Cryptococcus neoformans is the etiological agent of cryptococcal meningoencephalitis. The recommended available treatment has low efficiency, with high toxicity and resistance as recurrent problems. In the search of new treatment protocols, the proposal of new pharmacological approaches is considered an innovative strategy, mainly nanotechnological systems considering fungal diseases. The antiarrhythmic drug amiodarone has demonstrated antifungal activity against a range of fungi, including C. neoformans. Here, considering the importance of calcium storage mediated by transporters on cryptococcal virulence, we evaluated the use of the calcium channel blocker amiodarone as an alternative therapy for cryptococcosis. C. neoformans displayed high sensitivity to amiodarone, which was also synergistic with fluconazole. Amiodarone treatment influenced some virulence factors, interrupting the calcium-calcineurin signaling pathway. Experiments with murine cryptococcosis models revealed that amiodarone treatment increased the fungal burden in the lungs, while its combination with fluconazole did not improve treatment compared to fluconazole alone. In addition, we have developed different innovative nanotechnological formulations, one of which combining two drugs with different mechanisms of action. Lipid-core nanocapsules (LNC) loaded with amiodarone (LNCAMD), fluconazole (LNCFLU) and both (LNCAMD+FLU) were produced to achieve a better efficacy in vivo. In an intranasal model of treatment, all the LNC formulations had an antifungal effect. In an intraperitoneal treatment, LNCAMD showed an enhanced anticryptococcal effect compared to the free drug, whereas LNCFLU or LNCAMD+FLU displayed no differences from the free drugs. In this way, nanotechnology using amiodarone formulations could be an effective therapy for cryptococcal infections.
Keywords: Amiodarone; Cryptococcus neoformans; Fluconazole; Lipid-core nanocapsules; Nanoformulation; New strategy.
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