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Open AccessArticle

In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease

1
Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
2
Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University, Kumamoto 862-0973, Japan
3
Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 862-0973, Japan
4
School of Pharmacy, Kumamoto University, Japan
5
Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan
6
Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan
7
Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Nanomaterials 2019, 9(5), 802; https://doi.org/10.3390/nano9050802
Received: 17 April 2019 / Revised: 23 May 2019 / Accepted: 23 May 2019 / Published: 25 May 2019
(This article belongs to the Special Issue Nanoconstructs Based on Cyclodextrins)
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-β-cyclodextrin (HP-β-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-β-CyD for the treatment of hepatomegaly is to actively deliver β-cyclodextrin (β-CyD) to hepatocytes. Previously, we synthesized lactosyl-β-CyD (Lac-β-CyD) and demonstrated that it lowers cholesterol in NPC model liver cells. In the present study, we studied the efficacy and safety of Lac-β-CyD treatment of hepatomegaly in Npc1−/− mice. After subcutaneous administration, Lac-β-CyD accumulated in the liver and reduced hepatomegaly with greater efficacy than HP-β-CyD. In addition, subcutaneous administration of a very high dose of Lac-β-CyD was less toxic to the lungs than HP-β-CyD. Notably, the accumulation of intracellular free cholesterol in endolysosomes of NPC-like liver cells was significantly lower after administration of Lac-β-CyD than after treatment with HP-β-CyD. In conclusion, these results suggest that Lac-β-CyD is a candidate for the effective treatment of hepatomegaly in NPC. View Full-Text
Keywords: Cyclodextrins; cholesterol; Niemann-Pick Type C disease; hepatomegaly; liver targeting Cyclodextrins; cholesterol; Niemann-Pick Type C disease; hepatomegaly; liver targeting
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Maeda, Y.; Motoyama, K.; Nishiyama, R.; Higashi, T.; Onodera, R.; Nakamura, H.; Takeo, T.; Nakagata, N.; Yamada, Y.; Ishitsuka, Y.; Kondo, Y.; Irie, T.; Era, T.; Arima, H. In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease. Nanomaterials 2019, 9, 802.

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