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The compound 2\u2010hydroxypropyl\u2010\u03b2\u2010cyclodextrin (HP\u03b2CD) has high cholesterol complexation capacity and is currently under clinical investigation for the NPC treatment. However, due to its short blood half\u2010life, high doses are required to produce a therapeutic effect. In this work, stable polymerized HP\u03b2CD is generated to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8\u2013312\u00a0kDa) display a ninefold greater cholesterol complexation capacity than monomeric HP\u03b2CD but are taken up to a lower extent, resulting in an overall comparable in vitro effect. In vivo, the 19.3\u00a0kDa HP\u03b2CD exhibits a longer half\u2010life than the monomeric HP\u03b2CD but it does not increase the life span of <jats:italic>Npc1<\/jats:italic> mice, possibly due to reduced brain penetration. This is circumvented by the application of magnetic resonance imaging\u2010guided low intensity\u2010pulsed focused ultrasound (MRIg\u2010FUS), which increases the brain penetration of the CD. In conclusion, stable polymerized HP\u03b2CDs can elucidate CDs\u2019 mechanism of action while the use of MRIg\u2010FUS warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the NPC treatment.<\/jats:p>","DOI":"10.1002\/smll.202004735","type":"journal-article","created":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T15:24:12Z","timestamp":1603207452000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Investigating the Mechanism of Cyclodextrins in the Treatment of Niemann\u2010Pick Disease Type C Using Crosslinked 2\u2010Hydroxypropyl\u2010\u03b2\u2010cyclodextrin"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1760-5052","authenticated-orcid":false,"given":"Dario","family":"Carradori","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Z\u00fcrich  Z\u00fcrich 8049 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsintsung","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford  Oxford OX1 3QT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beat","family":"Werner","sequence":"additional","affiliation":[{"name":"Center for MR\u2010Research University Children's Hospital  Z\u00fcrich 8032 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aagam S.","family":"Shah","sequence":"additional","affiliation":[{"name":"Institute of Neuroinformatics ETH Z\u00fcrich and University of Z\u00fcrich  Z\u00fcrich 8057 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Leonardi","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Z\u00fcrich  Z\u00fcrich 8049 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattia","family":"Usuelli","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology ETH Z\u00fcrich  Z\u00fcrich 8092 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaele","family":"Mezzenga","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology ETH Z\u00fcrich  Z\u00fcrich 8092 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances","family":"Platt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford  Oxford OX1 3QT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5601-1292","authenticated-orcid":false,"given":"Jean\u2010Christophe","family":"Leroux","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Z\u00fcrich  Z\u00fcrich 8049 Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,10,20]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5323.228"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.06976.x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2016.11.008"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2018.08.001"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2004.08.009"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31735"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-8-166"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498250601094543"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(07)70194-1"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-015-0240-y"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-019-0996-6"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"e20191438","DOI":"10.1542\/peds.2019-1438","volume":"144","author":"Tikkanen A. 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