Abstract
In this study, we describe a nano-carrier system for propolis that is able to cross an in vitro model of the blood-brain barrier (BBB) and effectively reduce the virulence of Cryptococcus neoformans in animal models. Antimicrobial properties of propolis have been widely studied. However, propolis applications are limited by its low water solubility and poor bioavailability. Therefore, we recently formulated novel poly (n-butyl cyanoacrylate) nanoparticles (PBCA-NP) containing propolis. PBCA-NP are biocompatible, biodegradable and have been shown to effectively cross the BBB using apolipoprotein E (ApoE) as a ligand. Prepared nanoparticles were characterized for particle size, zeta potential, propolis entrapment efficiency and in vitro release. Additionally, the PBCA-NP were functionalized with polysorbate 80, which then specifically adsorbs ApoE. Using an in vitro BBB model of human brain microvascular endothelial cells hCMEC/D3, it was shown that fluorescence labelled ApoE-functionalized PBCA-NP were internalized by the cells and translocated across the cell monolayer. Propolis-loaded PBCA-NP had in vitro, antifungal activity against C. neoformans, which causes meningitis. To utilize the invertebrate model, Galleria mellonella larvae were infected with C. neoformans and treated with propolis-loaded PBCA-NP. The larvae exhibited normal behavior in toxicity testing, and treatment with propolis-loaded PBCA-NP increased survival in the C. neoformans-infected larvae group. In addition, following cryptococcal infection and then 7 days of treatment, the tissue fungal burden of mice treated with propolis-loaded PBCA-NP was significantly lower than control groups. Therefore, our ApoE-functionalized propolis-loaded PBCA-NP can be deemed as a potential targeted nanoparticle in the therapeutic treatment of cerebral cryptococcosis.
Highlights
Cryptococcal meningitis remains a common cause of infectious morbidity and mortality especially among HIV-positive patients living in resource-poor settings, in Southeast Asia and Africa
The obtained nanoparticles were spherical in shape and displayed a monomodal size distribution, which is confirmed by the scanning electron microscope (SEM) observation
Overall survival studies of C. neoformans infection revealed that significantly prolonged (p < 0.001) in propolis-loaded poly (n-butyl cyanoacrylate) nanoparticles (PBCA-NP) treatment than in empty PBCA-NP and untreated G. mellonella larvae groups. These results indicated that C. neoformans infection using an insect model could be cured by administering propolis-loaded PBCA-NP
Summary
Cryptococcal meningitis remains a common cause of infectious morbidity and mortality especially among HIV-positive patients living in resource-poor settings, in Southeast Asia and Africa. A natural brown resinous mixture produced by honeybees, has been shown to exert a variety of biological and pharmacological properties. It has long been used for the prevention and treatment of a variety of diseases due to its antimicrobial, antioxidant, anti-inflammatory, and immune-strengthening properties (Sforcin, 2016; Cornara et al, 2017). Ethanolic extracts of propolis have been found to be effective against a broad range of bacteria, viruses, and fungi. These antimicrobial activities have been related with contained phenolics, flavonoids and derivatives of caffeic acid. Extraction with ethanol is suitable for revealing the mode of propolis against fungal virulence factors, it has some limitations of application because of its scarce solubility in water
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