In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease
In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease
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DOI：
10.3390/nano9050802
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发表时间：
2019-05-01
期刊：
影响因子：
5.3
通讯作者：
Arima, Hidetoshi
中科院分区：
文献类型：
--
作者：
Maeda, Yuki;Motoyama, Keiichi;Arima, Hidetoshi
C型尼曼-匹克病（Niemann-Pick type C disease，NPC）是一种致死性的常染色体隐性遗传疾病，其引起内溶酶体中游离胆固醇的过度积聚，导致进行性肝肿大和神经变性。目前，2-羟丙基-β-环糊精（HP-β-CyD）以高剂量用于治疗NPC，在治疗期间存在肺毒性和听力损失的风险。减少用于治疗肝肿大的HP-β-CyD所需剂量的一种方法是主动递送β-环糊精（β-CyD）至肝细胞。以前，我们合成了乳糖基-β-CyD（Lac-beta-CyD），并证明它可以降低NPC模型肝细胞中的胆固醇。在本研究中，我们研究了Lac-beta-CyD治疗Npc 1（-/-）小鼠肝肿大的有效性和安全性。皮下给药后，Lac-β-CyD在肝脏中蓄积，减轻肝肿大，疗效高于HP-β-CyD。此外，皮下给予非常高剂量的Lac-β-CyD对肺的毒性低于HP-β-CyD。值得注意的是，在施用Lac-β-CyD后，NPC样肝细胞的内溶酶体中细胞内游离胆固醇的积累显著低于用HP-β-CyD处理后。总之，这些结果表明，Lac-β-CyD是一种有效治疗NPC肝肿大的候选药物。
Niemann-Pick type C disease (NPC) is a fatal, autosomal recessive disorder, which causes excessive accumulation of free cholesterol in endolysosomes, resulting in progressive hepatomegaly and neurodegeneration. Currently, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) is used at a high dose for the treatment of NPC, risking lung toxicity and hearing loss during treatment. One method to reduce the required dose of HP-beta-CyD for the treatment of hepatomegaly is to actively deliver beta-cyclodextrin (beta-CyD) to hepatocytes. Previously, we synthesized lactosyl-beta-CyD (Lac-beta-CyD) and demonstrated that it lowers cholesterol in NPC model liver cells. In the present study, we studied the efficacy and safety of Lac-beta-CyD treatment of hepatomegaly in Npc1(-/-) mice. After subcutaneous administration, Lac-beta-CyD accumulated in the liver and reduced hepatomegaly with greater efficacy than HP-beta-CyD. In addition, subcutaneous administration of a very high dose of Lac-beta-CyD was less toxic to the lungs than HP-beta-CyD. Notably, the accumulation of intracellular free cholesterol in endolysosomes of NPC-like liver cells was significantly lower after administration of Lac-beta-CyD than after treatment with HP-beta-CyD. In conclusion, these results suggest that Lac-beta-CyD is a candidate for the effective treatment of hepatomegaly in NPC.