Rajesh Sarigama, Gangadoo Sheeana, Nguyen Han, Zhai Jiali, Dekiwadia Chaitali, Drummond Calum J, Chapman James, Truong Vi Khanh, Tran Nhiem
School of Science, RMIT University, 124 La Trobe St., Melbourne, VIC 3000, Australia.
Biomedical Nanoengineering Lab, College of Medicine and Public Health, Flinders University, Bedford Park 5043, South Australia.
ACS Appl Mater Interfaces. 2022 Jul 18. doi: 10.1021/acsami.2c05165.
is a yeast-like fungus that can cause the life-threatening disease cryptococcal meningitis. Numerous reports have shown increased resistance of this fungus against antifungal treatments, such as fluconazole (Fluc), contributing to an 80% global mortality rate. This work presents a novel approach to improve the delivery of the antifungal agent Fluc and increase the drug's targetability and availability at the infection site. Exploiting the acidic environment surrounding a infected site, we have developed pH-sensitive lipid nanoparticles (LNP) encapsulating Fluc to inhibit the growth of resistant . The LNP-Fluc delivery system consists of a neutral lipid monoolein (MO) and a novel synthetic ionizable lipid 2-morpholinoethyl oleate (O2ME). At neutral pH, because of the presence of O2ME, the nanoparticles are neutral and exhibit a liquid crystalline hexagonal nanostructure (hexosomes). At an acidic pH, they are positively charged with a cubic nanostructure (cubosomes), which facilitates the interaction with the negatively charged fungal cell wall. This interaction results in the MIC50 and MIC90 values of the LNP-Fluc being significantly lower than that of the free-Fluc control. Confocal laser scanning microscopy and scanning electron microscopy further support the MIC values, showing fungal cells exposed to LNP-Fluc at acidic pH were heavily distorted, demonstrating efflux of cytoplasmic molecules. In contrast, fungal cells exposed to Fluc alone showed cell walls mostly intact. This current study represents a significant advancement in delivering targeted antifungal therapy to combat fungal antimicrobial resistance.
是一种酵母样真菌，可引起危及生命的隐球菌性脑膜炎。大量报告显示，这种真菌对氟康唑（Fluc）等抗真菌治疗的耐药性增加，导致全球死亡率达到80%。这项工作提出了一种新方法，以改善抗真菌药物氟康唑的递送，并提高药物在感染部位的靶向性和可及性。利用感染部位周围的酸性环境，我们开发了包裹氟康唑的pH敏感脂质纳米颗粒（LNP），以抑制耐药菌的生长。LNP-氟康唑递送系统由中性脂质单油酸甘油酯（MO）和新型合成可电离脂质2-吗啉代乙基油酸酯（O2ME）组成。在中性pH值下，由于O2ME的存在，纳米颗粒呈中性，并呈现液晶六方纳米结构（六边体）。在酸性pH值下，它们带正电荷，具有立方纳米结构（立方相脂质体），这有利于与带负电荷的真菌细胞壁相互作用。这种相互作用导致LNP-氟康唑的MIC50和MIC90值显著低于游离氟康唑对照。共聚焦激光扫描显微镜和扫描电子显微镜进一步支持了MIC值，显示在酸性pH值下暴露于LNP-氟康唑的真菌细胞严重变形，表明细胞质分子外流。相比之下，单独暴露于氟康唑的真菌细胞显示细胞壁大多完整。这项研究代表了在提供靶向抗真菌治疗以对抗真菌抗菌耐药性方面的重大进展。
