Ultrasmall AuNPs Research Articles

Dose Dependencies and Biocompatibility of Renal Clearable Gold Nanoparticles: From Mice to Non-human Primates.

While dose dependencies in pharmacokinetics and clearance are often observed in clinically used small molecules, very few studies have been dedicated to the understandings of potential dose-dependent in vivo transport of nanomedicines. Here we report that the pharmacokinetics and clearance of renal clearable gold nanoparticles (GS-AuNPs) are strongly dose-dependent once injection doses are above 15 mg kg-1 : high dose expedited the renal excretion and shortened the blood retention. As a result, the no-observed-adverse-effect-level (NOAEL) of GS-AuNPs was >1000 mg kg-1 in CD-1 mice. The efficient renal clearance and high compatibility can be translated to the non-human primates: no adverse effects were observed within 90 days after intravenous injection of 250 mg kg-1 GS-AuNPs. These fundamental understandings of dose effect on the in vivo transport of ultrasmall AuNPs open up a pathway to maximize their biomedical potentials and minimize their toxicity in the future clinical translation.

Dose Dependencies and Biocompatibility of Renal Clearable Gold Nanoparticles: From Mice to Non‐human Primates

AbstractWhile dose dependencies in pharmacokinetics and clearance are often observed in clinically used small molecules, very few studies have been dedicated to the understandings of potential dose‐dependent in vivo transport of nanomedicines. Here we report that the pharmacokinetics and clearance of renal clearable gold nanoparticles (GS‐AuNPs) are strongly dose‐dependent once injection doses are above 15 mg kg−1: high dose expedited the renal excretion and shortened the blood retention. As a result, the no‐observed‐adverse‐effect‐level (NOAEL) of GS‐AuNPs was >1000 mg kg−1 in CD‐1 mice. The efficient renal clearance and high compatibility can be translated to the non‐human primates: no adverse effects were observed within 90 days after intravenous injection of 250 mg kg−1 GS‐AuNPs. These fundamental understandings of dose effect on the in vivo transport of ultrasmall AuNPs open up a pathway to maximize their biomedical potentials and minimize their toxicity in the future clinical translation.

Size-Controlled Green Synthesis of Highly Stable and Uniform Small to Ultrasmall Gold Nanoparticles by Controlling Reaction Steps and pH

Synthesis of gold nanoparticles (AuNPs) with controllable particle size and stable dispersion through green chemistry without using toxic regents is crucial for biomedical applications. In this study, spherical AuNPs with controllable particle size in the range of 8 to 18 nm were synthesized by the reduction of HAuCl4 using only fruit juices/extract without adding any other chemicals. By controlling the chemical reaction steps and adjusting the pH of the solution at a later stage of the reaction, the sizes of the spherical AuNPs were fine tuned to 4.5 ± 2.0 nm, 5.9 ± 2.5 nm, and 6.0 ± 1.5 nm with fruit juices/extract of A. deliciosa, P. persica, and M. domestica, respectively. For the first time, spherical ultrasmall AuNPs of 2.6 ± 1.1 nm with uniform distribution were successfully achieved using M. Acuminate extract at pH 10 and 11. The ultrasmall and small AuNPs were imaged again by transmission electron microscopy (TEM) after 4 months stored at the room temperature and 72 h incubation in 1 mM NaCl, whi...

In-situ generation of gold nanoparticles on MnO2 nanosheets for the enhanced oxidative degradation of basic dye (Methylene Blue)

In this work, the gold nanoparticles (Au-NPs) were in-situ generated on the surface of MnO2 nanosheets to form MnO2/Au-NPs nanocomposite in a simple and cost-effective way. Multiple experiments were carried out to optimize the oxidation of basic dye (Methylene Blue (MB)), including the molar ratio of MnO2 to chloroauric acid (HAuCl4), the pH of the solution and the effect of initial material. Under the optimal condition, the highest degradation efficiency for MB achieved to 98.9% within 60 min, which was obviously better than commercial MnO2 powders (4.3%) and MnO2 nanosheets (74.2%). The enhanced oxidative degradation might attribute to the in-situ generation of ultra-small and highly-dispersed Au-NPs which enlarged the synergistic effect and/or interfacial effect between MnO2 nanosheets and Au-NPs and facilitated the uptake of electrons by MnO2 from MB during the oxidation, thus validating the application of MnO2/Au-NPs nanocomposite for direct removal of organic dyes from wastewater in a simple and convenient fashion.

