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In Vitro Evaluation of 2-hydroxyalkylated β-cyclodextrins as Potential Therapeutic Agents for Niemann-Pick Type C Disease

In Vitro Evaluation of 2-hydroxyalkylated β-cyclodextrins as Potential Therapeutic Agents for Niemann-Pick Type C Disease

Yuki Kondo, Hiroko Tokumaru, Yoichi Ishitsuka, Tomoko Matsumoto, Makiko Taguchi, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Muneaki Matsuo, Katsumi Higaki, Kousaku Ohno, Tetsumi Irie

Mol Genet Metab. 2016 Jul;118(3):214-9.

PMID: 27184436

Abstract:

This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-β-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥8mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated β-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-β-cyclodextrin (HEBCD) and 2-hydroxybutyl-β-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD≫HPBCD>HEBCD, HBBCD=HPBCD>HEBCD and HBBCD≫HPBCD=HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP128446322	(2-Hydroxyethyl)-β-cyclodextrin		128446-32-2	Price

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