RESUMO
Bacterial keratitis is a serious ocular disease that affects millions of people worldwide each year, among which ≈25% are caused by Staphylococcus aureus. With the spread of bacterial resistance, refractory keratitis caused by methicillin-resistant S. aureus (MRSA) affects ≈120 000-190 000 people annually and is a significant cause of infectious blindness. Atomically precise gold nanoclusters (GNCs) recently emerged as promising antibacterial agents; although how the GNC structure and capping ligands control the antibacterial properties remains largely unexplored. In this study, by adjusting the ratio of a "bulky" thiol fragrance to a linear zwitterionic ligand, the GNC conformation is transformed from Au25 (SR)18 to Au23 (SR)16 species, simultaneously converting both inactive thiol ligands into potent antibacterial nanomaterials. Surprisingly, mixed-ligand capped Au23 (SR)16 GNCs exhibit superior antibacterial potency compared to their monoligand counterparts. The optimal GNC is highly potent against MRSA, showing >1024-fold lower minimum inhibitory concentration than the corresponding free ligands. Moreover, it displays excellent potency in treating MRSA-induced keratitis in mice with greatly accelerated corneal recovery (by approximately ninefold). Thus, this study establishes a feasible method to synthesize antibacterial GNCs by adjusting the ligand ratio to control GNC conformation and active non-antibacterial ligands, thereby greatly increasing the repertoires for combating multidrug-resistant bacterial infections.
RESUMO
Developing effective lymph-node (LN) targeting and imaging probes is crucial for the early detection and diagnosis of tumor metastasis to improve patient survival. Most current clinical LN imaging probes are based on small organic dyes (e.g., indocyanine green) or radioactive 99mTc-complexes, which often suffer from limitations, such as rapid photobleaching, poor signal contrast, and potential biosafety issues. Moreover, these probes cannot easily incorporate therapeutic functions to realize beneficial theranostics without affecting their LN-targeting ability. Herein, we have developed dual-ligand-/multiligand-capped gold nanoclusters (GNCs) for specific targeting, near-infrared (NIR) fluorescence imaging, diagnosis, and treatment of LN cancer metastasis in in vivo mouse models. By optimizing the surface ligand coating, we have prepared Au25(SR1)n(SR2)18-n (where SR1 and SR2 are different functional thiol ligands)-type GNCs, which display highly effective LN targeting, excellent stability and biocompatibility, and optimal body-retention time. Moreover, they can provide continuous NIR fluorescence imaging of LNs for >3 h from a single dose, making them well-suited for fluorescence-guided surgery. Importantly, we have further incorporated methotrexate, a chemotherapeutic drug, into the GNCs without affecting their LN-targeting ability. Consequently, they can significantly improve the efficiency of methotrexate delivery to target LNs, achieving excellent therapeutic efficacy with up to 4-fold lower hepatotoxicity. Thus, the GNCs are highly effective and safe theranostic nanomedicines against cancer lymphatic metastasis.
Assuntos
Ouro , Verde de Indocianina , Animais , Camundongos , Metástase Linfática/diagnóstico por imagem , Ligantes , Metotrexato , Imagem Óptica/métodos , Corantes , Compostos de SulfidrilaRESUMO
Infections caused by multidrug-resistant (MDR) bacteria are an increasing global healthcare concern. In this study, we developed a dual-ligand-functionalised Au25(SR1) x (SR2)18-x -type gold nanocluster and determined its antibacterial activity against MDR bacterial strains. The pyridinium ligand (SR1) provided bactericidal potency and the zwitterionic ligand (SR2) enhanced the stability and biocompatibility. By optimising the ligand ratio, our gold nanocluster could effectively kill MDR Gram-positive bacteria via multiple antibacterial actions, including inducing bacterial aggregation, disrupting bacterial membrane integrity and potential, and generating reactive oxygen species. Moreover, combining the optimised gold nanocluster with common antibiotics could significantly enhance the antibacterial activity against MDR bacteria both in in vitro and animal models of skin infections. Furthermore, the fluorescence of the gold nanocluster at the second near-infrared (NIR-II) biological window allowed for the monitoring of its biodistribution and body clearance, which confirmed that the gold nanoclusters had good renal clearance and biocompatibility. This study provides a new strategy to combat the MDR challenge using multifunctional gold nanomaterials.