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

Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease.
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Collins CJ, Loren BP, Alam MS, Mondjinou Y, Skulsky JL, Chaplain CR, Haldar K, Thompson DH,


Collins CJ, Loren BP, Alam MS, Mondjinou Y, Skulsky JL, Chaplain CR, Haldar K, Thompson DH, (click to view)

Collins CJ, Loren BP, Alam MS, Mondjinou Y, Skulsky JL, Chaplain CR, Haldar K, Thompson DH,

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Scientific reports 2017 04 287() 46737 doi 10.1038/srep46737
Abstract

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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