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A cyclic heptasaccharide, 2\u2010hydroxypropyl\u2010\u03b2\u2010cyclodextrin (HP\u2010\u03b2\u2010CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2\u2010hydroxypropyl\u2010\u03b3\u2010cyclodextrin (HP\u2010\u03b3\u2010CD), a cyclic octasaccharide with a larger cavity than HP\u2010\u03b2\u2010CD, as a candidate drug to treat NPC. However, the molecular target of HP\u2010\u03b3\u2010CD with respect to NPC and its potential for clinical application are still unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We investigated the mode of interaction between HP\u2010\u03b3\u2010CD and cholesterol by phase\u2010solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP\u2010\u03b3\u2010CD compared with HP\u2010\u03b2\u2010CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>HP\u2010\u03b3\u2010CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP\u2010\u03b2\u2010CD. In vitro, HP\u2010\u03b3\u2010CD and HP\u2010\u03b2\u2010CD amelioration of NPC\u2010related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP\u2010\u03b2\u2010CD shifted to the highly soluble 2:1 complex whereas that of HP\u2010\u03b3\u2010CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP\u2010\u03b3\u2010CD conferred it with significantly reduced toxicity compared with HP\u2010\u03b2\u2010CD, but equal efficacy in treating a mouse model of NPC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>HP\u2010\u03b3\u2010CD can serve as a fine\u2010tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP\u2010\u03b2\u2010CD in terms of ototoxicity and pulmonary toxicity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15464","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T03:05:16Z","timestamp":1617073516000},"page":"2727-2746","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Differential mode of cholesterol inclusion with 2\u2010hydroxypropyl\u2010cyclodextrins increases safety margin in treatment of Niemann\u2010Pick disease type 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