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

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...

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Main Authors:	Yuki Maeda, Keiichi Motoyama, Rena Nishiyama, Taishi Higashi, Risako Onodera, Hideaki Nakamura, Toru Takeo, Naomi Nakagata, Yusei Yamada, Yoichi Ishitsuka, Yuki Kondo, Tetsumi Irie, Takumi Era, Hidetoshi Arima
Format:	Article
Language:	English
Published:	MDPI AG 2019-05-01
Series:	Nanomaterials
Subjects:	Cyclodextrins cholesterol Niemann-Pick Type C disease hepatomegaly liver targeting
Online Access:	https://www.mdpi.com/2079-4991/9/5/802

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spelling	doaj-d1c3d790057b423abf4b4fc4b7782a542020-11-25T02:07:04ZengMDPI AGNanomaterials2079-49912019-05-019580210.3390/nano9050802nano9050802In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C DiseaseYuki Maeda0Keiichi Motoyama1Rena Nishiyama2Taishi Higashi3Risako Onodera4Hideaki Nakamura5Toru Takeo6Naomi Nakagata7Yusei Yamada8Yoichi Ishitsuka9Yuki Kondo10Tetsumi Irie11Takumi Era12Hidetoshi Arima13Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanSchool of Pharmacy, Kumamoto University, JapanFaculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, JapanCenter for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, JapanCenter for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, JapanGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanDepartment of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, JapanGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanNiemann-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 <i>Npc1</i><sup>−/−</sup> 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.https://www.mdpi.com/2079-4991/9/5/802CyclodextrinscholesterolNiemann-Pick Type C diseasehepatomegalyliver targeting
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Yuki Maeda Keiichi Motoyama Rena Nishiyama Taishi Higashi Risako Onodera Hideaki Nakamura Toru Takeo Naomi Nakagata Yusei Yamada Yoichi Ishitsuka Yuki Kondo Tetsumi Irie Takumi Era Hidetoshi Arima
spellingShingle	Yuki Maeda Keiichi Motoyama Rena Nishiyama Taishi Higashi Risako Onodera Hideaki Nakamura Toru Takeo Naomi Nakagata Yusei Yamada Yoichi Ishitsuka Yuki Kondo Tetsumi Irie Takumi Era Hidetoshi Arima In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease Nanomaterials Cyclodextrins cholesterol Niemann-Pick Type C disease hepatomegaly liver targeting
author_facet	Yuki Maeda Keiichi Motoyama Rena Nishiyama Taishi Higashi Risako Onodera Hideaki Nakamura Toru Takeo Naomi Nakagata Yusei Yamada Yoichi Ishitsuka Yuki Kondo Tetsumi Irie Takumi Era Hidetoshi Arima
author_sort	Yuki Maeda
title	In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease
title_short	In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease
title_full	In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease
title_fullStr	In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease
title_full_unstemmed	In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease
title_sort	in vivo efficacy and safety evaluation of lactosyl-β-cyclodextrin as a therapeutic agent for hepatomegaly in niemann-pick type c disease
publisher	MDPI AG
series	Nanomaterials
issn	2079-4991
publishDate	2019-05-01
description	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 <i>Npc1</i><sup>−/−</sup> 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.
topic	Cyclodextrins cholesterol Niemann-Pick Type C disease hepatomegaly liver targeting
url	https://www.mdpi.com/2079-4991/9/5/802
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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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