Engineering a nanoantibiotic system displaying dual mechanism of action

• 成果类型: Article
• 署名作者: Xing, Huihua; Pereira, Aramis Jose; Fiora, Maria Mercedes; Aguiar-Alves, Fabio; Tagliazucchi, Mario; Conda-Sheridan, Martin
• 署名单位: University of Nebraska System; University of Nebraska Medical Center; University of Buenos Aires; Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); University of Buenos Aires; Palm Beach Atlantic University West Palm Beach
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14442
• DOI: 10.1073/pnas.2321498121
• 发表日期: 2024-04-16
• 关键词: peptide amphiphiles; cancer; DRUG; nanostructures; virulence; micelles; efficacy; delivery; larvae; ph

摘要

In recent decades, peptide amphiphiles (PAs) have established themselves as promising efficacy. We studied two strategies: PA-LJC nanostructures (Encapsulation) and PA nanostructures + free LJC (Combination). Computational modeling using a molecular theory for amphiphile self- assembly captures and explains the morphology of PA-LJC nanostructures and the location of encapsulated LJC in agreement with transmission electron microscopy and two- dimensional (2D) NMR observations. The morphology and release profile of PA-LJC assemblies are strongly correlated to the PA:LJC ratio: high LJC loading induces an initial burst release. We then evaluated the antimicrobial activity of our nanosystems toward gram- positive and gram- negative bacteria. We found that the Combination broadens the spectrum of LJC, reduces the therapeutic concentrations of both agents, and is not impacted by the inoculum effect. Further, the Encapsulation provides additional benefits including bypassing water solubility limitations of LJC and modulating the release of this molecule. The different properties of PA-LJC nanostructures results in different killing profiles, and reduced cytotoxicity and hemolytic activity. Meanwhile, details in membrane alterations caused by each strategy were revealed by various microscopy and fluorescent techniques. Last, in vivo studies in larvae treated by the Encapsulation strategy showed better antimicrobial efficacy than polymyxin B. Collectively, this study established a multifunctional platform using a versatile PA to act as an antibiotic, membrane- penetrating assistant, and slow- release delivery vehicle.