Assessing the Intracellular Integrity of Phosphine-Stabilized Ultrasmall Cytotoxic Gold Nanoparticles Enabled by Fluorescence Labeling.

As the size of nanoparticles (NPs) is in the range of biological molecules and subcellular structures, they provide new perspectives in biomedicine. This work presents studies concerning the cellular uptake and distribution of phosphine-stabilized cytotoxic 1.4 nm sized AuNPs and their probable degradation during this process. Therefore, ultrasmall phosphine-stabilized AuNPs are modified by linking a fluorophore covalently to the ligand shell. Monitoring the fluorescence on a cellular level by means of flow cytometry and confocal laser scanning microscopy allows determining the fate of the ligand shell during AuNP cell internalization, due to the fact that the fluorescence of a fluorophore bound near to the AuNP surface is quenched. Cell fractionation is conducted in order to quantify the AuNP content at the cell membrane, in the cytoplasm, and the cell nucleus. The incubation of cells with the fluorophore-modified AuNPs reveals a partial loss of the ligand shell upon AuNP cell interaction, evident by the emerging fluorescence signal. This loss is the precondition to unfold high AuNP cytotoxicity. Together with their significantly different biodistribution and enhanced circulation times compared to larger AuNPs, the findings demonstrate the high potential of ultrasmall AuNPs for drug development or therapy.

Synthesis of Water Dispersible and Catalytically Active Gold-Decorated Cobalt Ferrite Nanoparticles.

Hetero-nanoparticles represent an important family of composite nanomaterials that in the past years are attracting ever-growing interest. Here, we report a new strategy for the synthesis of water dispersible cobalt ferrite nanoparticles (CoxFe3-xO4 NPs) decorated with ultrasmall (2-3 nm) gold nanoparticles (Au NPs). The synthetic procedure is based on the use of 2,3-meso-dimercaptosuccinic acid (DMSA), which plays a double role. First, it transfers cobalt ferrite NPs from the organic phase to aqueous media. Second, the DMSA reductive power promotes the in situ nucleation of gold NPs in proximity of the magnetic NP surface. Following this procedure, we achieved a water dispersible nanosystem (CoxFe3-xO4-DMSA-Au NPs) which combines the cobalt ferrite magnetic properties with the catalytic features of ultrasmall Au NPs. We showed that CoxFe3-xO4-DMSA-Au NPs act as an efficient nanocatalyst to reduce 4-nitrophenol to 4-aminophenol and that they can be magnetically recovered and recycled. It is noteworthy that such nanosystem is more catalytically active than Au NPs with equal size. Finally, a complete structural and chemical characterization of the hetero-NPs is provided.

Biointeractions of Ultrasmall Gold Nanoparticles: Influence of Nanoparticle Size and Surface Chemistry

Recent studies have shown that gold nanoparticles (AuNPs) in the ultrasmall size regime (< 3 nm in diameter) can present distinct advantages for applications in nanomedicine, such as an efficient renal clearance in vivo. Herein we perform a systematic investigation of the effects of size and surface chemistry on the in vitro biointeractions of ultrasmall AuNPs. Nanoparticle surface chemistry was modulated using small peptides as passivating ligands; size and uniformity were carefully characterized with dark-field scanning transmission electron microscopy (STEM) and analytical ultracentrifugation; and nanoparticle aggregation and serum protein adsorption were evaluated both experimentally by analytical ultracentrifugation as well as computationally by molecular dynamics simulations. First, our results showed that the colloidal stability of ultrasmall AuNPs in biological media can depend on seemingly small variations in core diameter. Our investigations also established how the surface chemistry could be tuned to produce ultrasmall AuNPs highly resistant to aggregation and adsorption from serum proteins.

Biointeractions of ultrasmall glutathione-coated gold nanoparticles: effect of small size variations.

