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Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease

Niemann-Pick Type C disease (NPC) is a rare metabolic disorder characterized by disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments available for NPC patients. Recently, the cycloheptaglucoside 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has s...

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Autores principales: Collins, Christopher J., Loren, Bradley P., Alam, Md Suhail, Mondjinou, Yawo, Skulsky, Joseph L., Chaplain, Cheyenne R., Haldar, Kasturi, Thompson, David H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408228/
https://www.ncbi.nlm.nih.gov/pubmed/28452365
http://dx.doi.org/10.1038/srep46737
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author Collins, Christopher J.
Loren, Bradley P.
Alam, Md Suhail
Mondjinou, Yawo
Skulsky, Joseph L.
Chaplain, Cheyenne R.
Haldar, Kasturi
Thompson, David H.
author_facet Collins, Christopher J.
Loren, Bradley P.
Alam, Md Suhail
Mondjinou, Yawo
Skulsky, Joseph L.
Chaplain, Cheyenne R.
Haldar, Kasturi
Thompson, David H.
author_sort Collins, Christopher J.
collection PubMed
description Niemann-Pick Type C disease (NPC) is a rare metabolic disorder characterized by disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments available for NPC patients. Recently, the cycloheptaglucoside 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has shown efficacy as a potential NPC therapeutic by extending lifetime in NPC mice, delaying neurodegeneration, and decreasing visceral and neurological cholesterol burden. Although promising, systemic HP-β-CD treatment is limited by a pharmacokinetic profile characterized by rapid loss through renal filtration. To address these shortcomings, we sought to design a family of HP-β-CD pro-drug delivery vehicles, known as polyrotaxanes (PR), capable of increasing the efficacy of a given injected dose by improving both pharmacokinetic profile and bioavailability of the HP-β-CD agent. PR can effectively diminish the cholesterol pool within the liver, spleen, and kidney at molar concentrations 10-to-100-fold lower than monomeric HP-β-CD. In addition to this proof-of-concept, use of PR scaffolds with differing physiochemical properties reveal structure-activity relationships in which PR characteristics, including hydrophobicity, threading efficiency and surface charge, were found to both decisively and subtly effect therapeutic efficacy. PR scaffolds exhibit absorption, pharmacokinetics, and biodistribution patterns that are significantly altered from monomeric HP-β-CD. In all, PR scaffolds hold great promise as potential treatments for visceral disease in NPC patients.
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spelling pubmed-54082282017-05-02 Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease Collins, Christopher J. Loren, Bradley P. Alam, Md Suhail Mondjinou, Yawo Skulsky, Joseph L. Chaplain, Cheyenne R. Haldar, Kasturi Thompson, David H. Sci Rep Article Niemann-Pick Type C disease (NPC) is a rare metabolic disorder characterized by disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments available for NPC patients. Recently, the cycloheptaglucoside 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has shown efficacy as a potential NPC therapeutic by extending lifetime in NPC mice, delaying neurodegeneration, and decreasing visceral and neurological cholesterol burden. Although promising, systemic HP-β-CD treatment is limited by a pharmacokinetic profile characterized by rapid loss through renal filtration. To address these shortcomings, we sought to design a family of HP-β-CD pro-drug delivery vehicles, known as polyrotaxanes (PR), capable of increasing the efficacy of a given injected dose by improving both pharmacokinetic profile and bioavailability of the HP-β-CD agent. PR can effectively diminish the cholesterol pool within the liver, spleen, and kidney at molar concentrations 10-to-100-fold lower than monomeric HP-β-CD. In addition to this proof-of-concept, use of PR scaffolds with differing physiochemical properties reveal structure-activity relationships in which PR characteristics, including hydrophobicity, threading efficiency and surface charge, were found to both decisively and subtly effect therapeutic efficacy. PR scaffolds exhibit absorption, pharmacokinetics, and biodistribution patterns that are significantly altered from monomeric HP-β-CD. In all, PR scaffolds hold great promise as potential treatments for visceral disease in NPC patients. Nature Publishing Group 2017-04-28 /pmc/articles/PMC5408228/ /pubmed/28452365 http://dx.doi.org/10.1038/srep46737 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Collins, Christopher J.
Loren, Bradley P.
Alam, Md Suhail
Mondjinou, Yawo
Skulsky, Joseph L.
Chaplain, Cheyenne R.
Haldar, Kasturi
Thompson, David H.
Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease
title Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease
title_full Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease
title_fullStr Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease
title_full_unstemmed Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease
title_short Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease
title_sort pluronic based β-cyclodextrin polyrotaxanes for treatment of niemann-pick type c disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408228/
https://www.ncbi.nlm.nih.gov/pubmed/28452365
http://dx.doi.org/10.1038/srep46737
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