title: Lysosomal-specific cholesterol reduction by biocleavable polyrotaxanes for ameliorating Niemann-Pick type C disease.
abstract: Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal trafficking disorder, in which the cholesterols are abnormally accumulated in lysosomes. Recently, the β-cyclodextrin (CD) derivatives are revealed to show therapeutic effect for NPC disease through the removal of accumulated cholesterols in lysosomes. Herein, to enhance the therapeutic effect and reduce the toxicity of β-CD derivatives, biocleavable Pluronic/β-CD-based polyrotaxanes (PRXs) bearing terminal disulfide linkages that can release threaded β-CDs in lysosomes were developed. The biocleavable PRXs show negligible interaction with the plasma membrane, leading to avoiding the toxicity of β-CDs derived from their hydrophobic cavity. Additionally, lysosomal release of threaded β-CDs from biocleavable PRXs by the intracellular cleavage of terminal disulfide linkages is found to achieve approximately 100-fold higher cholesterol removal ability from NPC disease-derived cells than β-CD derivatives. Consequently, the biocleavable PRXs is considered to be a noninvasive and effective therapeutics for NPC disease.
authors.affiliation: Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.affiliation: Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Yui
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry*; D004912:Erythrocytes / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011060:Poloxalene / Q000737:chemistry*; D058105:Polymerization; D061251:Primary Cell Culture; D051381:Rats; D043862:Rotaxanes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D047392:beta-Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D043862:Rotaxanes; D047392:beta-Cyclodextrins; C464484:pluronic block copolymer P123; D011060:Poloxalene; D002784:Cholesterol