Synthesis, Characterization, and Evaluation of Pluronic-Based 尾-Cyclodextrin Polyrotaxanes for Mobilization of Accumulated Cholesterol from Niemann-Pick Type C Fibroblasts

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• 作者：Christopher J. Collins ; Leslie A. McCauliff ; Seok-Hee Hyun ; Zhaorui Zhang ; Lake N. Paul ; Aditya Kulkarni ; Klaus Zick ; Mary Wirth ; Judith Storch ; David H. Thompson
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：May 14, 2013
• 年：2013
• 卷：52
• 期：19
• 页码：3242-3253
• 全文大小：617K
• 年卷期：v.52,no.19(May 14, 2013)
• ISSN：1520-4995

文摘

Several lines of evidence suggest that 尾-cyclodextrin (尾-CD) derivatives initiate the efflux of accumulated, unesterified cholesterol from the late endosomal/lysosomal compartment in Niemann Pick C (NPC) disease models. Unfortunately, repeated injections or continuous infusions of current 尾-CD therapies are required to sustain suppression of symptoms and prolong life. In an effort to make CD treatment a more viable option by boosting efficacy and improving pharmacokinetics, a library of Pluronic surfactant-based 尾-CD polyrotaxanes has been developed using biocompatible poly(ethylene glycol) (PEG)鈥損olypropylene glycol (PPG)鈥揚EG triblock copolymers. These compounds carry multiple copies of 尾-CD as shown by ¹H NMR, 2D nuclear Overhouser effect spectroscopy, gel permeation chromatography/multiangle light scattering, analytical ultracentrifugation analysis, matrix assisted laser desorption/ionization mass spectrometry, and diffusion-ordered spectroscopy. Analyses of free 尾-cyclodextrin contamination in the compounds were made by reverse phase high pressure liquid chromatography and hydrophilic interaction liquid chromatography. Dethreading kinetics were studied by reverse phase high pressure liquid chromatography, UV/vis, and ¹H NMR analysis. Filipin staining studies using npc2^{鈥?鈥?/sup>} fibroblasts show significant reversal of cholesterol accumulation after treatment with polyrotaxane compounds. The rate and efficacy of reversal is similar to that achieved by equivalent amounts of monomeric 尾-CD alone.