Treatment of fungal endophthalmitis with controlled-release voriconazole using a pH-responsive zeolitic-imidazolate-framework-based drug delivery system

Abstract

Fungal endophthalmitis is a severe infectious disease that can result in permanent vision loss. Its poor visual prognosis is associated with the short half-lives of current antifungal medications and the formation of fungal biofilms. In this study, we designed and synthesized a pH-sensitive, positively charged antifungal nanocarrier based on a metal–organic framework, voriconazole-inbuilt zeolitic imidazolate framework-8 (VCZ@ZIF-8), as an efficient therapy for fungal infections and the eradication of biofilm during fungal endophthalmitis. With its strategic design, the injected VCZ@ZIF-8 arrived at and penetrated the fungal biofilm after its positively charged exterior interacted with the negative charge on the fungal cell surface. It then decomposed in response to the acid environment of the biofilm. The basic characteristics of VCZ@ZIF-8 were evaluated, including its biocompatibility, toxicity, the rate of cargo release, and thermal stability. Its antifungal effects and antibiofilm properties in fungal endophthalmitis were also investigated. In vitro, VCZ@ZIF-8 exerted significant antifungal effects and excellent biofilm penetration against Candida albicans. In an in vivo endophthalmitis model, VCZ@ZIF-8 showed better eradication of intraocular infections induced by Candida albicans than voriconazole, with negligible retinal toxicity or adverse effects on other organs. Our findings demonstrate that VCZ@ZIF-8 offers a safe and effective option for the treatment of fungal endophthalmitis.