Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution
Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution
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DOI：
10.1021/acsomega.9b02307
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发表时间：
2019-10-15
期刊：
影响因子：
4.1
通讯作者：
Noguchi, Noriko
中科院分区：
文献类型：
--
作者：
Shibuya, Kimiyuki;Morikawa, Shigeru;Noguchi, Noriko
作为一种酰基辅酶A：胆固醇O-酰基转移酶-1（ACAT-1/SOAT-1）抑制剂，K-604是治疗阿尔茨海默病和胶质母细胞瘤的一种有前途的候选药物;然而，它在中性水中的溶解度差，穿过血脑屏障的渗透性低。在本研究中，我们报告了使用羟基羧酸溶液通过鼻内途径将K-604成功递送至小鼠大脑。在脑组织中，鼻内给药（10 μ L; 108 μ g K-604/小鼠）后K-604的AUC为772 ng.min/g，而经口给药（166 μ g K-604/小鼠）后为8.9 ng.min/g。因此，基于剂量转换，脑靶向效率指数为133倍。即使每天一次鼻内给予K-604 7天，小鼠脑中的胆固醇酯水平也从0.70 μ mol/g显著降低至0.04 μ mol/g。因此，这种应用将是大脑中ACAT-1过表达疾病的关键治疗解决方案。
An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer's disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood brain barrier. In this study, we report the successful delivery of K-604 to the brain via the intranasal route in mice using a hydroxycarboxylic acid solution. In cerebral tissue, the AUC of K-604 after intranasal administration (10 mu L; 108 mu g of K-604/mouse) was 772 ng.min/g, whereas that after oral administration (166 mu g of K-604/mouse) was 8.9 ng.min/g. Thus, the index of brain-targeting efficiency was 133-fold based on the dose conversion. Even with intranasal administration of K-604 once per day for 7 days, the level of cholesteryl esters markedly decreased from 0.70 to 0.04 mu mol/g in the mouse brain. Thus, this application will be a crucial therapeutic solution for ACAT-1 overexpressing diseases in the brain.