Application of Fluconazole-Loaded pH-Sensitive Lipid Nanoparticles for Enhanced Antifungal Therapy

Sarigama Rajesh, Sheeana Gangadoo, Han Nguyen, Jiali Zhai, Chaitali Dekiwadia, Calum J. Drummond, James Chapman, Vi Khanh Truong, Nhiem Tran

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Cryptococcus neoformans 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 C. neoformans infected site, we have developed pH-sensitive lipid nanoparticles (LNP) encapsulating Fluc to inhibit the growth of resistant C. neoformans. 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.

Original languageEnglish
Pages (from-to)32845–32854
Number of pages10
JournalACS Applied Materials and Interfaces
Issue number29
Early online date18 Jul 2022
Publication statusPublished - 27 Jul 2022


  • aminolipids
  • antimicrobial resistance
  • Cryptococcus neoformans
  • cubosomes
  • fluconazole
  • hexosomes
  • lipid nanoparticles
  • monoolein
  • pH-responsive nanoparticles


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