Recent in vivo studies have established ultrasmall (<3 nm) gold nanoparticles coated with glutathione (AuGSH) as a promising platform for applications in nanomedicine. However, systematic in vitro investigations to gain a more fundamental understanding of the particles' biointeractions are still lacking. Herein we examined the behavior of ultrasmall AuGSH in vitro, focusing on their ability to resist aggregation and adsorption from serum proteins. Despite having net negative charge, AuGSH particles were colloidally stable in biological media and able to resist binding from serum proteins, in agreement with the favorable bioresponses reported for AuGSH in vivo. However, our results revealed disparate behaviors depending on nanoparticle size: particles between 2 and 3 nm in core diameter were found to readily aggregate in biological media, whereas those strictly under 2 nm were exceptionally stable. Molecular dynamics simulations provided microscopic insight into interparticle interactions leading to aggregation and their sensitivity to the solution composition and particle size. These results have important implications, in that seemingly small variations in size can impact the biointeractions of ultrasmall AuGSH, and potentially of other ultrasmall nanoparticles as well.

MnO2 nanowires decorated with Au ultrasmall nanoparticles for the green oxidation of silanes and hydrogen production under ultralow loadings

Although green catalytic transformations are very attractive, they often remain limited by low conversion percentages and selectivity. Here, we demonstrate that high catalytic performances (TOF=590,000h−1) could be achieved towards the green oxidation of silanes and H2 production under ultralow Au loadings (0.001–0.0002mol% in terms of Au) employing H2O as the oxidant, 25°C as the reaction temperature, and MnO2 nanowires decorated with ultrasmall Au NPs (3nm) as catalysts. In addition to these high activities towards a variety of substrates, the MnO2–Au NPs displayed good stability/recyclability, in which no morphological changes or loss of activity were observed even after 10 reaction cycles. The improved catalytic activities observed for the MnO2–Au NPs can be assigned to: (i) the metal–support interactions, in which the presence of Au NPs could facilitate oxidative processes and thus yield high performances towards the oxidation of hydrosilanes; (ii) the significant concentration of Auδ+ species and oxygen vacancies at the catalyst surface that represent highly catalytically active sites towards oxidation reactions, and (iii) the Au NPs ultrasmall sizes at the MnO2 surface that enable the exposure of high energy Au surface/facets, high surface-to-volume ratios, and their uniform dispersion. The MnO2–Au NPs could be synthesized by a facile approach based on the utilization of MnO2 nanowires as physical templates for Au deposition without any prior surface modification/functionalization steps. The utilization of supported ultrasmall Au NPs having controlled sizes and dispersion may inspire the design of novel catalysts capable of enabling high catalytic performances towards green transformations at ultralow metal loadings.

Enhancing photothermal cancer therapy by clustering gold nanoparticles into spherical polymeric nanoconstructs

Gold nanoparticles (AuNPs) have been proposed as agents for enhancing photothermal therapy in cancer and cardiovascular diseases. Different geometrical configurations have been used, ranging from spheres to rods and more complex star shapes, to modulate optical and ablating properties. In this work, multiple, ultra-small 6nm AuNPs are encapsulated into larger spherical polymeric nanoconstructs (SPNs), made out of a poly(lactic acid-co-glycol acid) (PLGA) core stabilized by a superficial lipid-PEG monolayer. The optical and photothermal properties of the resulting nanoconstructs (Au-SPNs) are modulated by varying the initial loading input of AuNPs, ranging between 25 and 150μgAu. Au-SPNs exhibit a hydrodynamic diameter varying from ~100 to 180nm, growing with the gold content, and manifest up to 2-fold increase in thermal energy production per unit mass of gold for an initial input of 100μgAu. Au-SPNs are stable under physiological conditions up to 7 days and have direct cytotoxic effect on tumor cells. The superior photothermal performance of Au-SPNs is assessed in vitro on monolayers of breast cancer cells (SUM-159) and tumor spheroids of glioblastoma multiforme cells (U87-MG). The encapsulation of small AuNPs into larger spherical nanoconstructs enhances photothermal ablation and could favor tumor accumulation.

