Development of nose-to-brain delivery of ketoconazole by nanostructured lipid carriers against cryptococcal meningoencephalitis in mice
Development of nose-to-brain delivery of ketoconazole by nanostructured lipid carriers against cryptococcal meningoencephalitis in mice
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通过纳米结构脂质载体将酮康唑从鼻到脑输送以治疗小鼠隐球菌性脑膜脑炎的研究进展
DOI：
10.1016/j.colsurfb.2019.110446
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发表时间：
2019-11-01
影响因子：
5.8
通讯作者：
Ding, Chen
中科院分区：
文献类型：
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作者：
Du, Wei;Li, Hailong;Ding, Chen
新型隐球菌介导的脑膜脑炎是人类中枢神经系统的一种严重感染性疾病。然而，由于血脑屏障（BBB）穿透性差，对该疾病的有效治疗受到限制。在此，我们利用纳米结构脂质载体（NLCs）开发了一种鼻-脑给药系统。我们证明，负载荧光染料的NLCs能有效被包被的新型隐球菌细胞的细胞质摄取。与现有的抗真菌药物相比，酮康唑（keto）-NLCs在各种生长条件下体内对新型隐球菌显示出显著增强的抗真菌活性。NLCs显示出增强的组织定植特性。重要的是，通过动物成像分析，NLCs经鼻内给药能够通过嗅球区域进入脑组织，绕过血脑屏障。此外，NLCs在组织中保持较长时间的停留。在小鼠脑组织中，经鼻内给药时，酮康唑-NLCs显示出显著增强的抗真菌活性，极大地减轻了新型隐球菌的负担。总之，NLCs不仅提高了酮康唑对包被的新型隐球菌细胞的穿透效率，还提高了抗真菌药物的疗效。最重要的是，酮康唑-NLCs通过嗅觉系统绕过血脑屏障，对小鼠隐球菌性脑膜脑炎的治疗有显著贡献。
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.