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Published on: November 28, 2019
Cell Wall Destruction and Internal Cascade Synergistic Antifungal Strategy for Fungal Keratitis
Yang Ye1,2, Jian He1,3, Hanle Wang1,2
1Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People's Republic of China.
Abstract:
Fungal keratitis is one of the most common blindness-causing diseases, but clinical antifungal treatment remains a challenge. The fungal cell wall and biofilm matrix which severely confine the drug preparation are the critical obstructive factors to therapeutic effects. Herein, we report ethylenediaminetetraacetic acid (EDTA) modified AgCu2O nanoparticles (AgCuE NPs) to disrupt the cell wall and then eradicate C. albicans through the internal cascade synergistic effects of ion-released chemotherapy, chemodynamic therapy, photodynamic therapy, and mild photothermal therapy. AgCuE NPs exhibited excellent antifungal activity both in preventing biofilm formation and in destroying mature biofilms. Furthermore, AgCuE NP based gel formulations were topically applied to kill fungi, reduce inflammation, and promote wound healing, using optical coherence tomography and photoacoustic imaging to monitor nanogel retention and therapeutic effects on the infected murine cornea model. The AgCuE NP gel showed good biosafety and no obvious ophthalmic and systemic side effects. This study suggests that the AgCuE NP gel is an effective and safe antifungal strategy for fungal keratitis with a favorable prognosis and potential for clinical translation.
Insights
New AgCuE nanoparticles effectively treat fungal keratitis by disrupting fungal cell walls and biofilms. This novel antifungal strategy shows promise for clinical application, promoting healing with minimal side effects.
Area of Science:
- Biomaterials Science
- Ophthalmology
- Nanotechnology
Background:
- Fungal keratitis is a leading cause of blindness, posing significant treatment challenges due to fungal cell walls and biofilms.
- Existing antifungal therapies are limited by drug penetration and efficacy against resistant fungal structures.
Purpose of the Study:
- To develop novel ethylenediaminetetraacetic acid (EDTA) modified AgCu2O nanoparticles (AgCuE NPs) for treating fungal keratitis.
- To investigate the synergistic antifungal mechanisms of AgCuE NPs, including disruption of fungal cell walls and biofilms.
- To evaluate the therapeutic efficacy and biosafety of AgCuE NP-based gel formulations in a murine cornea model.
Main Methods:
- Synthesis and characterization of EDTA-modified AgCu2O nanoparticles (AgCuE NPs).
- Assessment of AgCuE NPs' antifungal activity against Candida albicans, including biofilm inhibition and eradication.
- Formulation of AgCuE NP-based hydrogel for topical ocular delivery.
- In vivo evaluation of therapeutic efficacy and biosafety in a fungal keratitis murine model using advanced imaging techniques.
Main Results:
- AgCuE NPs demonstrated potent antifungal activity, effectively preventing biofilm formation and destroying mature biofilms.
- The nanoparticles leverage multiple synergistic mechanisms: ion-released chemotherapy, chemodynamic therapy, photodynamic therapy, and mild photothermal therapy.
- Topical application of AgCuE NP gel in a murine model promoted fungal eradication, reduced inflammation, and accelerated corneal wound healing.
- Optical coherence tomography and photoacoustic imaging confirmed nanogel retention and therapeutic effects.
- The AgCuE NP gel exhibited excellent biosafety, with no observed ophthalmic or systemic adverse effects.
Conclusions:
- AgCuE NP gel represents a promising, safe, and effective strategy for treating fungal keratitis.
- The multi-modal therapeutic approach of AgCuE NPs overcomes challenges associated with fungal cell walls and biofilms.
- This study highlights the potential for clinical translation of AgCuE NP gel as an advanced antifungal treatment for ocular infections.