Molecularly stabilised ultrasmall gold nanoparticles: synthesis, characterization and bioactivity

Gold nanoparticles (AuNPs) are widely used as contrast agents in electron microscopy as well as for diagnostic tests. Due to their unique optical and electrical properties and their small size, there is also a growing field of potential applications in medical fields of imaging and therapy, for example as drug carriers or as active compounds in thermotherapy. Besides their intrinsic optical properties, facile surface decoration with (bio)functional ligands renders AuNPs ideally suited for many industrial and medical applications. However, novel AuNPs may have toxicological profiles differing from bulk and therefore a thorough analysis of the quantitative structure-activity relationship (QSAR) is required. Several mechanisms are proposed that cause adverse effects of nanoparticles in biological systems. Catalytic generation of reactive species due to the large and chemically active surface area of nanomaterials is well established. Because nanoparticles approach the size of biological molecules and subcellular structures, they may overcome natural barriers by active or passive uptake. Ultrasmall AuNPs with sizes of 2 nm or less may even behave as molecular ligands. These types of potential interactions would imply a size and ligand-dependent behaviour of any nanomaterial towards biological systems. Thus, to fully understand their QSAR, AuNPs bioactivity should be analysed in biological systems of increasing complexity ranging from cell culture to whole animal studies.

Ionic Liquid-Modified Porous Materials for Gas Separation and Heterogeneous Catalysis

This work examines important physicochemical and thermophysical properties of ultrathin ionic liquid (IL) layers under confinement into the pore structure of siliceous supports and brings significant advances toward understanding the effects of these properties on the gas separation and catalytic performance of the developed supported ionic liquid phase (SILP) and solid catalysts with ionic liquid layers (SCILL). SILPs were developed by making use of functionalized and nonfunctionalized ILs, such as 1-(silylpropyl)-3-methyl-imidazolium hexafluorophosphate and 1-butyl-3-methyl-imidazolium hexafluorophosphate ILs, whereas the SCILL was prepared by effectively dispersing gold nanoparticles (AuNPs) onto the IL layers inside the open pores of the SILP. The information derived from the gas absorption/diffusivity and heterogeneous catalysis experiments was exemplified in relation to the liquid crystalline ordering and orientation of the IL molecules, investigated by X-ray diffraction (XRD) and modulated differential scanning calorimetry (MDSC). The extent of pore blocking was elucidated with small angle neutron scattering (SANS) and was proven to be a decisive factor for the gas separation efficiency of the SILPs. CO2/CO separation values above 50 were obtained in cases where liquid crystalline ordering of the IL layers and extended pore blocking had occurred. The presence of the IL layer in the developed SCILL assisted the formation of ultrasmall (2–3 nm) and well-stabilized AuNPs. The low-temperature CO oxidation efficiency was 22%. The catalytic experiments showed an additional functionality of the IL, acting as an “in-situ trap” that abstracts the product (CO2) from the reaction site and improves yield.

Synthesis, characterization, and direct intracellular imaging of ultrasmall and uniform glutathione-coated gold nanoparticles.

Gold nanoparticles (AuNPs) with core sizes below 2 nm and compact ligand shells constitute versatile platforms for the development of novel reagents in nanomedicine. Due to their ultrasmall size, these AuNPs are especially attractive in applications requiring delivery to crowded intracellular spaces in the cytosol and nucleus. For eventual use in vivo, ultrasmall AuNPs should ideally be monodisperse, since small variations in size may affect how they interact with cells and how they behave in the body. Here we report the synthesis of ultrasmall, uniform 144-atom AuNPs protected by p-mercaptobenzoic acid followed by ligand exchange with glutathione (GSH). Quantitative scanning transmission electron microscopy (STEM) reveals that the resulting GSH-coated nanoparticles (Au(GSH)) have a uniform mass distribution with cores that contain 134 gold atoms on average. Particle size dispersity is analyzed by analytical ultracentrifugation, giving a narrow distribution of apparent hydrodynamic diameter of 4.0 ± 0.6 nm. To evaluate the nanoparticles' intracellular fate, the cell-penetrating peptide TAT is attached noncovalently to Au(GSH), which is confirmed by fluorescence quenching and isothermal titration calorimetry. HeLa cells are then incubated with both Au(GSH) and the Au(GSH)-TAT complex, and imaged without silver enhancement of the AuNPs in unstained thin sections by STEM. This imaging approach enables unbiased detection and quantification of individual ultrasmall nanoparticles and aggregates in the cytoplasm and nucleus of the cells.