Kaiyuan Zheng

Antimicrobial Cluster Bombs: Silver Nanoclusters Packed with Daptomycin

Integration of two distinctive bactericides into one entity is a promising platform to improve the efficiency of antimicrobial agents. We report an efficient antimicrobial hybrid formed through conjugating silver nanoclusters (AgNCs) with daptomycin. The as-designed antimicrobial hybrid (D-AgNCs) inherits intrinsic properties of both bactericides with an enhanced synergistic performance. In particular, the chemically integrated D-AgNCs showed improved bacterial killing efficiency over the physically mixed daptomycin and AgNCs (D+AgNCs). More interestingly, the as-designed D-AgNCs could effectively damage the bacterial membrane. Propidium iodide (PI) stain showed bacterial membrane damage in about 85% of the bacteria population after treatment with D-AgNCs through creation of larger pores on the membrane as compared to D+AgNCs, largely due to the localization of daptomycin within the hybrid structure. These larger pores facilitated the entry of the D-AgNCs into the cell and led to more severe DNA damage of the bacterial DNA as compared to D+AgNCs in genomic DNA PAGE analysis. TUNEL assay further depicted more bacterial DNA breaks induced by D-AgNCs. The RecA gene expression level was upregulated, suggestive of DNA repair activation. The strong induced DNA damage benefited from the localization of AgNCs in the core of the antimicrobial hybrid structure, which could generate localized high ROS concentration and work as a critical ROS reservoir to continually generate ROS within the bacterium. The continual bombardments by these ROS generators restrict the ability of the bacteria to now develop resistance against this.

Recent advances in the synthesis, characterization, and biomedical applications of ultrasmall thiolated silver nanoclusters

With ultrasmall particle sizes of ∼1 nm, thiolate-protected silver nanoclusters (or thiolated Ag NCs) have recently emerged as an attractive frontier of nanoparticle research because of their unique molecular-like properties, such as well-defined molecular structures, HOMO–LUMO transitions, quantized charging, and strong luminescence. Such intriguing physicochemical properties have made thiolated Ag NCs a new class of promising theranostic agents for a wide spectrum of biomedical applications, such as bioimaging, antimicrobial agents, and disease diagnostics and therapy. In turn, the promising applications of thiolated Ag NCs have also fuelled the cluster community to develop more efficient strategies to synthesize high-quality Ag NCs with well-defined size, structure, and surface. In this review article, we first survey recent advances in developing efficient synthetic strategies for thiolated Ag NCs, highlighting the underlying chemistry that makes the delicate control of their sizes and surfaces possible. In the second section, we discuss recent advances in characterization techniques for ultrasmall thiolated Ag NCs, including their physical, chemical, and biological properties. The emerging characterization techniques are central to the development of cluster chemistry. In the last section, we highlight some examples demonstrating the vast possibilities of thiolated Ag NCs for biomedical applications. We conclude this review article by pointing out some challenging issues related to thiolated Ag NCs, and hopefully these can encourage more concerted efforts on their study from the research communities of cluster chemistry, noble metal chemistry, biology, biomedicine, etc.

Antimicrobial Gold Nanoclusters

Bulk gold (Au) is known to be chemically inactive. However, when the size of Au nanoparticles (Au NPs) decreases to close to 1 nm or sub-nanometer dimensions, these ultrasmall Au nanoclusters (Au NCs) begin to possess interesting physical and chemical properties and likewise spawn different applications when working with bulk Au or even Au NPs. In this study, we found that it is possible to confer antimicrobial activity to Au NPs through precise control of their size down to NC dimension (typically less than 2 nm). Au NCs could kill both Gram-positive and Gram-negative bacteria. This wide-spectrum antimicrobial activity is attributed to the ultrasmall size of Au NCs, which would allow them to better interact with bacteria. The interaction between ultrasmall Au NCs and bacteria could induce a metabolic imbalance in bacterial cells after the internalization of Au NCs, leading to an increase of intracellular reactive oxygen species production that kills bacteria consequently.

Storage of Gold Nanoclusters in Muscle Leads to their Biphasic in Vivo Clearance

Ultrasmall gold nanoclusters (Au NCs) show great potential in biomedical applications. Long-term biodistribution, retention, toxicity, and pharmacokinetics profiles are pre-requisites in their potential clinical applications. Here, the biodistribution, clearance, and toxicity of one widely used Au NC species-glutathione-protected Au NCs or GSH-Au NCs-are systematically investigated over a relatively long period of 90 days in mice. Most of the Au NCs are cleared at 30 days post injection (p.i.) with a major accumulation in liver and kidney. However, it is surprising that an abnormal increase of the Au amount in the heart, liver, spleen, lung, and testis is observed at 60 and 90 days p.i., indicating that the injected Au NCs form a V-shaped time-dependent distribution profile in various organs. Further investigations reveal that Au NCs are steadily accumulating in the muscle in the first 30 days p.i., and the as-stored Au NCs gradually release into the blood in 30-90 days p.i., which induces a re-distribution and re-accumulation of Au NCs in all blood-rich organs. Further hematology and biochemistry studies show that the re-accumulation of Au NCs still causes some liver toxicity at 30 days p.i. The muscle storage and subsequent release may give rise to the potential accumulation and toxicity risk of functional nanomaterials over long periods of time.