Advancing antifungal therapy: exploring targeted CFW-PEc-enhanced ethosomal formulations of amphotericin B against cryptococcal pneumonia

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Abstract
Cryptococcus neoformans is a significant and pathogenic encapsulated basidiomycete fungus responsible for cryptococcosis, particularly in immunocompromised individuals. With increasing incidence rates globally, there is an urgent need for improved therapeutic strategies. This study presents the development of a fungal-targeted nanodrug delivery system utilizing a calcofluor white-phosphatidylethanolamine conjugate (CFW-PEc) to enhance the delivery and efficacy of amphotericin B against C. neoformans . We successfully formulated AmB-loaded CFW-PEc-ethosomes, which demonstrated favorable physicochemical properties, including suitable particle size, zeta potential, and high drug entrapment efficiency. In vitro antifungal assessments revealed that CFW-PEc-AmB-ethosomes exhibited superior antifungal activity compared to conventional AmB formulations, maintaining high inhibition rates at lower concentrations, while also demonstrating a favorable safety profile with reduced cytotoxicity. Additionally, in vivo studies in a mouse model of cryptococcal pneumonia illustrated remarkable reductions in fungal burdens and improved histopathological outcomes, attributing these effects to effective targeting of C. neoformans via CFW-PEc. Our findings underscore the potential of CFW-PEc in enhancing the therapeutic efficacy and safety profile of antifungal treatments, paving the way for advanced treatment strategies against cryptococcal pneumonia. IMPORTANCE: Cryptococcal pneumonia presents a significant global health burden with limited therapeutic options due to inherent toxicity and suboptimal bioavailability of conventional antifungal agents. This investigation demonstrates the innovative application of calcofluor white-phosphatidylethanolamine conjugate (CFW-PEc) to enhance amphotericin B (AmB) delivery via ethosomes for cryptococcal infection treatment. Our findings elucidate that CFW-PEc significantly potentiates the antifungal efficacy of AmB-loaded ethosomes against Cryptococcus neoformans while concomitantly mitigating associated cytotoxicity at optimal concentrations. In murine models of pulmonary cryptococcosis, this novel formulation achieved a remarkable 10-fold reduction in fungal burden compared to controls, while preserving pulmonary histoarchitecture and attenuating inflammatory responses. This delivery system’s integrated strategy of increasing antifungal effectiveness while reducing adverse effects marks a significant leap forward in developing safer and more targeted nanomaterial-mediated antifungal treatments. These results have profound implications for developing more efficacious and less toxic treatment modalities for cryptococcal pneumonia and potentially other invasive fungal infections.

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