesis of thiolate-protected Au(25) nanoclusters with atomic precision.

We report a NaOH-mediated NaBH4 reduction method for the synthesis of mono-, bi-, and tri-thiolate-protected Au25 nanoclusters (NCs) with precise control of both the Au core and thiolate ligand surface. The key strategy is to use NaOH to tune the formation kinetics of Au NCs, i.e., reduce the reduction ability of NaBH4 and accelerate the etching ability of free thiolate ligands, leading to a well-balanced reversible reaction for rapid formation of thermodynamically favorable Au25 NCs. This protocol is facile, rapid (≤3 h), versatile (applicable for various thiolate ligands), and highly scalable (>1 g Au NCs). In addition, bi- and tri-thiolate-protected Au25 NCs with adjustable ratios of hetero-thiolate ligands were easily obtained. Such ligand precision in molecular ratios, spatial distribution and uniformity resulted in richly diverse surface landscapes on the Au NCs consisting of multiple functional groups such as carboxyl, amine, and hydroxy. Analysis based on NMR spectroscopy revealed that the hetero-ligands on the NCs are well distributed with no ligand segregation. The unprecedented synthesis of multi-thiolate-protected Au25 NCs may further promote the practical applications of functional metal NCs.

The role of the tumor suppressor p53 pathway in the cellular DNA damage response to zinc oxide nanoparticles.

In this paper, we explored how ZnO nanoparticles cross-interact with a critical tumor suppressive pathway centered around p53, which is one of the most important known tumor suppressors that protects cells from developing cancer phenotypes through its control over major pathways like apoptosis, senescence and cell cycle progression. We showed that the p53 pathway was activated in BJ cells (skin fibroblasts) upon ZnO nanoparticles treatment with a concomitant decrease in cell numbers. This suggests that cellular responses like apoptosis in the presence of ZnO nanoparticles require p53 as the molecular master switch towards programmed cell death. This also suggests that in cells without robust p53, protective response can be tipped towards carcinogenesis when stimulated by DNA damage inducing agents like ZnO nanoparticles. We observed this precarious tendency in the same BJ cells with p53 knocked down using endogeneous expressing shRNA. These p53 knocked down BJ cells became more resistant to ZnO nanoparticles induced cell death and increased cell progression. Collectively, our results suggest that cellular response towards specific nanoparticle induced cell toxicity and carcinogenesis is not only dependent on specific nanoparticle properties but also (perhaps more importantly) the endogenous genetic, transcriptomic and proteomic landscape of the target cells.

Nanoparticles strengthen intracellular tension and retard cellular migration.

Nanoparticles can have profound effects on cell biology. Here, we show that after TiO2, SiO2, and hydroxyapatite nanoparticles treatment, TR146 epithelial cell sheet displayed slower migration. Cells after exposure to the nanoparticles showed increased cell contractility with significantly impaired wound healing capability however without any apparent cytotoxicity. We showed the mechanism is through nanoparticle-mediated massive disruption of the intracellular microtubule assembly, thereby triggering a positive feedback that promoted stronger substrate adhesions thus leading to limited cell motility.

Autocrine Fibroblast Growth Factor 2 Increases the Multipotentiality of Human Adipose‐Derived Mesenchymal Stem Cells

Multipotent mesenchymal stem cells (MSCs), first identified in the bone marrow, have subsequently been found in many other tissues, including fat, cartilage, muscle, and bone. Adipose tissue has been identified as an alternative to bone marrow as a source for the isolation of MSCs, as it is neither limited in volume nor as invasive in the harvesting. This study compares the multipotentiality of bone marrow‐derived mesenchymal stem cells (BMSCs) with that of adipose‐derived mesenchymal stem cells (AMSCs) from 12 age‐ and sex‐matched donors. Phenotypically, the cells are very similar, with only three surface markers, CD106, CD146, and HLA‐ABC, differentially expressed in the BMSCs. Although colony‐forming units‐fibroblastic numbers in BMSCs were higher than in AMSCs, the expression of multiple stem cell‐related genes, like that of fibroblast growth factor 2 (FGF2), the Wnt pathway effectors FRAT1 and frizzled 1, and other self‐renewal markers, was greater in AMSCs. Furthermore, AMSCs displayed enhanced osteogenic and adipogenic potential, whereas BMSCs formed chondrocytes more readily than AMSCs. However, by removing the effects of proliferation from the experiment, AMSCs no longer out‐performed BMSCs in their ability to undergo osteogenic and adipogenic differentiation. Inhibition of the FGF2/fibroblast growth factor receptor 1 signaling pathway demonstrated that FGF2 is required for the proliferation of both AMSCs and BMSCs, yet blocking FGF2 signaling had no direct effect on osteogenic differentiation.