Journal
COLLOIDS AND SURFACES B-BIOINTERFACES
Volume 183, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.colsurfb.2019.110446
Keywords
Ketoconazole; Nanostructure lipid carrier; Cryptococcus neoformans; Meningoencephalitis
Funding
- National Natural Science Foundation of China [31300974, 31870140]
- Fundamental Research Funds for the Central Universities of China [N142005001, N172002001]
- Liaoning Revitalization Talents Program [XLYC1807001]
- Shenyang high-level innovative talents program [RC180347]
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Cryptococcus neoformans-mediated meningoencephalitis is a critical infectious disorder of the human central nervous system. However, efficient treatment for the disease is limited due to the poor penetration across the blood brain barrier (BBB). Here, we develop a nose-to-brain drug delivery system utilizing nanostructured lipid carriers (NLCs). We demonstrated that fluorescent-dye-loaded NLCs efficiently uptake into the cytoplasm of encapsulated C. neoformans cells. In comparison with current antifungal drugs, the ketoconazole (keto)-NLCs show significantly increased antifungal activity against C. neoformans in vivo under various growth conditions. The NLCs show enhanced tissue colonization properties. Importantly, using animal imaging analyses, NLCs are able to enter brain tissues via the olfactory bulb region by intranasal administration, bypassing the BBB. In addition, NLCs maintain prolonged residence in tissues. In mouse brain tissue, keto-NLCs showed significantly enhanced antifungal activity when administered intranasally, drastically dampening the C. neoformans burden. Taken together, NLCs not only improve the ketoconazole penetration efficiency against capsulated C. neoformans cells, but also boost the efficacy of antifungal drugs. Most importantly, keto-NLCs significantly contribute to the treatment of cryptococcal meningoencephalitis in mice by bypassing the BBB via the olfactory system.
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