Article ; Online: Structure-function relationships of cholesterol mobilization from the endo-lysosome compartment of NPC1-deficient human cells by β-CD polyrotaxanes.
2022 Volume 17, Issue 12, Page(s) e0268613
Abstract: Niemann-Pick Type C is a rare metabolic disorder characterized by the cellular accumulation of cholesterol within endosomal and lysosomal compartments. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) containing polyrotaxanes represent an attractive approach for ...
| Abstract | Niemann-Pick Type C is a rare metabolic disorder characterized by the cellular accumulation of cholesterol within endosomal and lysosomal compartments. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) containing polyrotaxanes represent an attractive approach for treating this disease due to their ability to circulate in the blood stream for longer periods of time as a prodrug form of HP-β-CD. Once inside the cell, the macromolecular structure is thought to break down into the Pluronic precursor and the active cyclodextrin agent that promotes cholesterol mobilization from the aberrant accumulations within NPC-deficient cells. We now report that both cholesterol and decaarginine (R10) endcapped polyrotaxanes are able to remove cholesterol from NPC1 patient fibroblasts. R10 endcapped materials enter these cells and are localized within endosomes after 16 h. The cholesterol mobilization from endo-lysosomal compartments of NPC1 cells by the polyrotaxanes was directly related to their extent of endcapping and their threading efficiency. Incorporation of 4-sulfobutylether-β-cyclodextrin (SBE-β-CD) significantly improved cholesterol mobilization due to the improved solubility of the compounds. Additionally, in our efforts to scale-up the synthesis for preclinical studies, we prepared a library of polyrotaxanes using a solid phase synthesis method. These compounds also led to significant cholesterol mobilization from the cells, however, cytotoxicity studies showed that they were substantially more toxic than those prepared by the solvent-assisted method, thus limiting the therapeutic utility of agents prepared by this expedited method. Our findings demonstrate that complete endcapping of the polyrotaxanes and improved solubility are important design features for delivering high copy numbers of therapeutic β-CD to promote enhanced sterol clearance in human NPC1-deficient cells. |
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| MeSH term(s) | Humans ; 2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; 2-Hydroxypropyl-beta-cyclodextrin/therapeutic use ; Rotaxanes/chemistry ; Rotaxanes/metabolism ; Rotaxanes/therapeutic use ; Cholesterol/metabolism ; Lysosomes/metabolism ; Structure-Activity Relationship ; Niemann-Pick Disease, Type C/metabolism ; Niemann-Pick C1 Protein |
| Chemical Substances | 2-Hydroxypropyl-beta-cyclodextrin (1I96OHX6EK) ; Rotaxanes ; Cholesterol (97C5T2UQ7J) ; NPC1 protein, human ; Niemann-Pick C1 Protein |
| Language | English |
| Publishing date | 2022-12-30 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural |
| ZDB-ID | 2267670-3 |
| ISSN | 1932-6203 ; 1932-6203 |
| ISSN (online) | 1932-6203 |
| ISSN | 1932-6203 |
| DOI | 10.1371/journal.pone.0268613 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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